Influence of Safety Warnings on the Prescribing Attitude of JAK Inhibitors for Rheumatoid Arthritis in Italy.

Background/Objectives: The Janus kinase inhibitors (JAKi) tofacitinib (TOFA), baricitinib (BARI), upadacitinib (UPA), and filgotinib (FILGO) are effective drugs for the treatment of rheumatoid arthritis. However, the US Food and Drug Administration (FDA) raised concerns about the safety of TOFA after its approval. This prompted the European Medicines Agency (EMA) to issue two safety warnings for limiting TOFA use, then extended a third warning to all JAKi in patients at high risk of developing serious adverse effects (SAE). These include thrombosis, major adverse cardiac events (MACE), and cancer. The purpose of this work was to analyze how the first two safety warnings from the EMA affected the prescribing of JAKi by rheumatologists in Italy. Methods: All patients with rheumatoid arthritis who had been prescribed JAKi for the first time in a 36-month period from 1 July 2019, to 30 June 2022 were considered. Data were obtained from the medical records of 29 Italian tertiary referral rheumatology centers. Patients were divided into three groups of 4 months each, depending on whether the JAKi prescription had occurred before the EMA's first safety alert (1 July-31 October 2019, Group 1), between the first and second alerts (1 November 2019-29 February 2020, Group 2), or between the second and third alerts (1 March 2021-30 June 2021, Group 3). The percentages and absolute changes in the patients prescribed the individual JAKi were analyzed. Differences among the three groups of patients regarding demographic and clinical characteristics were also assessed. Results: A total of 864 patients were prescribed a JAKi during the entire period considered. Of these, 343 were identified in Group 1, 233 in Group 2, and 288 in Group 3. An absolute reduction of 32% was observed in the number of patients prescribed a JAKi between Group 1 and Group 2 and 16% between Group 1 and Group 3. In contrast, there was a 19% increase in the prescription of a JAKi in patients between Group 2 and Group 3. In the first group, BARI was the most prescribed drug (227 prescriptions, 66.2% of the total), followed by TOFA (115, 33.5%) and UPA (1, 0.3%). In the second group, the most prescribed JAKi was BARI (147, 63.1%), followed by TOFA (65, 27.9%) and UPA (33, 11.5%). In the third group, BARI was still the most prescribed JAKi (104 prescriptions, 36.1%), followed by UPA (89, 30.9%), FILGO (89, 21.5%), and TOFA (33, 11.5%). The number of patients prescribed TOFA decreased significantly between Group 1 and Group 2 and between Group 2 and Group 3 (p ˂ 0.01). The number of patients who were prescribed BARI decreased significantly between Group 1 and Group 2 and between Group 2 and Group 3 (p ˂ 0.01). In contrast, the number of patients prescribed UPA increased between Group 2 and Group 3 (p ˂ 0.01). Conclusions: These data suggest that the warnings issued for TOFA were followed by a reduction in total JAKi prescriptions. However, the more selective JAKi (UPA and FILGO) were perceived by prescribers as favorable in terms of the risk/benefit ratio, and their use gradually increased at the expense of the other molecules.

Forty-Eight-Month Monitoring of Disease Activity in Patients with Long-Standing Rheumatoid Arthritis Treated with TNF-α Inhibitors: Time for Clinical Outcome Prediction and Biosimilar vs Biologic Originator Performance.

BACKGROUND AND OBJECTIVES: Long-term treatment of patients with rheumatoid arthritis with tumor necrosis factor-α inhibitors leads to initial changes in disease activity that can predict a late treatment response. This observational and retrospective study aimed to determine when it is possible to foresee the response to therapy in the case of long-standing rheumatoid arthritis comparing also the efficacy of the original biologics with their biosimilars. METHODS: A total of 1598 patients were recruited and treated with the original biologics, adalimumab and etanercept, or with biosimilars. Patients were monitored over a period of 48 months and disease activity scores (28-Joint Disease Activity Score, Simplified Disease Activity Index, and Clinical Disease Activity Index) were measured every 6 months. RESULTS: No differences in disease activity levels were observed in etanercept versus biosimilars (GP2015/SB4) and adalimumab versus biosimilar (GP2017) patient groups. All scores significantly decreased in all treatments during the first 18 months of therapy, and after 24 months reached a minimum that lasted up to 48 months. CONCLUSIONS: We conclude that biosimilars of adalimumab and etanercept have equivalent effectiveness over a long period of time compared to their originator drugs, and also that the levels of disease activity after 6 months of tumor necrosis factor-α inhibitors (originator drugs and biosimilars) might predict the response to therapy at 4 years in patients with long-standing rheumatoid arthritis.

Long-Term Retention Rate of Tofacitinib in Rheumatoid Arthritis: An Italian Multicenter Retrospective Cohort Study.

Background: Tofacitinib (TOFA) was the first Janus kinase inhibitor (JAKi) to be approved for the treatment of rheumatoid arthritis (RA). However, data on the retention rate of TOFA therapy are still far from definitive. Objective: The goal of this study is to add new real-world data on the TOFA retention rate in a cohort of RA patients followed for a long period of time. Methods: A multicenter retrospective study of RA subjects treated with TOFA as monotherapy or in combination with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) was conducted in 23 Italian tertiary rheumatology centers. The study considered a treatment period of up to 48 months for all included patients. The TOFA retention rate was assessed with the Kaplan-Meier method. Hazard ratios (HRs) for TOFA discontinuation were obtained using Cox regression analysis. Results: We enrolled a total of 213 patients. Data analysis revealed that the TOFA retention rate was 86.5% (95% CI: 81.8-91.5%) at month 12, 78.8% (95% CI: 78.8-85.2%) at month 24, 63.8% (95% CI: 55.1-73.8%) at month 36, and 59.9% (95% CI: 55.1-73.8%) at month 48 after starting treatment. None of the factors analyzed, including the number of previous treatments received, disease activity or duration, presence of rheumatoid factor and/or anti-citrullinated protein antibody, and presence of comorbidities, were predictive of the TOFA retention rate. Safety data were comparable to those reported in the registration studies. Conclusions: TOFA demonstrated a long retention rate in RA in a real-world setting. This result, together with the safety data obtained, underscores that TOFA is a viable alternative for patients who have failed treatment with csDMARD and/or biologic DMARDs (bDMARDs). Further large, long-term observational studies are urgently needed to confirm these results.

Real life use of prostacyclin analog (iloprost), a multi-centric survey data from the Scleroderma study group Emilia Romagna (Sclero-RER) and review of the literature.

BACKGROUND AND AIM: Iloprost is recommend worldwide for the treatment of RP and the healing of DUs. The aim of this study is to report the regimens of Iloprost administered in different rheumatological centers within the same regional Health System Methods: A questionnaire exploring different items related to the use of Iloprost was developed and reviewed by three expert rheumatologists. The questionnaire was distributed as an online survey to all local SSc referral centers in Emilia-Romagna (Italy). Data are reported as percentage or median with interquartile range (IQR), as appropriate. An updated review of world literature on this topic was also carried out. RESULTS: All the invited centers completed the survey. There were both local (8) and university hospitals (4). The majority (58%) had a rheumatologist as head physician. All centers used Iloprost: a single monthly administration was the most common treatment (75%). The cycle lasted 1 [IQR 1-2] days with a 0.5-2.0 ng/Kg/min dose according to the drug tolerance of the patients. There were overall 68 spots (beds, reclining armchair, or simple armchair); 2.0 [1.5-4.0] patients were able to receive Iloprost at the same time. University Hospitals had more physicians at their disposal than local hospitals but less paramedic personnel (respectively: 1.8 vs 1.2 physicians, 1.5 vs 2.1 nurses). CONCLUSIONS: These observations were in line with the majority of previous studies reporting different regimens, comparing similar (but not identical) dose and schedule administration, however, despite differences being at times substantial, no standard infusion method is yet available.

Therapeutic Effects of Apremilast on Enthesitis and Dactylitis in Real Clinical Setting: An Italian Multicenter Study.

INTRODUCTION: Enthesitis and dactylitis are difficult-to-treat features of psoriatic arthritis (PsA), leading to disability and affecting quality of life. OBJECTIVE: The aim of this study is to evaluate enthesitis (using the Leed enthesitis index (LEI)) and dactylitis at 6 and 12 months in patients treated with apremilast. METHODS: Patients affected by PsA from fifteen Italian rheumatological referral centers were screened. The inclusion criteria were: (a) enthesitis or dactylitisphenotype; (b) treatment with apremilast 30 mg bid. Clinical and treatment history, including PsA disease activity, were recorded. Mann-Whitney and chi-squared tests were used to assess the differences between independent groups, and Wilcoxon matched pairs signed-rank test assessed the differences between dependent samples. A p-value of <0.05 was considered statistically significant. RESULTS: The Eph cohort consisted of 118 patients (median LEI 3); the Dph cohort included 96 patients with a median dactylitis of 1 (IQR 1-2). According to an intention to treat analysis, 25% and 34% of patients with enthesitis achieved remission (i.e., LEI = 0) in T1 and T2. The remission of dactylitis was 47% in T1 and 44% in T2. The per protocol analysis (patients observed for at least 12 months) showed that both dactylitis and LEI significantly improved in T1 (median LEI 1 (IQR 1-3)) and T2 (median LEI 0 (IQR 1-2)). CONCLUSION: Eph and Dph PsA patients treated with apremilast experienced a significant improvement in enthesitis and dactylitis activity. After 1 year, enthesitis and dactylitis remission was achieved in more than one-third of patients.

Predictors of DAPSA Response in Psoriatic Arthritis Patients Treated with Apremilast in a Retrospective Observational Multi-Centric Study.

BACKGROUND: To date, only a few real-world-setting studies evaluated apremilast effectiveness in psoriatic arthritis (PsA). The aims of this retrospective observational study are to report long-term Disease Activity Index for Psoriatic Arthritis (DAPSA) response of apremilast in PsA patients and to analyze the predictors of clinical response. METHODS: All PsA consecutive patients treated with apremilast in fifteen Italian rheumatological referral centers were enrolled. Anamnestic data, treatment history, and PsA disease activity (DAPSA) at baseline, 6 months, and 12 months were recorded. The Mann-Whitney test and chi-squared tests assessed the differences between independent groups, whereas the Wilcoxon matched pairs signed-rank test assessed the differences between dependent samples. Logistic regressions verified if there were factors associated with achievement of DAPSA low disease activity or remission at 6 and 12 months. RESULTS: DAPSA low disease activity or remission rates at 6 and 12 months were observed, respectively, in 42.7% (n = 125) and 54.9% (n = 161) patients. Baseline DAPSA was inversely associated with the odds of achieving low disease activity or remission at 6 months (odds ratio (OR) 0.841, 95% confidence interval (CI) 0.804-0.879; p < 0.01) and at 12 months (OR 0.911, 95% CI 0.883-0.939; p < 0.01). CONCLUSIONS: Almost half of the PsA patients receiving apremilast achieved DAPSA low disease activity or remission at 6 and 12 months. The only factor associated with achievement of low disease activity or remission at both 6 and 12 months was baseline DAPSA.

Apremilast retention rate in clinical practice: observations from an Italian multi-center study.

OBJECTIVE: There are few real-world setting studies focused on apremilast effectiveness (i.e., retention rate) in psoriatic arthritis (PsA). The main aim of this retrospective observational study is the assessment of apremilast 3-year retention rate in real-world PsA patients. Moreover, the secondary objective is to report the reasons of apremilast discontinuation and the factors related to treatment persistence. METHODS: In fifteen Italian rheumatological referral centers, all PsA consecutive patients who received apremilast were enrolled. Anamnestic data, treatment history, and PsA disease activity (DAPSA) at baseline were recorded. The Kaplan-Meier curve and the Cox analysis computed the apremilast retention rate and treatment persistence-related risk factors. A p-value < 0.05 was considered statistically significant. RESULTS: The 356 enrolled patients (median age 60 [interquartile range IQR 52-67] yrs; male prevalence 42.7%) median observation period was 17 [IQR 7-34] months (7218 patients-months). The apremilast retention rate at 12, 24, and 36 months was, respectively, 85.6%, 73.6%, and 61.8%. The main discontinuation reasons were secondary inefficacy (34% of interruptions), gastro-intestinal intolerance (24%), and primary inefficacy (19%). Age and oligo-articular phenotype were related to treatment persistence (respectively hazard ratio 0.98 IQR 0.96-0.99; p = 0.048 and 0.54 IQR 0.31-0.95; p = 0.03). CONCLUSION: Almost three-fifths of PsA patients receiving apremilast were still in treatment after 3 years. This study confirmed its effectiveness and safety profile. Apremilast appears as a good treatment choice in all oligo-articular PsA patients and in those ones burdened by relevant comorbidities. Key Points • Apremilast retention rates in this real-life cohort and trials are comparable. • The oligo-articular phenotype is associated with long-lasting treatment (i.e., 3 years). • No different or more prevalent adverse events were observed.

Clinical and radiological characteristics of SAPHO syndrome.

The peculiar bone involvement, represented by osteitis, is the common denominator of SAPHO syndrome. Hyperostosis and osteitis are chronic inflammatory reactions involving the cortical and trabecular bone respectively; both are characterised by increased sclerosis. Hyperostosis appears radiologically as chronic endosteal and periosteal thickening with narrowing of the medullary canal, but areas of ostelysis may also be present. Conversely, osteitis appears as increased osteosclerosis involving the trabecular infrastructure of cancellous bone. The occurrence of hyperostosis with little or no osteitis is not uncommon. SAPHO syndrome may have a prolonged course with phases of reacutization and remission; the long-term prognosis is usually fairly good, but sometimes a disabling course may occur. Our experience demonstrated that the majority of patients suffering from SAPHO syndrome experienced a chronic course, requiring continous treatment, whilst in a third of the cases the patients reported multiple remission and exacerbations of the disease with flares lasting till to 8 months. Only in a minority of cases the bone inflammation faded and never recurred. Female sex, peripheral arthritis, ACW involvement, the coexistence of more than one cutaneous symptoms, and high inflammatory indices are correlated with a chronic disease course and involvement of new osteoarticular sites.

Multicentric reticulohistiocytosis and fibroblastic rheumatism.

Multicentric reticulohistiocytosis (MRH) and fibroblastic rheumatism (FR) are uncommon disorders with similar joint and skin manifestations. They are usually included among the non-Langerhans histiocytoses, but recent insights drive some criticism. The diagnosis is often challenging and must be confirmed by the histological typical features. If the skin manifestations are missing, the arthritic complaints may be confused with those of other rheumatic disorders. In these cases, only a careful clinical and radiological evaluation leads to the correct diagnosis. The natural course of the diseases may rapidly develop into disabling manifestations, making an aggressive treatment strongly recommendable. There is emerging evidence that anti-tumour necrosis factor-α agents and bisphosphonates are promising drugs for MRH, while a course of methotrexate and steroids seems to be the best option for FR. Finally, the clinician should be aware that in many cases MRH, but not FR, is associated with a large number of systemic manifestations and with malignancy. This eventuality must be accurately ruled out.

The evolution of adult-onset Still disease: an observational and comparative study in a cohort of 76 Italian patients.

OBJECTIVES: Adult-onset Still's disease (AOSD) is a potentially crippling or life-threatening rare disease that may be self-limited, intermittent, and chronic. Clinical predictors of outcome are still lacking, as is information on the rate of progress of its chronic course. The main objective is to identify factors that improve our ability to predict the course of AOSD, and factors associated with the rate of progress of its chronic course. A comparison with the literature is included. METHODS: A retrospective cohort observational study conducted at the tertiary-referral Rheumatology Unit in Ferrara, Italy. RESULTS: Seventy-six patients (44 females and 32 males) referred to the Unit and who satisfied the criteria for AOSD were identified. Our findings on white AOSD patients are largely compatible with those previously published. Ferritin level, as well disease activity score (DAS(28)), is associated with the rate of progression of the articular manifestations of the disease. A polyarthritis persisting over 6 months is associated with the development of a chronic articular course, irrespective of the size of the involved joints. CONCLUSIONS: Ferritin, being associated with the course of AOSD, could play a role in the diagnosis of the disease. Together with DAS(28), it might also serve as a useful predictor for the rate of progress of the chronic course of the disease, as measured with simple erosion narrowing score.