Effectiveness and safety of filgotinib in rheumatoid arthritis patients: data from the GISEA registry.

OBJECTIVES: The aim of this study was to evaluate the effectiveness and safety profile of filgotinib, a JAK1 preferential inhibitor, in rheumatoid arthritis (RA) patients included in Italian GISEA (Group for the Study of Early Arthritis) registry. METHODS: Data from RA patients treated with filgotinib, recorded in the GISEA registry, were analysed. Disease activity scores and patient-reported outcomes (PROs) were assessed at baseline, as well as during 12-month follow-up. A difficult-to-treat (D2T) RA patient was defined according with EULAR criteria. Retention rate of filgotinib was estimated by the Kaplan-Meier method and factors influencing drug discontinuation were estimated by Cox regression models. RESULTS: 246 RA patients (female 89%, 57.6±12.2 years old) started filgotinib, mostly as second (22%) or further (43.9%) b/tsDMARDs line of treatment. At 3 and 12 months, 18.8% and 27.5% of patients achieved Clinical Diseases Activity Index based remission and 30.1% and 37.7% obtained a visual analogue scale of pain ≤20 (all p<0.01 vs. baseline). Filgotinib survival rate was 84.5% at the 6-month and 75.8% at 12-month follow-up, and was comparable either in monotherapy or combination therapy, and irrespective of glucocorticoid intake. b/tsDMARD naive patients had the lowest hazard ratio (HR) of filgotinib discontinuation (HR 0.29, 95%CI 0.14-0.64), while D2T-RA the highest (HR 1.82, 95%CI 1.01-3.3). Eight patients (3.3%) discontinued filgotinib due to adverse events. CONCLUSIONS: In an Italian real-life setting, filgotinib is confirmed to be safe and with a good effectiveness profile both in monotherapy and without glucocorticoids.

Efficacy of COVID-19 mRNA vaccination in patients with autoimmune disorders: humoral and cellular immune response.

BACKGROUND: The impact of immunosuppressive therapies on the efficacy of vaccines to SARS-CoV-2 is not completely clarified. We analyzed humoral and T cell-mediated response after COVID-19 mRNA vaccine in immunosuppressed patients and patients with common variable immunodeficiency disease (CVID). PATIENTS: We enrolled 38 patients and 11 healthy sex- and age-matched controls (HC). Four patients were affected by CVID and 34 by chronic rheumatic diseases (RDs). All patients with RDs were treated by corticosteroid therapy and/or immunosuppressive treatment and/or biological drugs: 14 patients were treated with abatacept, 10 with rituximab, and 10 with tocilizumab. METHODS: Total antibody titer to SARS-CoV-2 spike protein was assessed by electrochemiluminescence immunoassay, CD4 and CD4-CD8 T cell-mediated immune response was analyzed by interferon-γ (IFN-γ) release assay, the production of IFN-γ-inducible (CXCL9 and CXCL10) and innate-immunity chemokines (MCP-1, CXCL8, and CCL5) by cytometric bead array after stimulation with different spike peptides. The expression of CD40L, CD137, IL-2, IFN-γ, and IL-17 on CD4 and CD8 T cells, evaluating their activation status, after SARS-CoV-2 spike peptides stimulation, was analyzed by intracellular flow cytometry staining. Cluster analysis identified cluster 1, namely the "high immunosuppression" cluster, and cluster 2, namely the "low immunosuppression" cluster. RESULTS: After the second dose of vaccine, only abatacept-treated patients, compared to HC, showed a reduced anti-spike antibody response (mean: 432 IU/ml ± 562 vs mean: 1479 IU/ml ± 1051: p = 0.0034), and an impaired T cell response, compared with HC. In particular, we found a significantly reduced release of IFN-γ from CD4 and CD4-CD8 stimulated T cells, compared with HC (p = 0.0016 and p = 0.0078, respectively), reduced production of CXCL10 and CXCL9 from stimulated CD4 (p = 0.0048 and p = 0.001) and CD4-CD8 T cells (p = 0.0079 and p = 0.0006). Multivariable General Linear Model analysis confirmed a relationship between abatacept exposure and impaired production of CXCL9, CXCL10, and IFN-γ from stimulated T cells. Cluster analysis confirms that cluster 1 (including abatacept and half of rituximab treated cases) showed a reduced IFN-γ response, as well as reduced monocyte-derived chemokines All groups of patients demonstrated the ability to generate specific CD4 T activated cells after spike proteins stimulation. After the third dose of vaccine, abatacept-treated patients acquired the ability to produce a strong antibody response, showing an anti-S titer significantly higher compared to that obtained after the second dose (p = 0.0047), and comparable with the anti-S titer of the other groups. CONCLUSIONS: Patients treated with abatacept showed an impaired humoral immune response to two doses of COVID-19 vaccine. The third vaccine dose has been demonstrated to be useful to induce a more robust antibody response to balance an impaired T cell-mediated one. All patients, exposed to different immunosuppressive drugs, were able to produce specific CD4-activated T cells, after spike proteins stimulation. TRIAL REGISTRATION: Local Ethical Committee NP4187.

CXCL-13 serum levels in patients with rheumatoid arthritis treated with abatacept.

OBJECTIVES: C-X-C motif chemokine 13 (CXCL-13), which is expressed by synovial follicular dendritic cells and activated mature antigen-experienced T-helper cells, has been described as a surrogate marker of lymphoid phenotype of synovitis in rheumatoid arthritis (RA). A preferential response to anti-interleukin-6 receptor (IL-6R) as compared to anti-tumour necrosis factor alpha (TNFα) monotherapy has been described in patients with increased levels of CXCL-13. We hypothesised that serum levels of CXCL-13 could be used as a biomarker of response to treatment with abatacept (ABA), a T-cell co-stimulation blocker. METHODS: Serum levels of CXCL-13 and of soluble intracellular adhesion molecule 1 (sICAM-1) (a putative marker of the myeloid subtype of synovitis) were measured by indirect solid-phase enzyme immunoassays, before (T0) and after 6 months of therapy with ABA (T6) in 63 patients with RA. Circulating T follicular helper cells and B cell subpopulations were identified by flow-cytometry. RESULTS: At T0, CXCL-13 serum levels were higher in RA patients than in healthy controls (p=0.0001) and correlated with disease activity, while no difference between the two groups was observed as far as sICAM-1 levels. Serum levels of CXCL-13 levels decreased after therapy with ABA both in patients who achieved a clinical response (p<0.01) and in non-responders (p=0.01), whereas sICAM-1 levels did not significantly change. When comparing RA patients who responded to ABA with non-responders no significant difference of baseline serum levels of CXCL-13 was observed. CONCLUSIONS: CXCL-13 serum levels are raised in RA patients and decrease after therapy with ABA. We were not able to demonstrate that serum CXCL-13 levels predict the clinical response to ABA in RA patients.

Prevalence of COVID infections in a population of rheumatic patients from Lombardy and Marche treated with biological drugs or small molecules: A multicentre retrospective study.

OBJECTIVE: The COVID-19 pandemic has raised questions about the management of systemic immunosuppressive treatments for rheumatic conditions. It is well known that rheumatic patients are at risk of developing infections because of their immunocompromised state. Moreover, drugs such as hydroxychloroquine or tocilizumab that are widely used to treat rheumatic diseases are now being used to treat COVID-19. The aim of this multicentre retrospective study of rheumatic patients in the Italian regions of Lombardy and Marche was to determine whether patients receiving biological or small molecules treatment are more susceptible to the development of COVID-19 than the general population. METHODS: The local registry data of 10,260 rheumatic patients being treated with bDMARDs or small molecules were evaluated from 15 March to 23 April 2020. The final analysis was based on the registry data relating to 7.204, telephone contacts and/or outpatient visits. RESULTS: Forty-seven of the 7.204 patients were diagnosed with COVID-19, seven of whom died; the patients who had symptoms resembling those of COVID-19 but had negative swabs were considered negative for the disease. The overall infection rate was 0.65, and the crude case fatality risk (CFR) in the patients with COVID-19 was 14.9%. There was no difference in the mortality rate among the patients receiving the different individual biological drugs or small molecules. CONCLUSIONS: Our findings suggest that the susceptibility of rheumatic patients to COVID-19 is the same as that of the general population, but confirm that age, disease duration, and the number of co-morbidities are associated with an increased risk of a severe form of the disease. It seems that immunosuppressants drugs do not effectively represent a risk factor for COVID- 19.

Anti-carbamylated protein antibodies as a clinical response predictor in rheumatoid arthritis patients treated with abatacept.

OBJECTIVES: Carbamylation is an irreversible post-translational modification of proteins. The presence of anti-carbamylated protein antibodies (anti-CarP) has been observed in rheumatoid arthritis (RA). This study was focused to verify whether anti-CarP antibodies can be used as a predictive factor of clinical response to abatacept (CTLA4-Ig) in RA patients. METHODS: Sixty RA patients treated with abatacept were enrolled. A home-made ELISA for anti-CarP and a commercial anti-CCP3.1 kit for anti-citrullinated proteins antibodies (anti-CCP) were applied to determine serum levels every six months of therapy. Rheumatoid factor (RF) was also tested. RESULTS: Anti-CarP positive patients (n=18) were younger (p=0.01) and with a longer disease duration (p=0.05) when compared to anti-CarP negative patients (n=42) at baseline. Considering the entire cohort, a significant reduction of anti-CarP titre after twelve-months of treatment was shown (p<0.01). A significant reduction of Disease Activity Score (DAS) 28-C-reactive protein (CRP) in the first six months of therapy was found in the subgroup of anti-CarP positive patients in comparison with the negative ones (p=0.003). No significant results were found by dividing the cohort using the positivity to anti-CCP and/or RF. CONCLUSIONS: Earlier onset and a longer disease duration in anti-CarP positive patients might suggest they are specific risk factors for RA in this subgroup of patients. The correlation between the anti-CarP positivity at baseline and the reduction of disease activity during the first six months of treatment with abatacept allowed us to hypothesise that anti-CarP antibodies, but not anti-CCP and/or RF, could be used as a good clinical response predictor.

Efficacy and safety of baricitinib in 446 patients with rheumatoid arthritis: a real-life multicentre study.

OBJECTIVES: Baricitinib, an oral Janus kinase (JAK) 1-2 inhibitor, is currently used along biologic DMARDs (bDMARDs) after the failure of methotrexate (MTX) in rheumatoid arthritis (RA). We investigated the efficacy and safety of baricitinib in real life. METHODS: We prospectively enrolled 446 RA patients treated with baricitinib from 11 Italian centres. Patients were evaluated at baseline and after 3, 6, and 12 months. They were arrayed based on previous treatments as bDMARD-naïve and bDMARD-insufficient responders (IR) after the failure or intolerance to bDMARDs. A sub-analysis differentiated the effects of methotrexate (MTX) and the use of oral glucocorticoids (OGC). RESULTS: Our cohort included 150 (34%) bDMARD-naïve and 296 (66%) bDMARD-IR patients, with 217 (49%) using baricitinib as monotherapy. Considering DAS-28-CRP as the primary outcome, at 3 and 6 months, 114/314 (36%) and 149/289 (51.6%) patients achieved remission, while those in low disease activity (LDA) were 62/314 (20%) and 46/289 (15.9%), respectively; finally at 12 months 81/126 (64%) were in remission and 21/126 (17%) in LDA. At all-timepoints up to 12 months, bDMARDs-naïve patients demonstrated a better clinical response, independently of MTX. A significant reduction in the OGC dose was observed at 3 and 12 months in all groups. The serum positivity for both rheumatoid factors (RF) and anti-citrullinated protein antibodies (ACPA) conferred a lower risk of stopping baricitinib due to inefficacy. Fifty-eight (13%) patients discontinued baricitinib due to adverse events, including thrombotic events and herpes zoster reactivation. CONCLUSIONS: Real-life data confirm the efficacy and safety profiles of baricitinib in patients with RA and provide evidence that drug survival is higher in bDMARDs-naïve and seropositive 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.

Comparison of efficacy of first- versus second-line adalimumab in patients with rheumatoid arthritis: experience of the Italian biologics registries.

OBJECTIVES: Targeted drugs against key pathogenetic molecules such as TNF-alpha have significantly improved outcomes in rheumatoid arthritis (RA). They are widely used in clinical practice and drug registries give us information to support their use. Adalimumab (ADA) is able to induce a comprehensive disease control in RA by achieving clinical, functional and radiographic control. METHODS: By interrogating 2 Italian registries, LORHEN and GISEA, we analysed the efficacy of ADA in first- or second-line in a total of 2262 RA patients. RESULTS: Patients in 1st line were significantly older, with lower disease activity and HAQ scores compared to 2nd line. In 1st line, rates of DAS28-remission (DAS28rem) at 2 years were 34.4% while 26.5% in 2nd line (p=0.038). A normal HAQ score (HAQ≤0.5) was achieved in 53.5% after 2 years in 1st line versus 30.1% in 2nd (p<0.0001). DAS28rem+HAQ≤0.5, a combined parameter that we defined global clinical disease control, was reached in 20.7% in 1st line versus 13.3% in 2nd (p<0.01). Five-year-survival on therapy was higher for patients in 1st line (45.6% vs. 33.2%, p<0.0001). Discontinuation due to lack of efficacy was lower in 1st line (37.4 vs. 54.4%, p<0.0001). Rates of adverse events were similar. CONCLUSIONS: Responses in 1st line are generally significantly better than after a first anti-TNF-alpha failure but patients in 2nd line have a worse clinical and functional profile. A global disease control with clinical and functional remission is an achievable target in both lines.

Prospectively-followed pregnancies in patients with inflammatory arthritis taking biological drugs: an Italian multicentre study.

OBJECTIVES: Information on new drugs does not include their possible effects on pregnancy because pregnant women are excluded from clinical trials. Although not classified as teratogenic in animals, limited data is available on biological anti-rheumatic agents and their safety in human pregnancy. The aim of the study is to evaluate the safety of biological drugs in pregnant patients with chronic arthritis. METHODS: Pregnancy outcome and maternal disease variations were prospectively followed in six Italian Rheumatology Centres. Patients exposed to biological agents during the periconceptional period or during pregnancy were included in the study. The occurrence of congenital malformations as well as the obstetric and neonatal outcomes were assessed. RESULTS: Between 1999 and 2013 we identified 79 exposed pregnancies in 67 women affected by different rheumatic diseases with peripheral chronic arthritis. At the time of the start of pregnancy, 56 patients were taking etanercept, 13 adalimumab, 3 infliximab, 2 each certolizumab-pegol and rituximab, 1 each golimumab, anakinra and abatacept. Biological treatment was stopped after a mean of 41 days since documented pregnancy. Live births were reported in 66% of pregnancies. The rate of spontaneous pregnancy loss was 20%. Only one congenital malformation was reported. CONCLUSIONS: TNF-alpha inhibitors can be considered safe in the periconception period, representing a possible therapeutic choice also in young women affected by an aggressive form of chronic arthritis and hoping for a pregnancy. Reports of exposure during 2nd/3rd trimester are still limited and suggest caution. Experience with abatacept, tocilizumab, anakinra and rituximab in pregnancy is insufficient.

Retention rate of biologic and targeted synthetic anti-rheumatic drugs in elderly rheumatoid arthritis patients: data from GISEA registry.

Objectives: An increased number of elderly individuals affected by rheumatoid arthritis (RA) has been reported, including both patients with RA onset in advanced age and patients aged with the disease. In this registry-based study, we aimed to analyze the retention rate and cause of discontinuation of biologic (b) and targeted synthetic (ts)-disease-modifying anti-rheumatic drugs (DMARDs) in RA patients over 65 year old. Methods: RA patients enrolled in the Italian GISEA registry and starting a b- or a ts-DMARD over 65 years of age were included. Demographic, clinical, serologic, and therapeutic features were collected. Results: A total of 1,221 elderly RA patients were analyzed (mean age 71.6 ± 5.2 years). RA was diagnosed before 65 years in 72.5% of cases, a 60.6% of patients experienced a previous b- or ts-DMARD. In patients older than 65 initiating a new b- or ts-DMARDS, tumor necrosis factor alpha inhibitors (TNFi) were prescribed in 29.6% of patients, abatacept in 24.8%, anti-interleukin 6 receptor antagonists (anti-IL6R) in 16.3%, Janus kinases inhibitors (JAKi) in 24.9%, and rituximab in 4.4%. The main causes of discontinuation were primary or secondary inadequate responses (66.1%). The median retention rate for all treatments was 181.3 weeks. A statistically higher retention rate was observed for abatacept when compared to TNFi (p = 0.02), JAKi (p < 0.001), and anti-IL6R (p < 0.001), and for TNFi vs. JAKi (p = 0.013). Conclusion: We described, in a real-life setting, elderly RA patients treated with a biologic or a ts-DMARD in Italy. Loss of efficacy was the main cause of discontinuation, and the DMARD safety profile suggests that age does not contraindicate their use. Our study reinforced that the control of disease activity is mandatory.

Stopping bDMARDs at the beginning of pregnancy is associated with disease flares and preterm delivery in women with rheumatoid arthritis.

Objectives: Women with Rheumatoid Arthritis (RA) can experience flares during pregnancy that might influence pregnancy outcomes. We aimed at assessing the disease course during pregnancy and identifying risk factors for flares. Methods: Data about prospectively-followed pregnancies in RA were retrospectively collected before conception, during each trimester and in the post-partum period. Clinical characteristics, disease activity (DAS28-CRP3), medication use, and pregnancy outcomes were analysed with regard to disease flares. Results: Among 73 women who had a live birth, 64 (88%) were in remission/low disease activity before conception. During pregnancy, a flare occurred in 27 (37%) patients, mainly during first and second trimester. Flares during pregnancy were associated with the discontinuation of bDMARDs at positive pregnancy test (55% of patients with flare vs. 30% of patients with no flare, p 0.034, OR 2.857, 95% CI 1.112-8.323) and a previous use of >1 bDMARDs (33% of patients with flare vs. 10% of patients with no flare, p 0.019, OR 4.1, 95%CI 1.204-13.966). Preterm pregnancies were characterised by higher values of CRP [10 mg/L (5-11) vs. 3 mg/L (2.5-5), p 0.01] and DAS28-CRP3 [4.2 (1.9-4.5) vs. 1.9 (1.7-2.6), p 0.01] during the first trimester as compared with pregnancies at term. Preterm delivery was associated with the occurrence of flare during pregnancy (flare 27% vs. no-flare 7%, p 0.034, OR 4.625, 95%CI 1.027-20.829). Conclusion: Preterm delivery in RA patients was associated with flares during pregnancy. Flares occurred more frequently after the discontinuation of bDMARDs at positive pregnancy test. Women with aggressive RA on treatment with bDMARDs should be considered as candidates for continuing bDMARDs during pregnancy in order to reduce the risk of flare and adverse pregnancy outcomes.

Retention rate of a second line with a biologic DMARD after failure of a first-line therapy with abatacept, tocilizumab, or rituximab: results from the Italian GISEA registry.

OBJECTIVES: EULAR recommendations do not suggest which biologic disease-modifying anti-rheumatic drug (bDMARD) should be preferred after failure of a first bDMARD in the treatment of rheumatoid arthritis (RA). In particular, few data are available regarding the effectiveness of a second-line bDMARD after failure of abatacept (ABA), tocilizumab (TCZ), and rituximab (RTX). The aim of this study was to analyze the retention rate of a second line with tumor necrosis factor inhibitors (TNFi) or other mechanisms of action (MoAs), after the failure of either RTX, TCZ, or ABA. METHODS: Two hundred and seventy-eight RA patients from the Italian GISEA registry were included in the study. RTX was the first bDMARD in 18% of patients, ABA in 45.7%, and TCZ in 36.3%, while the second bDMARD was a TNFi (group 1) in 129 patients and an agent with a different MoA (group 2) in 149. RESULTS: During a median follow-up of 22 months (IQR 68), 129 patients discontinued their treatment; patients of group 1 discontinued the treatment more frequently than patients of group 2 (p<0.001) with retention rates of 33.6±5.7% and 63.6±4.6% after 104 weeks for group 1 and group 2, respectively (p<0.001). At multivariate analysis, the mechanism of action was the only predictor for the maintenance in therapy. CONCLUSIONS: According to our data, ABA, RTX, and TCZ seem to maintain a good retention rate also when used as a second-line therapy, suggesting their use after the failure of a non-TNFi as first-line therapy. However, specifically designed studies are needed to evaluate the more appropriate therapeutic strategies in RA, according to the first-line drug, including new targeted synthetic DMARDs. Key Points • A large proportion of rheumatoid arthritis patients fail the first biologic DMARD. • Few data are available about the efficacy of biologic DMARD after the failure of a non-TNF inhibitor. • Abatacept, rituximab, or tocilizumab seem to maintain a good retention rate after the failure of a first-course therapy with a non-TNF inhibitor.

Factors Predicting Early Failure of Etanercept in Rheumatoid Arthritis: An Analysis From the Gruppo Italiano di Studio sulla Early Arthritis (Italian Group for the Study of Early Arthritis) Registry.

OBJECTIVES: This study aims to investigate the factors associated with early discontinuation (within one year) of etanercept (ETA) in rheumatoid arthritis (RA) patients who began ETA as first biologic disease-modifying antirheumatic drug (bDMARD) and who were entered into the Gruppo Italiano di Studio sulla Early Arthritis (Italian Group for the Study of Early Arthritis; GISEA) registry. PATIENTS AND METHODS: This registry-based cohort study included 477 RA patients (95 males, 382 females; median age 53 years; range 18 to 83 years) who began ETA as first bDMARD. Patient demographics, disease features and drugs were re-evaluated after 12 months. Baseline predictors of ETA discontinuation were estimated by univariate and multivariate analyses using Cox regression model. RESULTS: Seventy patients (14.7%) discontinued ETA during the first year (for inefficacy in 55.8%, adverse events in 28.6%, and other reasons in 6.5%). Concurrent conventional synthetic DMARDs (csDMARDs) were reported in 54.3% of patients, mainly methotrexate (MTX), while 52.4% of subjects took low doses of glucocorticoids. Patients stopping ETA more frequently showed one or more comorbidities, mainly cardiovascular diseases (28.6% vs. 15.7% in patients stopping and continuing ETA, respectively, p=0.009). The presence of comorbidities and a combination therapy with csDMARDs other than MTX were independent factors associated with early discontinuation of ETA at multivariate Cox analysis. CONCLUSION: Although ETA demonstrated a high persistence in biologic-naïve RA patients, about 15% of patients discontinued the treatment within 12 months. The presence of comorbidities and a combination therapy with csDMARDs other than MTX were the main factors for an early withdrawal of the drug.

Tocilizumab for the treatment of severe COVID-19 pneumonia with hyperinflammatory syndrome and acute respiratory failure: A single center study of 100 patients in Brescia, Italy.

A hyperinflammatory syndrome (HIS) may cause a life-threatening acute respiratory distress syndrome (ARDS) in patients with COVID-19 pneumonia. A prospective series of 100 consecutive patients admitted to the Spedali Civili University Hospital in Brescia (Italy) between March 9th and March 20th with confirmed COVID-19 pneumonia and ARDS requiring ventilatory support was analyzed to determine whether intravenous administration of tocilizumab (TCZ), a monoclonal antibody that targets the interleukin 6 (IL-6) receptor, was associated with improved outcome. Tocilizumab was administered at a dosage of 8 mg/kg by two consecutive intravenous infusions 12 h apart. A third infusion was optional based on clinical response. The outcome measure was an improvement in acute respiratory failure assessed by means of the Brescia COVID Respiratory Severity Score (BCRSS 0 to 8, with higher scores indicating higher severity) at 24-72 h and 10 days after tocilizumab administration. Out of 100 treated patients (88 M, 12 F; median age: 62 years), 43 received TCZ in the intensive care unit (ICU), while 57 in the general ward as no ICU beds were available. Of these 57 patients, 37 (65%) improved and suspended noninvasive ventilation (NIV) (median BCRSS: 1 [IQR 0-2]), 7 (12%) patients remained stable in NIV, and 13 (23%) patients worsened (10 died, 3 were admitted to ICU). Of the 43 patients treated in the ICU, 32 (74%) improved (17 of them were taken off the ventilator and were discharged to the ward), 1 (2%) remained stable (BCRSS: 5) and 10 (24%) died (all of them had BCRSS≥7 before TCZ). Overall at 10 days, the respiratory condition was improved or stabilized in 77 (77%) patients, of whom 61 showed a significant clearing of diffuse bilateral opacities on chest x-ray and 15 were discharged from the hospital. Respiratory condition worsened in 23 (23%) patients, of whom 20 (20%) died. All the patients presented with lymphopenia and high levels of C-reactive protein (CRP), fibrinogen, ferritin and IL-6 indicating a HIS. During the 10-day follow-up, three cases of severe adverse events were recorded: two patients developed septic shock and died, one had gastrointestinal perforation requiring urgent surgery and was alive at day 10. In conclusion, our series showed that COVID-19 pneumonia with ARDS was characterized by HIS. The response to TCZ was rapid, sustained, and associated with significant clinical improvement.

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.

The Efficacy and Safety of Cyclosporin A in Pregnant Patients with Systemic Autoimmune Diseases.

PROBLEM: Cyclosporin A (CYS A) is an immunosuppressant agent administered in autoimmune diseases, and its use during pregnancy and lactation is a debated topic. METHOD OF STUDY: The demographic characteristics, the activity of the underlying disease, and the onset of fetal-maternal complications have been investigated in 21 consecutive patients (2 RA, 14 SLE, 2 PA, 1 SjS, 1 DM, 1 Churg-Strauss vasculitis), treated with CYS A throughout 29 gestations. A subanalysis of the SLE group was performed. RESULTS: We recorded a live birth rate of 86.2%. The median gestational age at birth was 38.2 weeks. The prevalence of maternal-fetal complications showed no differences with general population. Disease flares appeared in 4% of patients during gestation and in 12% during puerperium. CONCLUSION: We found no evidence justifying the suspension of CYS A when a pregnancy occurs. The drug does not appear to promote maternal-fetal complications and should be continued in patients who benefit from therapy. Data regarding breast-feeding during therapy are still scarce, but no evidence of toxicity has emerged.

Drug survival of adalimumab in patients with rheumatoid arthritis over 10 years in the real-world settings: high rate remission together with normal function ability.

The purpose of the study was to estimate the clinical profile of naïve biological patients with rheumatoid arthritis (RA) starting adalimumab through 3-year calendar periods and their clinical outcomes such as drug survival and global clinical disease control (GCDC). RA patients starting adalimumab as first biological drug between 2003 and 2012 were subdivided in 3-year calendar periods. Survival on therapy was estimated using the Kaplan-Meier analysis. One and 2-year clinical response was assessed by calculating percentage of patients attaining GCDC (28-joint Disease Activity Score (DAS28) ≤ 2.6 + Health Assessment Questionnaire (HAQ) ≤ 0.5), low disease activity (DAS28 ≤ 3.2), remission (DAS28 ≤ 2.6) and good European League Against Rheumatism (EULAR) response. Multivariate regression models were used to assess baseline predictors of drug discontinuation or achievement of clinical remission. We recruited 1695 RA patients. Overall drug persistence at 3 years was 40.6 %, while the global rate of nonswitching patients was 54.7 %. Compared to 2003-2005, initiators in more recent years had a significantly lower 3-year crude drug retention rate (log rank, p < 0.0001) and a significantly higher rate of switching to alternative biologics (log rank, p < 0.0001). No difference in adverse events or effectiveness rate among the calendar periods was found. A substantial proportion of patients (up to 27 %) achieved GCDC at 2 years, regardless of the calendar period. In real-life setting, RA patients starting adalimumab in more recent years had a higher rate of drug discontinuation not related to ineffectiveness or side effects but to switching, probably due to a wider availability of biologics. A meaningful proportion of patients attained GCDC without any difference across calendar periods.