Purpose of reviewActivation of the type 1 interferon (T1 IFN) pathway has been implicated in the pathogenesis of systemic sclerosis (SSc) by an increasing number of studies, most of which share key findings with similar studies in systemic lupus erythematosus (SLE). Here we will focus on the evidence for T1 IFN activation and dysregulation in SSc, and the rationale behind targeting the pathway going forward. Recent findingsAn increased expression and activation of T1 IFN-regulated genes has been shown to be present in a significant proportion of SSc patients. TI IFN activation markers have been found to predict and correlate with response to immunosuppressive treatment as well as severity of organ involvement. As inhibition of the IFN-a receptor has been proven to be effective in active SLE, benefit may be seen in targeting the IFN pathway in SSc. SummaryThe role played by T1 IFN and its regulatory genes in SSc is becoming increasingly evident and strikingly similar to the role observed in SLE. This observation, together with the benefit of type 1 IFN targeting in SLE, supports the notion of a potential therapeutic benefit in targeting T1 IFN in SSc.
ObjectivesTo assess antibody and T cell responses to SARS-CoV-2 vaccination in patients with rheumatoid arthritis (RA) on disease-modifying antirheumatic drugs (DMARDs).MethodsThis prospective study recruited 100 patients with RA on a variety of DMARDs for antibody and T cell analysis, pre-vaccination and 4 weeks post-vaccination. Positive antibody response was defined as sera IgG binding to ≥1 antigen. Those that remained seronegative after first vaccination were retested 4 weeks after second vaccination; and if still seronegative after vaccination three. A T cell response was defined an ELISpot count of ≥7 interferon (IFN)γ-positive cells when exposed to spike antigens. Type I IFN activity was determined using the luminex multiplex assay IFN score.ResultsAfter vaccine one, in patients without prior SARS-CoV-2 exposure, 37/83 (45%) developed vaccine-specific antibody responses, 44/83 (53%) vaccine-specific T cell responses and 64/83 (77%) developed either antibody or T cell responses. Reduced seroconversion was seen with abatacept, rituximab (RTX) and those on concomitant methotrexate (MTX) compared to 100% for healthy controls (p<0.001). Better seroconversion occurred with anti-tumour necrosis factor (TNF) versus RTX (p=0.012) and with age ≤50 (p=0.012). Pre-vaccine SARS-CoV-2 exposure was associated with higher quantitative seroconversion (≥3 antibodies) (p<0.001). In the subgroup of non-seroconverters, a second vaccination produced seroconversion in 54% (19/35), and after a third in 20% (2/10). IFN score analysis showed no change post-vaccine.ConclusionPatients with RA on DMARDs have reduced vaccine responses, particularly on certain DMARDs, with improvement on subsequent vaccinations but with approximately 10% still seronegative after three doses.
Background:Patient Reported Outcomes (PROs) are used to capture disease impact on patients’ Health Related Quality of Life (HRQoL) and they have been increasingly used as endpoints in clinical trials for Systemic Sclerosis (SSc). The DeSScipher project within the EUSTAR group highlighted dyspnea as one of the factors more strongly related with the highest SHAQ scores (1). Nevertheless, the SENSCIS trial in SSc-ILD (2) showed the efficacy of Nintedanib in reducing the annual rate of FVC loss, as compared to placebo, without significant changes in the PROs used as secondary endpoints (St. George’s Respiratory Questionnaire and the FACIT-Dyspnoea questionnaire). Since patient’s perspective is a crucial determinant to define the overall relevance of an intervention, the performance of PROs in reflecting different lung functional stages is a relevant issue in SSc.Objectives:To analyse in a prospective SSc cohort the inference of reduced lung function as measured by FVC on median PRO scores and the correlation among distinct commonly used PROs.Methods:A cross-sectional study was performed on data exported from the STRIKE database regarding SSc patients followed in Leeds Scleroderma Programme for SSc. Data included records of periodical visits with scores of different PROs commonly used in SSc (Scleroderma-Health Assessment Questionnaire (SHAQ), Cochin Hand Function Scale (CHFS) and Borg dyspnoea scale) and FVC%-predicted (%pFVC) and DLCO%-predicted (%pDLCO). SHAQ score was calculated as the mean value of HAQ (0-3) with the average of the 7-VAS scores divided by 3.33. The 7-VAS (score 1-10) were 1: pain, 2: general function, 3: arthritis, 4: gastro-intestinal, 5: dyspnoea, 6: Raynaud Phenomena; 7: digital ulcers. The correlation of FVC with distinct PROs, and the inter-PRO correlation, were analysed through the non-parametric Spearman test.Results:Complete data were available from 182 visits of 87 SSc patients (41 with diffuse and 46 with limited cutaneous involvement). Mean %pFVC was 95.16 ±24.93 (median 95) and mean %pDLCO was 59.31±16.51 (median 59). Overall, FVC and DLCO showed a moderate correlation with SHAQ (r=-0.36, p<0.001 and r=-0.24, p:0.001 respectively), while Borg score showed a stronger negative correlation with FVC and DLCO (r:-0.42 and r-0.38, p<0.001 for both). In a sub-analysis of patients grouped by FVC, patients with FVC 50-70% showed a significant correlation of FVC with SHAQ (r =-0.47, p:0.012), which was not present in patients with FVC 70-90% (r:-0.23, p:0.13). VAS-5 dyspnoea and Borg were not associated with FVC in these two subgroups of patients.Inter PROs analysis showed that CHFS score had a stronger correlation with SHAQ than Borg dyspnoea score in the overall population (r:0.86 vs. r:0.57, both p<0.001).Conclusion:The analysis of a single centre prospective cohort of SSc patients, suggests a small inference of lung function in the overall SHAQ. The stronger correlation of SHAQ with CHFS, than with Borg score, suggests a higher weight of hand function on SHAQ in this population with relatively conserved lung function. In patients with %pFVC <70%, the correlation with SHAQ was stronger than in patients with %pFVC >70%, suggesting that mild reductions in FVC might not be perceived by the patients, or at least they might not modify HrQoL as measured by SHAQ.References:[1]Jaeger VK, et al. Rheumatology 2017;57(3):441-50.[2]Distler O, et al. N Engl J Med 2019; 380:2518-2528.Disclosure of Interests:Maria Grazia Lazzaroni Grant/research support from: Boehringer-Ingelheim, Giuseppina Abignano: None declared, Michelle Wilson: None declared, Vishal Kakkar: None declared, Francesco Del Galdo Consultant of: Astra-Zeneca, Boehringer-Ingelheim, Mitsubishi-Tanabe, Capella Biosciences, Kymab, Actelion, Grant/research support from: Astra-Zeneca, Boehringer-Ingelheim, Mitsubishi-Tanabe, Capella Biosciences, Kymab, Actelion
Background/Aims Vascular involvement in systemic sclerosis (SSc) is known to start even before clinical diagnosis, driving digital ulcer (DU) disease. Later in the disease natural history, it can cause pulmonary artery hypertension (PAH) among other manifestations. Despite the proven immune origin of scleroderma, vascular involvement is not currently targeted by immune driven interventions. Similarly, few data are available on immune or inflammatory biomarkers and outcome measures of vascular disease in SSc. Digital artery volume index (DAVIX) has been recently proposed as an imaging surrogate outcome measure of vascular disease activity in SSc. Methods 86 patients attending our scleroderma program were consecutively enrolled for the evaluation of serum IFN score as previously described [2]. Clinical features, including presence or history of DUs, presence of PAH and DLCO, were recorded. DAVIX of the dominant hand’s fingers was calculated using time of flight magnetic resonance imaging analysed through IAG proprietary algorithm, as previously described [1]. Medians were compared by Mann-Whitney-Wilcoxon test; correlation with clinical parameters was performed using Spearman’s or Pearson test, as appropriate (R). Results 62 patients fulfilled the 2013 ACR/EULAR classification criteria for SSc (diffuse cutaneous 24.6%, limited cutaneous 75.4%), whereas 23 were classified as very early diagnosis of scleroderma (criteria score between 6 and 8). 23 patients had DU disease (history of DUs in the previous 24 weeks, presence of DUs at baseline assessment, or onset of new DUs during the following 24 weeks). 18 patients had reduced DLCO (<70) with FVC/DLCO>1.8 (suspected PAH). DAVIX showed a negative correlation with disease duration (r=-0.33 and p = 0.003) and with FVC/DLCO ratio (r=-0.34 and p = 0.009). Patients with DU disease presented lower DAVIX than patients without (p = 0.018). DAVIX showed a significant correlation with serum IFN score (r=-0.24, p < 0.032). Accordingly, patients classified as IFN-HI had lower DAVIX than those within the IFN-LO group (p = 0.016). Conclusion DAVIX correlated both with presence of DU disease, DLCO and disease duration. The correlation of DAVIX and serum IFN score does support the notion of innate immune involvement in vascular disease manifestations of SSc. Prospective testing in the context of randomised controlled trials will determine the value of DAVIX as a surrogate outcome measure of vascular disease severity in SSc. S. Di Donato: None. M. Hughes: None. K. Geloshi: None. E. De Lorenzis: None. V. Kakkar: None. R. Ross: None. P. O'Connor: None. O. Kubassova: Consultancies; Image Analysis Group CEO. F. Del Galdo: Grants/research support; Abbvie, AstraZeneca, Boeringher-Ingelheim, Capella, Chemomab, Janssen, Kymab, Mitsubishi-Tanabe.
BackgroundHand function deterioration is a major multifactorial driver of disability in Systemic Sclerosis (SSc) whose rate has been poorly described.ObjectivesThe aim of this study is to describe incidence and risk factors of hand functional worsening in a longitudinal, multicenter, observational SSc cohort.MethodsHand involvement and disability were evaluated in consecutively enrolled patients for 24 months. Patient-reported hand impairment was captured with Cochin Hand Disability Score (CHFS) and the corresponding minimal clinical important differences (MCID) and patient acceptable symptom state (PASS). Clinical association with CHFS change over time and clinically meaningful worsening (MCID-Worsening) were investigated.ResultsThree-hundred-ninety-six patients from 10 centres were evaluated and 201 SSc (age 55.7±12.2 years, male 13.4%) were included in the final analysis. Median (IQR) disease duration was 5 (2-11) years while the proportion of patients with diffuse cutaneous variant was the 29.9%. Fifty-six (27.8%) patients had a CHFS ≥PASS at baseline. CHFS increased over time 35.8% of patients reaching CHFS≥PASS (p<0.001), and 52.2% of patients reporting MCID-Worsening at 24 months. A LASSO model simultaneously exploring the effects of multiple baseline clinical variables showed that MCID-Worsening was associated with male gender, LeRoy diffuse variant, late capillaroscopy pattern, shorter disease duration, absence of digital ulcers, presence of tenosynovitis, pain, Raynaud’s phenomenon, and global and hand disability severity, together with treatment with immunosuppressants, vasoactive medications, and second-line analgesics.ConclusionHand function tends to deteriorate over time in one SSc patient in two despite available therapies and clinical assessment support risk stratification. These results pave the way to inform design of intervention studies aimed at improving the outcome of this major driver of disability in SSc.REFERENCES:NIL.Acknowledgements:NIL.Disclosure of InterestsNone Declared.
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