When facing an acute viral infection, our immune systems need to function with finite precision to enable the elimination of the pathogen, whilst protecting our bodies from immune-related damage. In many instances however this “perfect balance” is not achieved, factors such as ageing, cancer, autoimmunity and cardiovascular disease all skew the immune response which is then further distorted by viral infection. In SARS-CoV-2, although the vast majority of COVID-19 cases are mild, as of 24 August 2020, over 800,000 people have died, many from the severe inflammatory cytokine release resulting in extreme clinical manifestations such as acute respiratory distress syndrome (ARDS) and hemophagocytic lymphohistiocytosis (HLH). Severe complications are more common in elderly patients and patients with cardiovascular diseases. Natural killer (NK) cells play a critical role in modulating the immune response and in both of these patient groups, NK cell effector functions are blunted. Preliminary studies in COVID-19 patients with severe disease suggests a reduction in NK cell number and function, resulting in decreased clearance of infected and activated cells, and unchecked elevation of tissue-damaging inflammation markers. SARS-CoV-2 infection skews the immune response towards an overwhelmingly inflammatory phenotype. Restoration of NK cell effector functions has the potential to correct the delicate immune balance required to effectively overcome SARS-CoV-2 infection.

Objectives:The aim of this study was to determine the relationship between disease activity in adult patients with dermatomyositis (DM) and other biomarkers of disease activity such as C-reactive protein creatinine kinase and nailfold video capillaroscopy (NVC).Methods:We performed a prospective single center study of 15 adult patients with DM. Study participants underwent two assessments at least 9 months apart including clinical, laboratory and NVC evaluations. Patients received immunosuppressive medications for their dermatomyositis, and ongoing disease activity was measured by the Myositis Intention to Treat Index (MITAX). NVC evaluation included assessment of capillary density, capillary apical diameter (mm), and the number of microhemorrhages per digit.Results:Microvascular abnormalities were present in most DM patients. Of these, capillary density (4.71 vs. 6.84,p= 0.006) and mean apical diameter (56.09 vs. 27.79 μm,p= 0.003) significantly improved over the study period in concordance with improving disease control (MITAX 8.53 vs. 2.64,p= 0.002). Longitudinal analysis demonstrated that capillary density was independently associated with MITAX (β = −1.49 [CI −2.49, −0.33],p= 0.013), but not other parameters such as C-reactive protein and creatinine kinase.Conclusions:Nailfold capillary density is a dynamic marker of global disease activity in adult DM. NVC may be utilized as a non-invasive point-of-care tool to monitor disease activity and inform treatment decisions in patients with DM.

Systemic sclerosis (SSc) is associated with secondary malignancies. Previous studies have suggested that mutated cancer proteins, such as RNA polymerase III, are autoantigens promoting an inflammatory response in SSc. However, it has never been previously investigated whether non-neoplastic tissue in SSc harbors mutations which may play a role in SSc pathogenesis. Skin biopsies were obtained from 8 sequential patients with a progressive form of early stage SSc (with severe skin and/or lung involvement). Areas of dermal fibrosis were microdissected and analyzed with deep, whole exome sequencing. Gene mutation patterns were compared to autologous buccal mucosal cells as a control. SSc skin biopsies were hypermutated with an average of 58 mutations/10⁶ base pairs. The mutational pattern in all samples exhibited a clock-like signature, which is ubiquitous in cancers and in senescent cells. Of the 1997 genes we identified which were mutated in at least two SSc patients, 39 genes represented cancer drivers (i.e. tumor suppressor genes or oncogenes) which are commonly found in gynecological, squamous and gastrointestinal cancer signatures. Of all the mutations, the most common mutated genes were important in regulating pathways related to epigenetic histone modifications, DNA repair and genome integrity. Somatic hypermutation occurs in fibrotic skin in patients with early progressive SSc. Cancer driver gene mutations may potentially play a fundamental role in the pathogenesis of SSc.

Introduction: Nailfolds of patients with systemic sclerosis (SSc) provide an opportunity to directly visualize microvascular remodeling in SSc. Nailfold video capillaroscopy (NVC) remains the gold standard for assessing nailfold capillaroscopy (NFC). However, access to NVC is limited by expense and expertise. This review aims to synthesize current research on other NFC devices compared to NVC. Methods: The literature search included the primary research of adult patients with SSc as defined by the 2013 ACR/EULAR criteria. Methods of assessing NFC included stereomicroscopy/wide-field microscopy, ophthalmoscopy, dermatoscopy, smartphone devices, and digital USB microscopy. Primary outcomes included both qualitative (normal vs. abnormal nailfolds, overall pattern recognition, presence/absence of giant capillaries, hemorrhages, and abnormal morphology) and quantitative (capillary density and dimension) measures. Results: The search yielded 471 studies, of which 9 were included. Five studies compared NVC to dermatoscopy, two compared it to widefield/stereomicroscopy, one to smartphone attachments, and one to USB microscopy. In dermatoscopy studies, NVC had a higher percentage of images that were interpretable (63–77% vs. 100%), classifiable (70% vs. 84%), or gradable (70% vs. 79.3%) across three studies. Dermatoscopy had a lower sensitivity (60.2% vs. 81.6%) and higher specificity (92.5% vs. 84.6%) compared to NVC. One stereomicroscopy study found a significant difference between methods in capillary density in limited cutaneous SSc, while another found correlations in all parameters between stereomicroscopy and NVC. One smartphone lens had good agreement with NVC on abnormal capillary morphology and density. USB microscopy was able to differentiate between SSc and healthy controls using mean capillary width but not by capillary density. Discussion: A dermatoscope may serve as a more portable and affordable screening tool to identify a normal “scleroderma pattern”, and images that need further corroboration by NVC. NFC parameters reported are heterogenous and the standardization of these parameters is important, especially in non-gold-standard devices.

Objective: Interstitial lung disease (ILD) is a common and potentially lethal complication of systemic sclerosis (SSc). Screening by high‐resolution computed tomography (HRCT) is recommended in all patients with risk factors, including early disease. Little is known on late presentations of ILD. This study aimed to characterize the incidence, risk factors, and outcomes of late‐onset SSc‐ILD.Methods: Study participants enrolled in the Canadian Scleroderma Research Group cohort from 2004 to 2020 without prevalent ILD were included. Incidence and risk factors for ILD (on HRCT) were compared according to disease duration above (late) and below (earlier) seven years from the first non‐Raynaud manifestation. Risk of ILD progression was compared using Kaplan‐Meier and multivariable Cox models.Results: Overall, 199 (21%) of 969 patients developed incident ILD over a median of 2.4 (interquartile range 1.2–4.3) years. The incidence rate in late SSc (3.7/100 person‐years) was lower than in earlier SSc (relative risk 0.68, 95% confidence interval [CI] 0.51–0.92). Risk factors for incident ILD included male sex, diffuse subtype, myositis, antitopoisomerase I autoantibodies, and higher C‐reactive protein levels. Patients with late‐onset ILD were also less frequently White and more frequently had arthritis and anti‐RNA‐polymerase III autoantibodies. Lung disease severity was similar between late‐ and earlier‐onset SSc‐ILD (forced vital capacity 88% and 87%, diffusion capacity of the lungs for carbon monoxide 64% and 62%, respectively). Progression rates were also similar between late‐ and earlier‐onset SSc‐ILD (log rank P = 0.8, hazard ratio 1.11, 95% CI 0.58–2.10).Conclusion: ILD can present in late SSc. Risk factors and progression rates overlapped with earlier‐onset SSc‐ILD. Surveillance for ILD should continue in longstanding SSc. Frequency and modality of monitoring remain to be defined.