Biomarker analysis from the phase 2b randomized placebo-controlled trial of riociguat in early diffuse cutaneous systemic sclerosis.

OBJECTIVE: To examine disease and target engagement biomarkers in the RISE-SSc trial of riociguat in early diffuse cutaneous systemic sclerosis and their potential to predict the response to treatment. METHODS: Patients were randomized to riociguat (n = 60) or placebo (n = 61) for 52 weeks. Skin biopsies and plasma/serum samples were obtained at baseline and week 14. Plasma cyclic guanosine monophosphate (cGMP) was assessed using radio-immunoassay. Alpha smooth muscle actin (αSMA) and skin thickness were determined by immunohistochemistry, mRNA markers of fibrosis by qRT-PCR in skin biopsies, and serum CXC motif chemokine ligand 4 (CXCL-4) and soluble platelet endothelial cell adhesion molecule-1 (sPECAM-1) by enzyme-linked immunosorbent assay. RESULTS: By week 14, cGMP increased by 94 ± 78% with riociguat and 10 ± 39% with placebo (p < 0.001, riociguat vs placebo). Serum sPECAM-1 and CXCL-4 decreased with riociguat vs placebo (p = 0.004 and p = 0.008, respectively). There were no differences in skin collagen markers between the 2 groups. Higher baseline serum sPECAM-1 or the detection of αSMA-positive cells in baseline skin biopsies were associated with a larger reduction of modified Rodnan skin score from baseline at week 52 with riociguat vs placebo (interaction P-values 0.004 and 0.02, respectively). CONCLUSION: Plasma cGMP increased with riociguat, suggesting engagement with the nitric oxide-soluble guanylate cyclase-cGMP pathway. Riociguat was associated with a significant reduction in sPECAM-1 (an angiogenic biomarker) vs placebo. Elevated sPECAM-1 and the presence of αSMA-positive skin cells may help to identify patients who could benefit from riociguat in terms of skin fibrosis. TRIAL REGISTRATION: Clinicaltrials.gov, NCT02283762.

Safety and tolerability of intravenous immunoglobulin in patients with active dermatomyositis: results from the randomised, placebo-controlled ProDERM study.

BACKGROUND: Dermatomyositis is an idiopathic inflammatory myopathy characterised by rashes and progressive muscle weakness. The recent ProDERM (Progress in DERMatomyositis) study is the first large randomised, placebo-controlled trial to establish the efficacy and safety of intravenous immunoglobulin (IVIg) in adult patients with dermatomyositis. Objectives of this analysis were to closely examine the safety and tolerability of IVIg in patients from the ProDERM study. METHODS: ProDERM was a double-blind, randomised, placebo-controlled, multicentre, phase 3 study. In the first period (weeks 0-16), adults with active dermatomyositis received 2.0 g/kg IVIg (Octagam 10%; Octapharma AG) or placebo every 4 weeks. In the open-label extension period (weeks 16-40), all patients received IVIg for 6 additional cycles; dose reduction (1.0 g/kg) was permitted if patients were stable. Treatment-emergent adverse events (TEAEs) were documented. RESULTS: The 95 patients enrolled were randomised to receive IVIg (N = 47) or placebo (N = 48) in the first period, with 5 switching from placebo to IVIg. Overall, 664 IVIg infusion cycles were administered. During the first period, 113 TEAEs were possibly/probably related to treatment in 30/52 patients (57.7%) receiving IVIg and 38 in 11 patients (22.9%) on placebo. Eight patients discontinued therapy due to IVIg-related TEAEs. Eight thromboembolic events (TEEs) occurred in six patients on IVIg; six in five patients were deemed possibly/probably related to IVIg. Patients with TEEs exhibited more baseline TEE risk factors than those without TEEs (2.4-15.2-fold higher). Lowering infusion rate reduced the rate of TEEs, and none occurred at the lower IVIg dose. No haemolytic transfusion reactions or deaths occurred. CONCLUSIONS: Results from this study demonstrate that IVIg has a favourable safety profile for treatment of adult dermatomyositis patients and provides evidence that will help to inform treatment choice for these patients. Dermatomyositis patients receiving high-dose IVIg should be monitored for TEEs, and a low rate of infusion should be used to minimise TEE risk, particularly in those with pre-existing risk factors. TRIAL REGISTRATION: ProDERM study (NCT02728752).

Belimumab treatment of adult idiopathic inflammatory myopathy.

OBJECTIVE: To evaluate belimumab addition to the standard of care in patents with refractory idiopathic inflammatory myopathy (IIM). METHODS: We conducted a 40-week multicentre, randomized, double-blind, placebo-controlled trial with 1:1 IV belimumab 10 mg/kg or placebo randomization and a 24-week open-label extension. Clinical responses were measured by the definition of improvement (DOI) and total improvement score (TIS). Flow cytometry analyses were performed on available samples before randomization, at 24 and 60-64 weeks. Descriptive statistics, t-test, Fisher's exact test and analysis of variance tests were used. RESULTS: A total of 17 patients were randomized, 15 received five or more doses of belimumab or placebo and were included in the intention-to-treat analysis. More belimumab patients vs placebo attained a TIS ≥40 [55.5% vs 33.3%; P = non-significant (NS)] and achieved the DOI (33.3% vs 16.7%; P = NS) at weeks 40 and 64; the mean TIS was similar among groups. Two patients achieved major responses (TIS = 72.5) after week 40 in the belimumab arm and none in the placebo arm. No improvement in the placebo arm after switching to the open-label phase was observed. There was no steroid-sparing effect. No new safety signals were detected. Although total B cells were not reduced, belimumab induced naïve B cell depletion while enhancing the number and frequency memory B cells. CONCLUSION: The study did not meet the primary endpoint and no statistically significant differences were observed in clinical responses between arms. More patients achieved sustained TIS ≥40 and reached the DOI. Most patients who received belimumab for >40 weeks had clinical improvement. Phenotypic changes in B cell populations were not associated with clinical responses. CLINICAL TRIAL REGISTRATION NUMBER: Clinicaltrials.gov (https://clinicaltrials.gov/), NCT02347891.

Photoacoustic Imaging of COVID-19 Vaccine Site Inflammation of Autoimmune Disease Patients.

Based on the observations made in rheumatology clinics, autoimmune disease (AD) patients on immunosuppressive (IS) medications have variable vaccine site inflammation responses, whose study may help predict the long-term efficacy of the vaccine in this at-risk population. However, the quantitative assessment of the inflammation of the vaccine site is technically challenging. In this study analyzing AD patients on IS medications and normal control subjects, we imaged the inflammation of the vaccine site 24 h after mRNA COVID-19 vaccinations were administered using both the emerging photoacoustic imaging (PAI) method and the established Doppler ultrasound (US) method. A total of 15 subjects were involved, including 6 AD patients on IS and 9 normal control subjects, and the results from the two groups were compared. Compared to the results obtained from the control subjects, the AD patients on IS medications showed statistically significant reductions in vaccine site inflammation, indicating that immunosuppressed AD patients also experience local inflammation after mRNA vaccination but not in as clinically apparent of a manner when compared to non-immunosuppressed non-AD individuals. Both PAI and Doppler US were able to detect mRNA COVID-19 vaccine-induced local inflammation. PAI, based on the optical absorption contrast, shows better sensitivity in assessing and quantifying the spatially distributed inflammation in soft tissues at the vaccine site.

Current status of clinical outcome measures in inclusion body myositis: a systematised review.

OBJECTIVES: Sporadic inclusion body myositis (IBM) is a debilitating idiopathic inflammatory myopathy (IIM) which affects hand function, ambulation, and swallowing. There is no approved pharmacological therapy for IBM, and there is a lack of suitable outcome measure to assess the effect of an intervention. The IBM scientific interest group under IMACS reviewed the previously used outcome measures in IBM clinical studies to lay the path for developing a core set of outcome measures in IBM. METHODS: In this systematised review, we have extracted all outcome measures reported in IBM clinical studies to determine what measures were being used and to assess the need for optimising outcome measures in IBM. RESULTS: We found 13 observational studies, 17 open-label clinical trials, and 15 randomised control trials (RCTs) in IBM. Six-minute walk distance, IBM-functional rating scale (IBM-FRS), quantitative muscle testing, manual muscle testing, maximal voluntary isometric contraction testing, and thigh muscle volume measured by MRI were used as primary outcome measures. Twelve different outcome measures of motor function were used in IBM clinical trials. IBM-FRS was the most used measure of functionality. Swallowing function was reported as a secondary outcome measure in only 3 RCTs. CONCLUSIONS: There are inconsistencies in using outcome measures in clinical studies in IBM. The core set measures developed by the IMACS group for other IIMs are not directly applicable to IBM. As a result, there is an unmet need for an IBM-specific core set of measures to facilitate the evaluation of new potential therapeutics for IBM.

Riociguat in patients with early diffuse cutaneous systemic sclerosis (RISE-SSc): open-label, long-term extension of a phase 2b, randomised, placebo-controlled trial.

BACKGROUND: The phase 2b Riociguat Safety and Efficacy in Patients with Diffuse Cutaneous Systemic Sclerosis (RISE-SSc) trial investigated riociguat versus placebo in early diffuse cutaneous systemic sclerosis. The long-term extension evaluated safety and exploratory treatment effects for an additional year. METHODS: Patients were enrolled to RISE-SSc between Jan 15, 2015, and Dec 8, 2016. Those who completed the 52-week, randomised, parallel-group, placebo-controlled, double-blind phase were eligible for the long-term extension. Patients originally assigned to riociguat continued therapy (riociguat-riociguat group). Those originally assigned to placebo were switched to riociguat (placebo-riociguat group), adjusted up to 2·5 mg three times daily in a 10-week, double-blind dose-adjustment phase, followed by an open-label phase. Statistical analyses were descriptive. Safety including adverse events and serious adverse events was assessed in the long-term safety analysis set (all patients randomly assigned and treated with study medication in the double-blind phase who continued study medication in the long-term extension). The RISE-SSc trial is registered with ClinicalTrials.gov, NCT02283762. FINDINGS: In total, 87 (72%) of 121 patients in the main RISE-SSc study entered the long-term extension (riociguat-riociguat, n=42; placebo-riociguat, n=45). 65 (75%) of 87 patients were women, 22 (25%) were men, and 62 (71%) were White. Overall, 82 (94%) of 87 patients in the long-term extension had an adverse event; most (66 [76%] of 87) were of mild to moderate severity, with no increase in pulmonary-related serious adverse events in patients with interstitial lung disease. INTERPRETATION: No new safety signals were observed with long-term riociguat in patients with early diffuse cutaneous systemic sclerosis. Study limitations include the absence of a comparator group in this open-label extension study. FUNDING: Bayer and Merck Sharp & Dohme.

Trial of Intravenous Immune Globulin in Dermatomyositis.

BACKGROUND: Intravenous immune globulin (IVIG) for the treatment of dermatomyositis has not been extensively evaluated. METHODS: We conducted a randomized, placebo-controlled trial involving patients with active dermatomyositis. The patients were assigned in a 1:1 ratio to receive IVIG at a dose of 2.0 g per kilogram of body weight or placebo every 4 weeks for 16 weeks. The patients who received placebo and those without confirmed clinical deterioration while receiving IVIG could enter an open-label extension phase for another 24 weeks. The primary end point was a response, defined as a Total Improvement Score (TIS) of at least 20 (indicating at least minimal improvement) at week 16 and no confirmed deterioration up to week 16. The TIS is a weighted composite score reflecting the change in a core set of six measures of myositis activity over time; scores range from 0 to 100, with higher scores indicating greater improvement. Key secondary end points included at least moderate improvement (TIS ≥40) and major improvement (TIS ≥60), and change in score on the Cutaneous Dermatomyositis Disease Area and Severity Index. RESULTS: A total of 95 patients underwent randomization: 47 patients were assigned to the IVIG group, and 48 to the placebo group. At 16 weeks, 79% of the patients in the IVIG group (37 of 47) and 44% of those in the placebo group (21 of 48) had a TIS of at least 20 (difference, 35 percentage points; 95% confidence interval, 17 to 53; P<0.001). The results with respect to the secondary end points, including at least moderate improvement and major improvement, were generally in the same direction as the results of the primary end-point analysis, except for the change in creatine kinase level (an individual core measure of the TIS), which did not differ meaningfully between the two groups. Over 40 weeks, 282 treatment-related adverse events occurred in the IVIG group, including headache (in 42% of patients), pyrexia (in 19%), and nausea (in 16%). A total of 9 serious adverse events that were considered to be related to IVIG occurred, including 6 thromboembolic events. CONCLUSIONS: In this 16-week trial involving adults with dermatomyositis, the percentage of patients with a response of at least minimal improvement based on a composite score of disease activity was significantly greater among those who received IVIG than among those who received placebo. IVIG was associated with adverse events, including thromboembolism. (Funded by Octapharma Pharmazeutika; ProDERM ClinicalTrials.gov number, NCT02728752.).

COVID-19 vaccine effectiveness against omicron (B.1.1.529) variant infection and hospitalisation in patients taking immunosuppressive medications: a retrospective cohort study.

Background: There is a scarcity of research regarding the effectiveness of the mRNA-1273 (Moderna) and BNT162b2 (Pfizer-BioNTech) COVID-19 vaccines in patients taking immunosuppressant medications, and no data are published to date pertaining to their effectiveness against omicron (B.1.1.529) variant SARS-CoV-2 infection and hospitalisation. We aimed to assess the relationship between immunosuppressive medications, mRNA vaccination, omicron infection, and severe COVID-19 outcomes (ie, hospitalisation, ICU admission, death). Methods: We did a retrospective cohort study and included vaccinated and unvaccinated people aged 18 years or older in the Michigan Medicine health-care system, USA, during the omicron-dominant period of the pandemic (Dec 16, 2021-March 4, 2022). We collected data from electronic health records (demographics, diagnoses, medications) combined with immunisation data from the Michigan State Registry to determine vaccination status, and we collected COVID-19-related hospitalisation data by chart review. We used a Cox proportional hazards model based on calendar time to assess the effectiveness of the mRNA-1273 and BNT162b2 vaccines in people taking immunosuppressive medications (conventional synthetic disease-modifying antirheumatic drugs [DMARDs], biologic DMARDs, or glucocorticoids within the past 3 months), while controlling for participant characteristics. Using the same model, we assessed the effect of different classes of medication such as immunosuppressive DMARDs, immunomodulatory DMARDs, and glucocorticoids on SARS-CoV-2 infection and hospitalisation due to COVID-19. All analyses were done using complete cases after removing participants with missing covariates. Findings: 209 492 people were identified in Michigan Medicine, including 165 913 who were vaccinated and 43 579 who were unvaccinated. 41 078 people were excluded because they were younger than 18 years, partially vaccinated, had received a vaccine other than the two vaccines studied, or had incomplete covariate data. 168 414 people were included in the analysis; 97 935 (58%) were women, 70 479 (42%) were men, and 129 816 (77%) were White. 5609 (3%) people were taking immunosuppressive medications. In patients receiving immunosuppressants, three doses of BNT162b2 had a vaccine effectiveness of 50% (95% CI 31-64; p<0·0001) and three doses of mRNA-1273 had a vaccine effectiveness of 60% (42-73; p<0·0001) against SARS-CoV-2 infection. Three doses of either vaccine had an effectiveness of 87% (95% CI 73-93; p<0·0001) against hospitalisation due to COVID-19. Receipt of immunosuppressive DMARDs (hazard ratio 2·32, 95% CI 1·23-4·38; p=0·0097) or glucocorticoids (2·93, 1·77-4·86; p<0·0001) and a history of organ or bone marrow transplantation (3·52, 2·01-6·16; p<0·0001) were associated with increased risk of hospitalisation due to COVID-19 compared with those who had not received immunosuppressive medications or transplant. Interpretation: People taking immunosuppressive DMARDs or glucocorticoids are at substantially higher risk of hospitalisation due to COVID-19 than the general population. However, the mRNA-1273 and BNT162b2 vaccines remain effective within this group, and it is important that patients taking these medications remain up to date with vaccinations to mitigate their risk. Funding: National Institute of Allergy and Infectious Diseases, National Institutes of Health.

Successful use of secukinumab in two melanoma patients with immune checkpoint inhibitor-induced inflammatory arthropathy.

Immune-related adverse events (irAEs) are a major concern when treating cancer patients with immune checkpoint inhibitor (ICI) therapy. Selecting the most appropriate management of irAEs remains an ongoing challenge because prolonged use of glucocorticoids come with their own side effects and may counteract the antineoplastic effects from immunotherapy. In this case report, we present two patients with metastatic melanoma who developed symptoms of inflammatory arthritis attributed to ICI therapy. We found that treatment with secukinumab, an anti-IL-17A inhibitor, effectively managed their symptoms and did not lead to tumor progression. Our study suggests that secukinumab can be a safe and effective treatment option for ICI-induced inflammatory arthropathy.

Immune-related adverse events (irAEs) are unwanted side effects commonly seen in cancer patients treated with immunotherapy. A frequently underreported irAE is inflammation of the joints (ankles, knees, shoulders, etc.), which is known as inflammatory arthropathy. Inflammatory arthropathy is frequently treated with steroids, but there is concern that it may counteract the anticancer effect from immunotherapy. Alternative treatments are needed to better treat this irAE without compromising the benefit of immunotherapy. In this case report, we present two patients with stage 4 melanoma who developed immunotherapy-induced inflammatory arthropathy and were successfully treated with secukinumab. We found that treating the inflammatory arthropathy was safe, effective, and did not lead to cancer progression in either patient.

Sustained and improved guselkumab response in patients with active psoriatic arthritis regardless of baseline demographic and disease characteristics: pooled results through week 52 of two phase III, randomised, placebo-controlled studies.

OBJECTIVES: To evaluate the efficacy through 52 weeks of guselkumab, an interleukin 23-p19 subunit inhibitor, in subgroups of pooled psoriatic arthritis (PsA) patients from the DISCOVER-1 and DISCOVER-2 trials defined by baseline patient characteristics. METHODS: Adults with active PsA despite standard therapies were enrolled in DISCOVER-1 (≥3 swollen and ≥3 tender joints, C reactive protein (CRP) level ≥0.3 mg/dL) and DISCOVER-2 (≥5 swollen and ≥5 tender joints, CRP ≥0.6 mg/dL, biological-naïve). Randomised patients received 100 mg guselkumab at weeks 0, 4, and then every 4 or 8 weeks (Q4W/Q8W) or placebo. Guselkumab effects on joint (ACR20/50/70), skin (IGA 0/1, IGA 0), patient-reported outcome (Health Assessment Questionnaire Disability Index/Functional Assessment of Chronic Illness Therapy-Fatigue) and disease severity (minimal disease activity/PsA Disease Activity Score low disease activity) endpoints were evaluated by patient sex, body mass index, PsA duration, swollen/tender joint counts, CRP level, percent body surface area with psoriasis, Psoriasis Area and Severity Index score, and conventional synthetic disease-modifying antirheumatic drug use at baseline. RESULTS: Baseline patients characteristics in DISCOVER-1 (N=381) and DISCOVER-2 (N=739) were well balanced across randomised groups. At week 24, 62% (232/373) and 60% (225/375), respectively, of guselkumab Q4W-treated and Q8W-treated patients pooled across DISCOVER-1 and DISCOVER-2 achieved the primary endpoint of ACR20 response versus 29% (109/372) of placebo-treated patients. Guselkumab treatment effect at week 24 was observed across patient subgroups. Within each patient subgroup, response rates across all disease domains were sustained or increased at week 52 with both guselkumab regimens. CONCLUSIONS: Guselkumab Q4W and Q8W resulted in robust and sustained improvements in PsA signs and symptoms consistently in subgroups of patients defined by diverse baseline characteristics. TRIAL REGISTRATION NUMBERS: NCT03162796, NCT03158285.

Immune Checkpoint Inhibitors and Risk of Type 1 Diabetes.

OBJECTIVE: Type 1 diabetes mellitus (T1DM) is a rare, irreversible immune-related adverse event reported in patients receiving treatment with immune checkpoint inhibitors (ICI). However, clinical risk factors for ICI-induced T1DM (ICI-T1DM) and its impact on survival in patients remain unknown. RESEARCH DESIGN AND METHODS: We used Optum's Clinformatics Data Mart database for assessment of the incidence and characteristics of T1DM in a large de-identified cohort of patients treated with ICI between 2017 and 2020. We applied Fine-Gray and cause-specific hazard models to study associations between patient/treatment characteristics and ICI-T1DM and applied the Cox model with ICI-T1DM as a time-varying covariate to assess the impact of ICI-T1DM on survival. RESULTS: ICI-T1DM was observed in 261 of 30,337 (0.86%) patients. Dual use of antibodies to cytotoxic T lymphocyte antigen 4 (CTLA-4) and programmed cell death 1 (PD-1) or programmed cell death ligand 1 (PD-L1) was associated with increasing risk of ICI-T1DM (hazard ratio [HR] 1.62; 95% CI 1.15-2.26) vs. anti-PD-L1 or anti-PD-1 alone. Younger age (HR 1.19 for every 5-year decrease; 95% CI 1.13-1.25) and preexisting non-T1DM diabetes (HR 4.48; 95% CI 3.45-5.83) were also associated with higher risk of ICI-T1DM. Conversely, prior use of immunosuppressive medications (HR 0.57; 95% CI 0.34-0.95) was associated with lower incidence of ICI-T1DM, but part of its protective effect may be due to the increased mortality rate. Development of ICI-T1DM does not seem to significantly impact patient survival. CONCLUSIONS: The risk of ICI-T1DM is associated with the type of ICI therapy, patient age, and preexisting non-T1DM diabetes. These data may help guide risk assessment and screening practices for patients during ICI therapy.

Comparative Effectiveness of Coronavirus Disease 2019 (COVID-19) Vaccines Against the Delta Variant.

BACKGROUND: There is a lack of data regarding how the Delta variant of coronavirus disease 2019 (COVID-19) has impacted the effectiveness of the BNT162b2 (Pfizer-BioNTech), mRNA-1273 (Moderna), and Ad26.COV2.S (Johnson & Johnson-Janssen) vaccines at preventing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and COVID-19 hospitalization. METHODS: We compared the effectiveness of the three vaccines during the pre- and post-Delta variant period (before and after 1 July 2021) in a large cohort of vaccinated and unvaccinated patients in the Michigan Medicine healthcare system. We assessed vaccine effectiveness (VE) using 2 analyses: an inverse propensity weighted (IPW) Kaplan-Meier (KM) analysis based on time from vaccination, and a Cox model based on calendar time with vaccination as a time-varying covariate. RESULTS: Compared to Ad26.COV2.S recipients, the risk of hospitalization for COVID-19 in the post-Delta variant period was lower for BNT162b2 recipients (hazard ratio [HR] = 0.37; 95% confidence interval [CI]: [.14-.98]; P = .05) and mRNA-1273 recipients (HR = 0.21; 95% CI: [.07-.64]; P = .006). Recipients of the mRNA-1273 vaccine had a lower risk of SARS-CoV-2 infection than Ad26.COV2.S recipients (HR = 0.6; 95% CI: [.43-.83]; P = .003) and BNT162b2 recipients (HR = 0.64; 95% CI: [.54-.76]; P < .001). After 1 July, efficacy against SARS-CoV-2 infection declined for Ad26.COV2.S recipients (VE = 76% before; VE = 49% after; P = .02), BNT162b2 recipients (VE = 87% before; VE = 52% after; P < .001), and mRNA-1273 recipients (VE = 92% before; VE = 70% after; P < .001). Waning immunity and the Delta variant contributed independently and significantly to this decline. CONCLUSIONS: Although there is a substantial decline in effectiveness, the approved COVID-19 vaccines remain effective against infection and hospitalization due to the Delta variant. The mRNA-based vaccines are more effective than the Ad26.COV2.S vaccine.

Efficacy of COVID-19 vaccines in patients taking immunosuppressants.

OBJECTIVES: We intended to assess the effectiveness of all three US Food and Drug Administration approved COVID-19 vaccines at preventing SARS-CoV-2 infection and COVID-19 hospitalisation in a large cohort of individuals on immunosuppressants for a diverse range of conditions. METHODS: We studied the effectiveness of BNT162b2 (Pfizer-BioNTech), mRNA-1273 (Moderna) and Ad26.COV2.S (Johnson & Johnson-Janssen) vaccines among individuals who take immunosuppressants (including disease-modifying antirheumatic drugs and glucocorticoids) by comparing vaccinated (n=97688) and unvaccinated (n=42094) individuals in the Michigan Medicine healthcare system from 1 January to 7 December 2021, using Cox proportional hazards modelling with time-varying covariates. RESULTS: Among vaccinated and unvaccinated individuals, taking immunosuppressants increased the risk of SARS-CoV-2 infection (adjusted HR (aHR)=2.17, 95% CI 1.69 to 2.79 for fully vaccinated and aHR=1.40, 95% CI 1.07 to 1.83 for unvaccinated). Among individuals taking immunosuppressants, we found: (1) vaccination reduced the risk of SARS-CoV-2 infection (aHR=0.55, 95% CI 0.39 to 0.78); (2) the BNT162b2 and mRNA-1273 vaccines were highly effective at reducing the risk of SARS-CoV-2 infection (n=2046, aHR=0.59, 95% CI 0.38 to 0.91 for BNT162b2; n=2064, aHR=0.52, 95% CI 0.33 to 0.82 for mRNA-1273); (3) with a smaller sample size (n=173), Ad26.COV2.S vaccine protection did not reach statistical significance (aHR=0.34, 95% CI 0.09 to 1.30, p=0.17); and (4) receiving a booster dose reduced the risk of SARS-CoV-2 infection (aHR=0.42, 95% CI 0.24 to 0.76). CONCLUSIONS: The mRNA-1273 and BNT162b2 vaccines are effective in individuals who take immunosuppressants. However, individuals who are vaccinated but on immunosuppressants are still at higher risk of SARS-CoV-2 infection and COVID-19 hospitalisation than the broader vaccinated population. Booster doses are effective and crucially important for individuals on immunosuppressants.

Detecting joint inflammation by an LED-based photoacoustic imaging system: a feasibility study (Erratum).

An error in the first author's name is corrected.

Imaging of enthesitis by an LED-based photoacoustic system (Erratum).

An error in the first author's name is corrected.

Imaging of enthesitis by an LED-based photoacoustic system.

SIGNIFICANCE: One key pathological characteristic of seronegative spondyloarthropathy (SpA) is inflammation at the insertion of tendons and ligaments into the bone (enthesitis). AIM: We explore the potential of the emerging photoacoustic (PA) imaging in diagnosis of SpA and review its feasibility in detecting SpA-associated Achilles tendon enthesitis. APPROACH: A light-emitting diode (LED)-based PA and ultrasound combined system was employed. The PA images, both along the long and the short axes of each Achilles tendon insertion region, were acquired at 850-nm wavelength, which is sensitive in depicting increased blood volume (i.e., hyperemia). To assess the hyperemia indicating enthesis inflammation, two parameters were quantified in the imaged tendons, including the average intensity and the density of the color pixels in the pseudo-color PA images. Ten SpA patients, all of which met Assessment of SpA International Society (ASAS) criteria for SpA and were found to have Achilles enthesitis by clinical exam according to a board-certified rheumatologist, were included in the study. RESULTS: The PA and Doppler ultrasound imaging of Achilles enthesitis resulting from these 10 SpA patients were compared to those from 10 healthy volunteers, leading to statistically significant differences (p < 0.05) in the applied t-tests. CONCLUSIONS: This preliminary clinical study suggests that the LED-based PA imaging holds a promise for sensitive and objective assessment of SpA enthesitis in an outpatient setting of the rheumatology clinic.

Complete Recovery from COVID-19 Bilateral Pneumonia in an Immunosuppressed Man with Immune-Mediated Necrotizing Myopathy.

Immune-mediated necrotizing myopathy (IMNM) is a rare form of idiopathic immune myopathy (IIM) that requires immunotherapies, including immunosuppressive medications, if severe. There is a paucity of data regarding outcomes of patients with immune-mediated polymyositis who continue immunosuppressive medications during the COVID-19 pandemic. This is the first reported case of COVID-19 in a patient with IMNM. Despite being on two immunotherapies, having risk factors, and having radiographic abnormalities on chest X-ray, the patient had an unremarkable COVID-19 course. He was discharged from the emergency department with a 7-day course of azithromycin and quickly resumed his immunotherapies, but he experienced a flare in his myositis. The 14-week follow-up computed tomography (CT) was negative for residual pneumonitis or fibrosis. More data are needed regarding management and prognosis of patients with connective tissue diseases who become infected with SARS-CoV-2.

Riociguat in patients with early diffuse cutaneous systemic sclerosis (RISE-SSc): randomised, double-blind, placebo-controlled multicentre trial.

OBJECTIVES: Riociguat is approved for pulmonary arterial hypertension and has antiproliferative, anti-inflammatory and antifibrotic effects in animal models of tissue fibrosis. We evaluated the efficacy and safety of riociguat in patients with early diffuse cutaneous systemic sclerosis (dcSSc) at high risk of skin fibrosis progression. METHODS: In this randomised, double-blind, placebo-controlled, phase IIb trial, adults with dcSSc of <18 months' duration and a modified Rodnan skin score (mRSS) 10-22 units received riociguat 0.5 mg to 2.5 mg orally three times daily (n=60) or placebo (n=61). The primary endpoint was change in mRSS from baseline to week 52. RESULTS: At week 52, change from baseline in mRSS units was -2.09±5.66 (n=57) with riociguat and -0.77±8.24 (n=52) with placebo (difference of least squares means -2.34 (95% CI -4.99 to 0.30; p=0.08)). In patients with interstitial lung disease, forced vital capacity declined by 2.7% with riociguat and 7.6% with placebo. At week 14, average Raynaud's condition score had improved ≥50% in 19 (41.3%)/46 patients with riociguat and 13 (26.0%)/50 patients with placebo. Safety assessments showed no new signals with riociguat and no treatment-related deaths. CONCLUSIONS: Riociguat did not significantly benefit mRSS versus placebo at the predefined p<0.05. Secondary and exploratory analyses showed potential efficacy signals that should be tested in further trials. Riociguat was well tolerated.

Utility of Coronary Calcium Scoring (CCS) in Connective Tissue Disorders (CTDs) for the Evaluation of Subclinical Coronary Atherosclerosis - A Systematic Review.

OBJECTIVE: To assess the current state of knowledge for the utility of coronary calcium scoring (CCS) in connective tissue disorders (CTDs) as it relates to the presence and quantification of coronary atherosclerosis. METHODS: Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, a literature search via PubMed, Embase, Scopus, Web of Science Core Collection, CINAHL, and Cochrane Database of Systematic Review retrieved 1019 studies (since database inception on May 7, 2018) from which 121 manuscripts were eligible for review. Inclusion criteria consisted of studies that investigated CCS in adults with respective CTDs. Studies were excluded if a complete manuscript was not written in English or was a case report. RESULTS: Thirty-one studies were included (27 with healthy age-/gender-matched control group for comparison and 4 without). CTDs analyzed in articles with control group: 11 rheumatoid arthritis (RA), 14 systemic lupus erythematosus (SLE), 4 systemic sclerosis (SSc), 1 idiopathic inflammatory myopathies (IIM), 1 Takayasu arteritis, and 1 psoriasis. Nine out of 11 RA studies, 12 out of 14 SLE studies, and 2 out of 4 SSc studies showed statistically significant increased CCS when compared with the control group. CTDs analyzed in studies without control group: two Kawasaki disease, one juvenile idiopathic arthritis (JIA), and one antiphospholipid syndrome (APS) article, which demonstrated increased coronary arterial calcium burden, however, without statistically significant data. CONCLUSION: CTDs, especially SLE and RA, are associated with higher CCS compared with the control group, indicating increased risk of coronary atherosclerosis. Our search did not elicit sufficient publications or statistically significant results in many other CTDs.