New molecular mechanisms that can be targeted with specific drugs have recently emerged for the treatment of systemic sclerosis (SSc) patients. Over the past 3 years, the achievement of one large ...phase 3 trial has led to the approval by drug agencies of the first drug licenced for SSc-related interstitial lung disease. Given this exciting time in the SSc field, we aimed to perform a systemic literature review of phase 1, phase 2 and phase 3 clinical trials and large observational studies about targeted therapies in SSc. We searched MEDLINE/PubMed, EMBASE, and ClinicalTrials.gov for clinical studies from 2016 with targeted therapies as the primary treatment in patients with SSc for skin or lung involvement as the primary clinical outcome measure. Details on the study characteristics, the trial drug used, the molecular target engaged by the trial drug, the inclusion criteria of the study, the treatment dose, the possibility of concomitant immunosuppression, the endpoints of the study, the duration of the study and the results obtained were reviewed. Of the 973 references identified, 21 (4 conference abstracts and 17 articles) were included in the systematic review. A total of 15 phase 1/phase 2 clinical trials, 2 phase 3 clinical trials and 2 observation studies were analysed. The drugs studied in phase 1/phase 2 studies included the following: inebilizumab, dabigatran, C-82, pomalidomide, rilonacept, romilkimab, tocilizumab, tofacitinib, pirfenidone, lenabasum, abatacept, belimumab, riociguat, SAR100842 and lanifibranor. All but 3 studies were performed in early diffuse SSc patients with different inclusion criteria, while 3 studies were performed in SSc patients with interstitial lung disease (ILD). Phase 3 clinical trials investigated nintedanib and tocilizumab. Nintedanib was investigated in SSc-ILD patients whereas tocilizumab focused on early diffuse SSc patients with inflammatory features. Two observational studies including > 50 patients with rituximab as the targeted drug were also evaluated. All these studies offer a real hope for SSc patients. The future challenges will be to customize patient-specific therapeutics with the goal to develop precision medicine for SSc.
Abstract
Introduction
Four clinical phenotypes of IgG4-related disease (IgG4-RD) have been recently identified by latent class analysis (LCA): pancreato-biliary (group 1); retroperitoneum/aortitis ...(group 2); head and neck limited (group 3); and Mikulicz/systemic (group 4). The reproducibility of this classification in clinical practice and its relevance for patient management, however, remain unknown.
Methods
The study included 179 patients. Four IgG4-RD experts were asked to classify a validation cohort of 40 patients according to published LCA-derived phenotypes based on clinical judgement. Agreement between LCA and clinical clustering was calculated. To assess differences among disease phenotypes, the following variables were recorded on an additional 139 patients: serum IgG4 and IgE; inflammatory markers; eosinophils; plasmablasts; IgG4-RD responder index (RI); history of atopy, diabetes, osteoporosis, relapses and malignancy; cumulative dose of glucocorticoids; and use of rituximab.
Results
Clinical judgement replicated LCA classification with strong agreement among IgG4-RD experts (κ = 0.841, P < 0.0005). At disease onset, group 1 showed the highest levels of serum IgG4 and IgE. Groups 2 and 4 had the lowest and highest IgG4-RD RI, respectively. At 2 years’ follow-up, group 3 received the highest cumulative dose of glucocorticoids, but higher incidences of diabetes mellitus were observed in groups 1 and 4, consistent with the higher likelihood of pancreatic involvement in groups 1 and 4. No difference among the four groups was observed in terms of disease recurrence, time to relapse and frequency of rituximab infusion.
Conclusion
Clinical phenotypes of IgG4-RD reflect differences in epidemiological features and prognostic outcomes.
Abstract
Objective
The aim of this study was to identify the main CT features that may help in distinguishing a progression of interstitial lung disease (ILD) secondary to SSc from COVID-19 ...pneumonia.
Methods
This multicentric study included 22 international readers grouped into a radiologist group (RADs) and a non-radiologist group (nRADs). A total of 99 patients, 52 with COVID-19 and 47 with SSc-ILD, were included in the study.
Results
Fibrosis inside focal ground-glass opacities (GGOs) in the upper lobes; fibrosis in the lower lobe GGOs; reticulations in lower lobes (especially if bilateral and symmetrical or associated with signs of fibrosis) were the CT features most frequently associated with SSc-ILD. The CT features most frequently associated with COVID- 19 pneumonia were: consolidation (CONS) in the lower lobes, CONS with peripheral (both central/peripheral or patchy distributions), anterior and posterior CONS and rounded-shaped GGOs in the lower lobes. After multivariate analysis, the presence of CONs in the lower lobes (P < 0.0001) and signs of fibrosis in GGOs in the lower lobes (P < 0.0001) remained independently associated with COVID-19 pneumonia and SSc-ILD, respectively. A predictive score was created that was positively associated with COVID-19 diagnosis (96.1% sensitivity and 83.3% specificity).
Conclusion
CT diagnosis differentiating between COVID-19 pneumonia and SSc-ILD is possible through a combination of the proposed score and radiologic expertise. The presence of consolidation in the lower lobes may suggest COVID-19 pneumonia, while the presence of fibrosis inside GGOs may indicate SSc-ILD.
Objective
IgG4‐related disease (IgG4‐RD) can cause fibroinflammatory lesions in nearly any organ, leading to organ dysfunction and failure. The IgG4‐RD Responder Index (RI) was developed to help ...investigators assess the efficacy of treatment in a structured manner. The aim of this study was to validate the RI in a multinational investigation.
Methods
The RI guides investigators through assessments of disease activity and damage in 25 domains, incorporating higher weights for disease manifestations that require urgent treatment or that worsen despite treatment. After a training exercise, investigators reviewed 12 written IgG4‐RD vignettes based on real patients. Investigators calculated both an RI score as well as a physician's global assessment (PhGA) score for each vignette. In a longitudinal assessment, 3 investigators used the RI in 15 patients with newly active disease who were followed up over serial visits after treatment. We assessed interrater and intrarater reliability, precision, validity, and responsiveness.
Results
The 26 physician investigators included representatives from 6 specialties and 9 countries. The interrater and intrarater reliability of the RI was strong (0.89 and 0.69, respectively). Correlations (construct validity) between the RI and PhGA were high (Spearman's r = 0.9, P < 0.0001). The RI was sensitive to change (discriminant validity). Following treatment, there was significant improvement in the RI score (mean change 10.5 95% confidence interval (95% CI) 5.4–12, P < 0.001), which correlated with the change in the PhGA. Urgent disease and damage were captured effectively.
Discussion
In this international, multispecialty study, we observed that the RI is a valid and reliable disease activity assessment tool that can be used to measure response to therapy.
Idiopathic inflammatory myopathies (IIM) represent a rare and heterogenous group diseases, and their treatment is not fully defined yet. According to previous small case series, the combination of ...mycophenolate mofetil (MMF) and rituximab (RTX) may be effective in controlling difficult-to-treat patients. Our aim was to further explore the efficacy and safety of this combined approach in patients with IIM.
Patients with IIM treated with the RTX/MMF combination in our Center were retrospectively identified. After the start of combination therapy, the efficacy was evaluated at 12 months (T12) according the 2016 ACR/EULAR response criteria for IIM. Cardiac imaging and pulmonary function tests were used to monitor disease activity in patients with myocarditis and interstitial lung disease, respectively. Adverse events were recorded over the follow-up period.
Among the 20 patients (median age 61 years; 70% female) included in the study, anti-synthetase syndrome was the most prevalent IIM subgroup (60%). At treatment start, muscle, heart, and lung were the most commonly actively affected organs. After 12 months, a moderate or major response was observed in all patients, and creatine kinase was significantly decreased (p-value = 0.012). Cardiac imaging and enzymes monitoring showed a reduction of heart inflammation, while pulmonary function tests improved in patients with lung involvement. No severe side effects were observed.
Our data show that combination of RTX and MMF is effective and safe in patients with severe and refractory IIM. Therefore, this combined treatment might represent a feasible approach for difficult-to-treat IIM cases.
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