Randomized controlled trials and real-world data: differences and similarities to untangle literature data.

Randomized controlled trials (RCTs) represent the gold-standard of medical evidence to assess the efficacy and safety of therapeutic interventions. However, the need to minimize bias and ensure the correct design to explore the study aims often affects the generalizability of results. As a consequence, the evidence derived from the most rigorous research strategy available is not always representative of the real-world settings for which this evidence is ultimately intended. Observational studies, in contrast, although affected by a number of potential confounders, can more effectively capture treatment characteristics and safety issues that had not been identified by previous RCTs, owing to the short duration of follow-up or highly selective inclusion criteria. The aim of this review is to provide a comparative summary of the main advantages and pitfalls of RCTs and real-world data, emphasizing the need for a constant integration of all available levels of evidence to provide the best care for patients.

Two-year retention rate of golimumab in rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis: data from the LORHEN registry.

OBJECTIVES: We aimed to provide data on golimumab real-life use in rheumatoid arthritis (RA), psoriatic arthritis (PsA) and ankylosing spondylitis (AS) from a multicentre observational registry of Northern Italy. METHODS: We extracted data of patients who started treatment with golimumab from October 2010, and who had at least one follow-up visit. Data were analysed until a maximum follow-up of 24 months. The two-year retention rate in the three diseases was assessed with Kaplan-Meier estimators. To compare crude survival between diagnoses and lines of treatment we used the log-rank test, while Cox proportional hazard models were used to adjust for confounders. RESULTS: Overall, 410 subjects were included: 180 patients with RA, 110 with PsA and 120 with AS. The two-year retention rate of patients with RA was 47.3%, 48% for PsA, and 62.8% for AS. Crude survival on treatment of patients with AS was significantly higher than that of RA patients (p=0.032), while no significant difference was found between AS and PsA and between RA and PsA. In patients with RA, subjects treated with concomitant sDMARDs showed a lower discontinuation rate than those receiving golimumab alone. The comparison between first and second line of treatment groups did not show any significant difference in mean survival time in patients with RA, PsA and AS. CONCLUSIONS: This is the first report of real-life data on two-year survival on treatment with golimumab in RA, PsA and AS. Golimumab showed a similar retention rate when given as first or second line of treatment.

Atherosclerosis and rheumatoid arthritis: more than a simple association.

In the last decades a large amount of evidence linked rheumatoid arthritis (RA) to atherosclerosis. In fact, RA patients have an increased risk of cardiovascular events that is not fully explained by other classic cardiovascular risk factors. RA and atherosclerosis may share several common pathomechanisms and inflammation undoubtedly plays a primary role. The proinflammatory cytokines such as tumor necrosis factor alpha and interleukin-6, involved in the pathogenesis of RA, are also independently predictive of subsequent cardiovascular disease (CVD). In RA, inflammation alters HDL constituents and the concentration of LDL and HDL, thus facilitating atherosclerosis and CVD events. On the other hand, also the increase of oxidative processes, frequently observed in RA, induces atherosclerosis. Interestingly, some genetic polymorphisms associated with RA occurrence enhance atherosclerosis, however, other polymorphisms associated with RA susceptibility do not increase CVD risk. Several other mechanisms may influence atherosclerotic processes in RA. Moreover, atherosclerosis may be directly mediated also by underlying autoimmune processes, and indirectly by the occurrence of metabolic syndrome and impaired physical activity. Finally, the effects of RA therapies on cardiovascular system in general and on atherosclerosis in particular are really wide and different. However, the starting point of every RA treatment is that disease control, or better remission, is the best way we have for the reduction of CVD occurrence.

[Access to medicines for rare diseases: regulatory aspects and public health priorities.] / L'accesso ai farmaci per malattie rare tra aspetti regolatori e priorità di salute pubblica.

INTRODUCTION: In the last decades, the development of drugs for rare diseases has been supported by regulatory and financial incentives. On the other hand, public health policies have increasingly taken into account the person affected by a rare disease in their strategies. In this perspective, we examined the relation between the regulatory framework on rare diseases and the regulatory framework on drug approval. Technical proposals have been brought forward to protect the needs of individuals. RESULTS: The legislative framework on rare diseases has developed both at a European and national level with the aim to strengthen the network of centers for diagnosis and care by increasing the degree of social and health protection, as well as to accelerate the assessment, approval and access to new drugs. Since 2000, 210 orphan drugs have been approved by the European Medicines Agency (EMA) (compared to an estimated 7-8,000 rare diseases). Of the 118 orphan drugs active in the community register as of 2020, 97 (82.2%) were available in Italy: 17 (17.5%) in class A; 58 (59.8%) in class H; 12 (12.4%) in class C; 10 (10.3%) in class C-nn. In 2020, expenditure on drugs with an orphan indication accounted for 6% of the total pharmaceutical expenditure (+47% since 2016). These drugs have benefited from incentives at both European and national levels, as well as inclusion in national early access programs. However, the average duration of the assessment process is above the 100-day limit set by law. DISCUSSION: The legislation on rare diseases has developed in different directions, and drug legislation has undoubtedly played a major role in terms of the results achieved. However, orphan drugs enter the market with a high price, which increasingly represents a problem of sustainability for health systems but notwithstanding Italy shows a high ratio between the level of social protection and access times. In this perspective, it is necessary to be provided with tools for a better system balance with a view to optimize these timeframes. Introducing in Italy a system for tracking the negotiation process that considers the clock stops as the EMA does, would allow to know at what point the negotiation process is. In addition, once the 100-day period is over (net of any clock stops) and in case of failure to reach a negotiation agreement, a second 60-day negotiation round could be proposed and so on. In this way, all the parts involved the system would have a clear scope of action to conclude the process in a flexible but certain timeframe. In this regard, the joint clinical assessments foreseen by the new HTA Regulations provide an additional opportunity to harmonize central decisions with national requirements.

Two-year persistence of golimumab as second-line biologic agent in rheumatoid arthritis as compared to other subcutaneous tumor necrosis factor inhibitors: real-life data from the LORHEN registry.

OBJECTIVES: To evaluate the 2-year retention rate of golimumab compared with etanercept and adalimumab as second-line biologic agent in rheumatoid arthritis (RA) patients who failed a previous tumor necrosis factor inhibitor (TNFi). METHODS: Data on RA patients treated with a second-line subcutaneous TNFi were extracted from a multicentric Italian cohort (the LORHEN registry). The analysis was limited to etanercept, adalimumab and golimumab in the period when all were available in Italy (since October 2010). The 2-year retention rate was calculated by Kaplan-Meier method and the comparative risk for discontinuation among individual TNFi was compared by a stratified log-rank test. RESULTS: One hundred and ninety-five RA patients treated with etanercept (n = 76), adalimumab (n = 68) or golimumab (n = 51) were included in the analysis. The 2-year retention rate (40% with a median time-on-drug of 12.9 months in the whole population) was significantly lower for adalimumab (31.2%, P = 0.018) and numerically lower for etanercept (39.8%, P = 0.068) compared with golimumab (53.4%) because of a higher discontinuation rate due to adverse events (P = 0.042 and P = 0.038 versus golimumab, respectively). Drug survival was greater in concomitant synthetic disease modifying anti-rheumatic drug (sDMARD) users (44.2%) compared with TNFi monotherapy (22.5%, P = 0.036). No difference was found in survival analysis according to first-line TNFi reason for discontinuation and pattern of TNFi switch (antibody-receptor, antibody-antibody or receptor-antibody). CONCLUSIONS: Our real-life data confirmed switching to a second TNFi as a good option for treating first-line TNFi failures in RA, especially in combination with sDMARDs. Second-line golimumab showed an overall better 2-year drug survival compared with adalimumab and etanercept.

Risk of hepatitis B virus reactivation in rheumatoid arthritis patients undergoing biologic treatment: Extending perspective from old to newer drugs.

Hepatitis B virus (HBV) reactivation in rheumatoid arthritis (RA) patients undergoing biological therapy is not infrequent. This condition can occur in patients with chronic hepatitis B as well as in patients with resolved HBV infection. Current recommendations are mainly focused on prevention and management strategies of viral reactivation under tumor necrosis factor-α inhibitors or chimeric monoclonal antibody rituximab. In recent years, growing data concerning HBV reactivation in RA patients treated with newer biological drugs like tocilizumab and abatacept have cumulated. In this review, epidemiology, pathogenesis and natural history of HBV infection have been revised first, mainly focusing on the role that specific therapeutic targets of current biotechnological drugs play in HBV pathobiology; finally we have summarized current evidences from scientific literature, including either observational studies and case reports as well, concerning HBV reactivation under different classes of biological drugs in RA patients. Taking all these evidences into account, some practical guidelines for screening, vaccination, prophylaxis and treatment of HBV reactivation have been proposed.

The multifaceted aspects of interstitial lung disease in rheumatoid arthritis.

Interstitial lung disease (ILD) is a relevant extra-articular manifestation of rheumatoid arthritis (RA) that may occur either in early stages or as a complication of long-standing disease. RA related ILD (RA-ILD) significantly influences the quoad vitam prognosis of these patients. Several histopathological patterns of RA-ILD have been described: usual interstitial pneumonia (UIP) is the most frequent one, followed by nonspecific interstitial pneumonia (NSIP); other patterns are less commonly observed. Several factors have been associated with an increased risk of developing RA-ILD. The genetic background plays a fundamental but not sufficient role; smoking is an independent predictor of ILD, and a correlation with the presence of rheumatoid factor and anti-cyclic citrullinated peptide antibodies has also been reported. Moreover, both exnovo occurrence and progression of ILD have been related to drug therapies that are commonly prescribed in RA, such as methotrexate, leflunomide, anti-TNF alpha agents, and rituximab. A greater understanding of the disease process is necessary in order to improve the therapeutic approach to ILD and RA itself and to reduce the burden of this severe extra-articular manifestation.