Tixagevimab/cilgavimab for the prevention of COVID-19 in vaccine-refractory patients with autoimmune diseases: a prospective cohort study.

OBJECTIVES: To investigate the effects of passive immunization with the anti-SARS-CoV-2 monoclonal antibodies tixagevimab/cilgavimab on humoral responses and on COVID-19 outcomes in vaccine-refractory patients with immune-mediated inflammatory diseases (IMID) at high risk of severe COVID-19. METHODS: A prospective cohort study was performed on a cohort of high-risk vaccine-refractory IMID patients treated with a single dose of tixagevimab/cilgavimab (150 mg/150 mg). COVID-19 outcomes as well as serum and salivary anti-SARS-CoV-2 IgG were assessed at baseline and for at least 6 months. Results were compared with an untreated high-risk vaccine-refractory IMID population. Standardised incidence ratios (SIR) of COVID-19 compared with the general population were calculated for both groups. RESULTS: 38 high-risk IMID patients received tixagevimab/cilgavimab and were compared with 114 untreated high-risk IMID controls. Serum anti-Spike IgG increased to 6.6 OD (SD: ±0.8) at day one and remained positive up to month 6 (6.3 ± 1.4 OD). Salivary anti-Spike IgG peaked at month 2 (1.6 ± 1.1 OD)) and decreased from month 3 (0.8 ± 0.3 OD)). No severe or extended infection was observed in the tixagevimab/cilgavimab group. Compared with the general population, the SIR of COVID-19 in treated patients was 0.76 (95% CI: 0.24-1.58) despite the increased risk profile. The SIR of the control group was 1.51 (1.07-2.02), corresponding to a significantly increased incidence. CONCLUSIONS: Passive immunization with tixagevimab/cilgavimab is safe and effective in inducing anti-SARS-CoV-2 immunity and potentially in preventing COVID-19 in high-risk vaccine-refractory IMID patients. These data provide a proof of concept for the use of monoclonal antibodies as a preventative strategy against SARS-CoV-2 in vulnerable populations.

Tocilizumab treatment in severe COVID-19: a multicenter retrospective study with matched controls.

Coronavirus disease-2019 (COVID-19) associated pneumonia may progress into acute respiratory distress syndrome (ARDS). Some patients develop features of macrophage activation syndrome (MAS). Elevated levels of IL-6 were reported to be associated with severe disease, and anti-IL-6R tocilizumab has been shown to be effective in some patients. This retrospective multicenter case-control study aimed to evaluate the efficacy of tocilizumab in hospitalized COVID-19 patients, who received standard of care with or without tocilizumab. Primary outcome was the progression to intubation or death. PSMATCH (SAS) procedure was used to achieve exact propensity score (PS) matching. Data from 1289 patients were collected, and study population was reduced to 1073 based on inclusion-exclusion criteria. The composite outcome was observed more frequently in tocilizumab-users, but there was a significant imbalance between arms in all critical parameters. Primary analyses were carried out in 348 patients (174 in each arm) after exact PS matching according to gender, ferritin, and procalcitonin. Logistic regression models revealed that tocilizumab significantly reduced the intubation or death (OR 0.40, p = 0.0017). When intubation is considered alone, tocilizumab-users had > 60% reduction in odds of intubation. Multiple imputation approach, which increased the size of the matched patients up to 506, provided no significant difference between arms despite a similar trend for intubation alone group. Analysis of this retrospective cohort showed more frequent intubation or death in tocilizumab-users, but PS-matched analyses revealed significant results for supporting tocilizumab use overall in a subset of patients matched according to gender, ferritin and procalcitonin levels.

Anatomical pattern of entheseal and synovial fibroblast activation in patients with psoriasis and its risk of developing psoriatic arthritis.

OBJECTIVES: To assess the presence and anatomical distribution of activated fibroblasts in the joints and entheses of patients with psoriasis with arthralgia and to test how fibroblast activation visualised by 68gallium-labelled fibroblast activation protein inhibitor-04 (68Ga-FAPI-04)-positron emission tomography (PET)/CT correlates with clinical tenderness, musculoskeletal ultrasound findings and progression to psoriatic arthritis (PsA). METHODS: We conducted a prospective cohort study in patients with psoriasis and arthralgia who underwent clinical and ultrasound evaluation and whole-body PET/CT imaging with 68Ga-FAPI-04. 68Ga-FAPI-04 uptake at synovial and entheseal sites was assessed by maximal standardised uptake values (SUVmax) and PET/CT Joint Index (JI); logistic regression models were used to investigate its correlation with clinical and ultrasound findings. Survival analyses were performed on patients with at least 6 months of follow-up. RESULTS: 36 patients with psoriasis were enrolled. 68Ga-FAPI-04 uptake was found in 318 (7.9%) joints and 369 (7.3%) entheses in 29 (80.6%) participants, with a mean SUVmax (SD) of 3.2 (1.8) for joints and 2.9 (1.6) for entheses. Large joints and the lower limbs were predominantly affected. A significant positive relationship was found between 68Ga-FAPI-04-PET/CT signal intensity and the 68 tender joint count (SUVmax: p<0.001; PET/CT-JI: p<0.001) and tender entheses count (SUVmax: p<0.001; PET/CT-JI: p=0.002). No correlations were found with ultrasound findings (SUVmax: p=0.969; PET/CT-JI: p=0.720). Patients with relevant synovio-entheseal 68Ga-FAPI-04 uptake showed a statistically significant higher risk of developing PsA (p=0.02), independent of ultrasound findings. CONCLUSIONS: Patients with psoriasis presenting with arthralgia show localised signs of resident tissue activation in joints and entheses, which are associated with higher risk of developing PsA.

Deep learning-based classification of erosion, synovitis and osteitis in hand MRI of patients with inflammatory arthritis.

OBJECTIVES: To train, test and validate the performance of a convolutional neural network (CNN)-based approach for the automated assessment of bone erosions, osteitis and synovitis in hand MRI of patients with inflammatory arthritis. METHODS: Hand MRIs (coronal T1-weighted, T2-weighted fat-suppressed, T1-weighted fat-suppressed contrast-enhanced) of rheumatoid arthritis (RA) and psoriatic arthritis (PsA) patients from the rheumatology department of the Erlangen University Hospital were assessed by two expert rheumatologists using the Outcome Measures in Rheumatology-validated RA MRI Scoring System and PsA MRI Scoring System scores and were used to train, validate and test CNNs to automatically score erosions, osteitis and synovitis. Scoring performance was compared with human annotations in terms of macro-area under the receiver operating characteristic curve (AUC) and balanced accuracy using fivefold cross-validation. Validation was performed on an independent dataset of MRIs from a second patient cohort. RESULTS: In total, 211 MRIs from 112 patients (14 906 region of interests (ROIs)) were included for training/internal validation using cross-validation and 220 MRIs from 75 patients (11 040 ROIs) for external validation of the networks. The networks achieved high mean (SD) macro-AUC of 92%±1% for erosions, 91%±2% for osteitis and 85%±2% for synovitis. Compared with human annotation, CNNs achieved a high mean Spearman correlation for erosions (90±2%), osteitis (78±8%) and synovitis (69±7%), which remained consistent in the validation dataset. CONCLUSIONS: We developed a CNN-based automated scoring system that allowed a rapid grading of erosions, osteitis and synovitis with good diagnostic accuracy and using less MRI sequences compared with conventional scoring. This CNN-based approach may help develop standardised cost-efficient and time-efficient assessments of hand MRIs for patients with arthritis.

Rationale, current state and opportunities in combining biologic disease modifying antirheumatic drugs in rheumatoid and psoriatic arthritis.

The advent of biologic disease modifying antirheumatic drugs (bDMARDs) has considerably improved patient outcomes in inflammatory arthritis. However, not all patients reach the state of remission, as disease can be resistant even to single cytokine inhibition by bDMARDs. Simultaneous or sequential inhibition of multiple cytokines may be considered in situations where disease control is not adequate under singular inhibition of cytokines. Although there have been some disappointing experiences in the past with combination of bDMARDs, the ongoing improvement of our understanding about inflammatory pathways and the overall better safety understanding of bDMARDs seem to make new biologic treatment combinations possible. This review covers the rationale and current evidence for bDMARDs combination in inflammatory arthritis.

Tolerability of low to moderate biomechanical stress during leisure sport activity in patients with psoriasis and psoriatic arthritis.

OBJECTIVES: To assess the impact of low to moderate biomechanical stress on entheses in patients with psoriasis and psoriatic arthritis (PsA). METHODS: We conducted a prospective interventional study on a cohort of psoriasis and PsA patients who underwent a 60 min badminton training session. Pain assessment by Visual Analogue Scale (VAS), physical examination of 29 entheses (SPARCC, LEI, MASES) and bilateral ultrasound at the lateral humeral epicondyle, inferior patellar pole and Achilles tendon were performed before and after training. Ultrasound changes were assessed using the OMERACT scoring system. A follow-up assessment of pain and adverse events was performed at 1 week. RESULTS: Sixteen patients were included (n=7 PsA; n=9 psoriasis) and 196 entheseal ultrasound scans were acquired. At baseline, median VAS pain (IQR) was 0.5 cm (0-2.3) and the total number of tender entheses was 12/464. Mean (min; max) Disease Activity Index for Psoriatic Arthritis was 6.1 (0.8; 19) and 5/7 PsA patients had an Minimal Disease Activity status. After training, no significant change in VAS pain (0.0 cm (0.0-2.0)) nor in tender entheses (13/464) emerged. Four patients (n=2 PsA, n=2 psoriasis) developed a grade-1 power Doppler-signal at six entheses, which, however, remained non-tender. At 1 week, median VAS pain remained stable (0.0 cm (0.0-3.0); p>0.05) and only one participant with active PsA at baseline reported increased arthralgias in three joints. CONCLUSIONS: Low to moderate physical strain, as in the context of leisure sport activity, seems well tolerated in psoriatic patients without increases in tenderness, pain and ultrasound-proven inflammation. Evidence-based recommendations for physical activity in PsA are direly needed and larger controlled studies should be conducted to define safe exercise thresholds.

Baricitinib Improves Bone Properties and Biomechanics in Patients With Rheumatoid Arthritis: Results of the Prospective Interventional BARE BONE Trial.

OBJECTIVE: Rheumatoid arthritis (RA) is characterized by erosive joint damage, deterioration of bone mass, and biomechanics. Preclinical evidence suggests a beneficial effect of Janus kinase inhibition (JAKi) on bone properties, but clinical data are scarce to date. In this study, we evaluated the effect of JAKi through baricitinib (BARI) on 1) volumetric bone mineral density (vBMD), bone microstructure, biomechanics, and erosion repair and 2) synovial inflammation in RA patients. METHODS: Prospective, single-arm, interventional, open-label, single-center phase 4 study in RA patients with pathological bone status and clinical indication of JAKi (BARE BONE trial). Participants received BARI (4 mg/day) over 52 weeks. To assess bone properties and synovial inflammation, high-resolution computed tomography scans and magnetic resonance imaging were performed at baseline (BL), week 24, and week 52. Clinical response and safety were monitored. RESULTS: Thirty RA patients were included. BARI significantly improved disease activity (Disease Activity Score in 28 joints using the erythrocyte sedimentation rate: 4.82 ± 0.90 to 2.71 ± 0.83) and synovial inflammation (RAMRIS synovitis score: 5.3 [4.2] to 2.7 [3.5]). We observed a significant improvement in trabecular vBMD with a mean change of 6.11 mgHA/mm3 (95% confidence interval [95% CI] 0.01-12.26). Biomechanical properties also improved with mean change from baseline in estimated stiffness of 2.28 kN/mm (95% CI 0.30-4.25) and estimated failure load of 98.8 N (95% CI 15.9-181.7). The number and size of erosions in the metacarpal joints remained stable. No new safety signals with BARI treatment were observed. CONCLUSION: Bones of RA patients improve with BARI therapy, as shown by an increase in trabecular bone mass and an improvement of biomechanical properties.

A case of palmoplantar pustular psoriasis induced by hydroxychloroquine in a patient with systemic lupus erythematosus.

Palmoplantar pustular psoriasis (PPP) is a rare clinical form of psoriasis. It is usually seen on the palms and soles, and affects patients' quality of life. In most cases, topical or systemic treatments are not sufficiently effective, so management of PPP is generally difficult. Hydroxychloroquine (HQ) is an antimalarial drug that is widely used in many autoimmune rheumatic diseases, mainly in systemic lupus erythematosus (SLE). Several reports describe the induction and exacerbation of psoriasis by HQ. Within this report, we aimed to put emphasis on considering possible drug effects by presenting a case of PPP, induced by HQ.

Intensity and longevity of SARS-CoV-2 vaccination response in patients with immune-mediated inflammatory disease: a prospective cohort study.

Background: Concerns have been raised about the reduced immunogenicity of vaccines against SARS-CoV-2 in patients with immune-mediated inflammatory diseases and the higher risk of breakthrough infections. The objective of our study was to investigate the intensity and longevity of SARS-CoV-2 vaccination responses in patients with immune-mediated inflammatory diseases, and to assess the effects of diagnosis, treatment, and adapted vaccination schedules. Methods: SARS-CoV-2 IgG antibody response after SARS-CoV-2 vaccination was measured over time in a large prospective cohort of healthy controls and participants with immune-mediated inflammatory diseases (attending or admitted to affiliated centres) between Dec 15, 2020, and Dec 1, 2021. Cohort participants with immune-mediated inflammatory diseases and control participants with no diagnosis of immune-mediated inflammatory diseases, were eligible for this analysis. Demographic data and disease-specific data were collected using a questionnaire. Humoral response was compared across treatment and disease groups, and with respect to the receipt of additional vaccinations. SARS-CoV-2 antibody response was measured by ELISA using optical density ratio units and modelled over time with age and sex adjustment using mixed-effects models. Using these models, marginal mean antibody titres and marginal risks of a poor response (optical density ratio <1·1) were calculated for each week starting from week 8 after the first vaccination to week 40. Findings: Among 5076 individuals registered, 2535 participants with immune-mediated inflammatory diseases (mean age 55·0 [15·2] years; 1494 [58·9%] women and 1041 [41·1%] men) and 1198 healthy controls (mean age 40·7 [13·5] years; 554 [46·2%] women and 644 [53·8%] men) were included in this analysis. Mean antibody titres were higher in healthy controls compared with people with immune-mediated inflammatory diseases at all timepoints, with a peak antibody response in healthy controls (mean optical density ratio 12·48; 95% CI 11·50-13·53) of more than twice that in participants with immune-mediated inflammatory diseases (5·50; 5·23-5·77; mean difference 6·98; 5·92-8·04). A poor response to vaccination was observed in participants with immune-mediated inflammatory diseases who were taking B-cell inhibitors (peak mean difference from healthy controls 11·68; 10·07-13·29) and T-cell inhibitors (peakmean difference from healthy controls 10·43; 8·33-12·53). Mean differences in antibody responses between different immune-mediated inflammatory diseases were small. Participants with immune-mediated inflammatory diseases who were given a third vaccine dose had higher mean antibody titres than did healthy controls vaccinated with two vaccine doses at 40 weeks after the initial vaccination (mean difference 1·34; 0·01-2·69). Interpretation: People with immune-mediated inflammatory diseases show a lower and less durable SARS-CoV-2 vaccination response and are at risk of losing humoral immune protection. Adjusted vaccination schedules with earlier booster doses or more frequent re-doses, or both, could better protect people with immune-mediated inflammatory diseases. Funding: Deutsche Forschungsgemeinschaft, Bundesministerium für Bildung und Forschung, European Research Council, Innovative Medicine Initiative, Friedrich-Alexander-Universität Erlangen-Nürnberg, Else Kröner-Memorial Foundation.

ANCA Associated Vasculitis and Related Pulmonary Alveolar Hemorrhage in a Patient with Pulmonary Alveolar Proteinosis.

ABSTRACT: Pulmonary Alveolar Proteinosis (PAP) is a rare lung disease characterized by accumulation of a lipoproteinous material in the alveoli and distal airways. Antibodies against granulocyte macropha-ge colony stimulant factor (GM-CSF) are thought to be responsible for its pathogenesis. Antineutrophilic cytoplasmic antibody (ANCA) associated vasculitis (AAV) is a group of vasculitis affecting small and medium vessels and often characterized by lung and kidney involvement. Here, we present a patient with PAP diagnosis who has been in remission for many years, developing AAV and associated pulmonary alveolar hemorrhage. Pulmonary Alveolar Proteinosis (PAP) is a rare lung disease characterized by accumulation of a lipoproteinous material in the alveoli and distal airways. Antibodies against granulocyte macropha-ge colony stimulant factor (GM-CSF) are thought to be responsible for its pathogenesis. Antineutrophilic cytoplasmic antibody (ANCA) associated vasculitis (AAV) is a group of vasculitis affecting small and medium vessels and often characterized by lung and kidney involvement. Here, we present a patient with PAP diagnosis who has been in remission for many years, developing AAV and associated pulmonary alveolar hemorrhage.

A practical approach for vaccinations including COVID-19 in autoimmune/autoinflammatory rheumatic diseases: a non-systematic review.

The COVID-19 pandemic has occupied the world agenda since December 2019. With no effective treatment yet, vaccination seems to be the most effective method of prevention. Recently developed vaccines have been approved for emergency use only and are currently applied to large populations. Considering both the underlying pathogenic mechanisms of autoimmune/autoinflammatory rheumatological diseases (AIIRDs) and the immunosuppressive drugs used in treatment, vaccination for COVID-19 deserves special attention in such patients. In this article, we aimed to give simple messages to the clinicians for COVID-19 vaccination in patients with AIIRDs based upon the current evidence regarding the use of other vaccines in this patient group. For this purpose, we conducted a "Pubmed search" using the following keywords: Influenza, Hepatitis B, Pneumococcal, and Shingles vaccines and the frequently used conventional and biologic disease-modifying antirheumatic drugs (DMARDs). Likewise, an additional search was performed for the COVID-19 immunization in patients with AIIRDs and considering such drugs. In summary, patients with AIIRDs should also be vaccinated against COVID-19, preferably when disease activity is under control and when there is no concurrent infection. Low-degree immunosuppression does not appear to decrease antibody responses to vaccines. Ideally, vaccinations should be done before the initiation of any biological DMARDs. Patients receiving rituximab should be vaccinated at least 4 weeks before or 6 months after treatment. Since tofacitinib may also reduce antibody responses, especially in combination with methotrexate, it may be appropriate to discontinue this drug before vaccination and to restart after 14 days of immunization. Key points • COVID-19 vaccinations should preferably be made during remission in patients with autoimmune/autoinflammatory rheumatological diseases. • Low-degree immunosuppression may not interfere with antibody response to vaccines. • Ideally, vaccinations should be made before the initiation of any biological DMARDs. • Timing of vaccination is especially important in the case of rituximab.