Tofacitinib treatment in anti-glycyl-tRNA synthetase antibody interstitial lung disease - A case report.

Anti-aminoacyl-transfer-RNA synthetase syndrome (ASS) related interstitial lung disease (ILD) is rarely presented initially alongside acute respiratory distress syndrome (ARDS), which in and of itself is a severe condition with a high mortality rate. Additionally, rapidly progressive change is not a common feature in ASS. Numerous case reports have described the efficacy which tofacitinib has on rapidly progressive ILD (RP-ILD). However, none have mentioned the use of tofacitinib in patients with impaired renal function. Herein, a case of ASS involving ILD is reported with the initial presentation of RP-ILD to ARDS being complicated by acute renal failure with an initial complete response to tofacitinib. Patients experiencing unexplained rapidly progressive interstitial pneumonia should be examined thoroughly for the diagnosis of ASS. Furthermore, tofacitinib can also be considered as a choice of treatment even in patients with impaired renal function.

Are Interstitial Lung Abnormalities a Prognostic Factor of Worse Outcome in COVID-19 Pneumonia?

PURPOSE: To assess the association between interstitial lung abnormalities (ILAs) and worse outcome in patients affected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) disease (COVID-19)-related pneumonia. MATERIALS AND METHODS: The study included patients older than 18 years, who were admitted at the emergency department between February 29 and April 30, 2020 with findings of COVID-19 pneumonia at chest computed tomography (CT), with positive reverse-transcription polymerase chain reaction nasal-pharyngeal swab for SARS-CoV-2, and with the availability of prepandemic chest CT. Prepandemic CTs were reviewed for the presence of ILAs, categorized as fibrotic in cases with associated architectural distortion, bronchiectasis, or honeycombing. Worse outcome was defined as intensive care unit (ICU) admission or death. Cox proportional hazards regression analysis was used to test the association between ICU admission/death and preexisting ILAs. RESULTS: The study included 147 patients (median age 73 y old; 95% CIs: 71-76-y old; 29% females). On prepandemic CTs, ILA were identified in 33/147 (22%) of the patients, 63% of which were fibrotic ILAs. Fibrotic ILAs were associated with higher risk of ICU admission or death in patients with COVID-19 pneumonia (hazard ratios: 2.73, 95% CIs: 1.50-4.97, P =0.001). CONCLUSIONS: In patients affected by COVID-19 pneumonia, preexisting fibrotic ILAs were an independent predictor of worse prognosis, with a 2.7 times increased risk of ICU admission or death. Chest CT scans obtained before the diagnosis of COVID-19 pneumonia should be carefully reviewed for the presence and characterization of ILAs.

Post-COVID interstitial lung disease in symptomatic patients after COVID-19 disease.

COVID-19 is often associated with long-lasting pulmonary symptoms. Data are scarce about interstitial lung disease (ILD) in patients following COVID-19 hospitalization with persistent symptoms. We retrospectively reviewed all cases sent to pulmonary post-COVID evaluation due to persistent symptoms between February 2021 and February 2022 (N = 318). All patients with suspected ILD (N = 44) were reviewed at the multidisciplinary discussion. Patient characteristics, symptoms, time since hospitalization, detailed lung function measurements and 6-min walk test (6MWT) were evaluated. The post-COVID ILD suspected group included more men (68.2 vs. 31.8%) with significantly older age compared to the control group (64.0 ± 12.3 vs. 51.3 ± 14.9 years). Most patient needed hospital care for COVID-19 pneumonia (68.6% of all patients and 84.1% of ILD suspected group) and average time since hospitalization was 2.4 ± 2.3 months. Persisting symptoms included fatigue (34%), dyspnoea (25.2%), cough (22.6%), and sleep disorders (insomnia 13.2%; sleepiness 8.2%). Post-COVID ILD presented more often with new symptoms of cough and sleepiness. Functional impairment, especially decreased walking distance and desaturation during 6-min walk test (6MWT) were detected in the ILD-suspected group. Respiratory function test in the post-COVID ILD group showed slight restrictive ventilatory pattern (FVC: 76.7 ± 18.1%, FEV1: 83.5 ± 19.1%, TLC: 85.6 ± 28.1%) and desaturation during 6MWT were detected in 41% of patients. LDCT changes were mainly ground glass opacities (GGO) and/or reticular abnormalities in most cases affecting < 10% of the lungs. Our data indicate that suspected post-COVID ILD is affecting 13.8% of symptomatic patients. High resolution chest CT changes were mainly low extent GGO/reticulation, while long-term lung structural changes need further evaluation.

Impact of COVID-19 pneumonia on interstitial lung disease: semi-quantitative evaluation with computed tomography.

OBJECTIVES: To evaluate the CT scores and fibrotic pattern changes in interstitial lung disease (ILD) patients, with and without previous COVID-19 pneumonia. METHODS: Patients with ILD (idiopathic pulmonary fibrosis (IPF) and connective tissue disease-associated ILD (CTD-ILD)) were retrospectively enrolled in the study which consisted of patients who had COVID-19 pneumonia while the control group had not. All patients had two CT scans, initial and follow-up, which were evaluated semi-quantitatively for severity, extent, and total CT scores, fibrosis patterns, and traction bronchiectasis. RESULTS: A total of 102 patients (pneumonia group n = 48; control group n = 54) were enrolled in the study. For both groups, baseline characteristics were similar and CT scores were increased. While there was a 4.5 ± 4.6 point change in the total CT score of the COVID-19 group, there was a 1.2 ± 2.7 point change in the control group (p < 0.001). In the IPF subgroup, the change in total CT score was 7.0 points (95% CI: 4.1 to 9.9) in the COVID-19 group and 2.1 points (95% CI: 0.8 to 3.4) in the control group. Seven patients (14.6%) in the COVID-19 group progressed to a higher fibrosis pattern, but none in the control group. CONCLUSIONS: Semi-quantitative chest CT scores in ILD patients demonstrated a significant increase after having COVID-19 pneumonia compared to ILD patients who had not had COVID-19 pneumonia. The increase in CT scores was more prominent in the IPF subgroup. There was also a worsening in the fibrosis pattern in the COVID-19 group. KEY POINTS: • The impact of COVID-19 pneumonia on existing interstitial lung diseases and fibrosis is unclear. • COVID-19 pneumonia may worsen existing interstitial lung involvement with direct lung damage and indirect inflammatory effect. • COVID-19 pneumonia may affect existing lung fibrosis by triggering inflammatory pathways.

COVID-19 Pneumonia Followed by Anti-signal Recognition Particle Antibody-positive Fibrosing Interstitial Lung Disease.

Coronavirus disease 2019 (COVID-19) pneumonia is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and is frequently accompanied by various sequelae. Interstitial lung diseases (ILDs) are observed in COVID-19 pneumonia patients after recovery, probably due to persistent inflammation in the lungs. We herein report a case of ILD with anti-signal recognition particle antibodies following severe COVID-19 pneumonia. The patient was diagnosed with ILD three months after COVID-19 pneumonia. Although the exact mechanism is unknown, the autoantibody-induced immune response might have been the pulmonary fibrosis trigger in this patient.

Roles of biomarkers in anti-MDA5-positive dermatomyositis, associated interstitial lung disease, and rapidly progressive interstitial lung disease.

BACKGROUND: Anti-melanoma differentiation-associated gene 5 (MDA5)-positive dermatomyositis (MDA5+ DM) is significantly associated with interstitial lung disease (ILD), especially rapidly progressive ILD (RPILD) due to poor prognosis, resulting in high mortality rates. However, the pathogenic mechanism of MDA5+ DM-RPILD is unclear. Although some MDA5+ DM patients have a chronic course of ILD, many do not develop RPILD. Therefore, the related biomarkers for the early diagnosis, disease activity monitoring, and prediction of the outcome of RPILD in MDA5+ DM patients should be identified. Blood-based biomarkers are minimally invasive and can be easily detected. METHODS: Recent relative studies related to blood biomarkers in PubMed were reviewed. RESULTS: An increasing number of studies have demonstrated that dysregulated expression of blood biomarkers related to ILD such as ferritin, Krebs von den Lungen-6 (KL-6), surfactant protein-D (SP-D), and cytokines, and some tumor markers in MDA5+ DM may provide information in disease presence, activity, treatment response, and prognosis. These studies have highlighted the great potentials of blood biomarker values for MDA5+ DM-ILD and MDA5+ DM-RPILD. This review provides an overview of recent studies related to blood biomarkers, besides highlighted protein biomarkers, including antibody (anti-MDA5 IgG subclasses and anti-Ro52 antibody), genetic (exosomal microRNAs and neutrophil extracellular traps related to cell-free DNA), and immune cellular biomarkers in MDA5+ DM, MDA5+ DM-ILD, and MDA5+ DM-RPILD patients, hopefully elucidating the pathogenesis of MDA5+ DM-ILD and providing information on the early diagnosis, disease activity monitoring, and prediction of the outcome of the ILD, especially RPILD. CONCLUSIONS: Therefore, this review may provide insight to guide treatment decisions for MDA5+ DM-RPILD patients and improve outcomes.

Pneumocystis jirovecii Pneumonia Associated with COVID-19 in Patients with Interstitial Pneumonia.

Here, we report two cases of patients with interstitial pneumonia (IP) on steroids who developed Pneumocystis jirovecii pneumonia (PJP) following coronavirus disease 2019 (COVID-19) infection. Case 1: A 69-year-old man on 10 mg of prednisolone (PSL) daily for IP developed new pneumonia shortly after his COVID-19 infection improved and was diagnosed with PJP based on chest computed tomography (CT) findings and elevated serum ß-D-glucan levels. Trimethoprim-sulfamethoxazole (TMP-SMZ) was administered, and the pneumonia resolved. Case 2: A 70-year-old woman taking 4 mg/day of PSL for IP and rheumatoid arthritis developed COVID-19 pneumonia, which resolved mildly, but her pneumonia flared up and was diagnosed as PJP based on CT findings, elevated ß-D-glucan levels, and positive polymerase chain reaction for P. jirovecii DNA in the sputum. The autopsy revealed diffuse alveolar damage, increased collagen fiver and fibrotic foci, mucinous component accumulation, and the presence of a P. jirovecii cyst. In conclusion, steroids and immunosuppressive medications are well-known risk factors for PJP. Patients with IP who have been taking these drugs for a long time are frequently treated with additional steroids for COVID-19; thus, PJP complications should be avoided in such cases.

Antimelanoma Differentiation-Associated Gene 5 Antibody-Positive Interstitial Lung Disease After Vaccination With COVID-19 mRNA Vaccines.

OBJECTIVE: Melanoma differentiation-associated gene 5 (MDA5) is a viral RNA sensor induced by SARS-CoV-2. Similarities have been reported between the clinical presentations of coronavirus disease 2019 (COVID-19) pneumonia and anti-MDA5 antibody-positive interstitial lung disease (anti-MDA5-ILD). However, it is unknown whether COVID-19 mRNA vaccines are associated with anti-MDA5-ILD. METHODS: We retrospectively reviewed consecutive patients with anti-MDA5-ILD admitted to our hospital between April 2017 and March 2022. In addition, we investigated the clinical presentations of patients who developed anti-MDA5-ILD after vaccination with COVID-19 mRNA vaccines. We also examined the annual number of anti-MDA5-ILD cases before and after the COVID-19 vaccination campaign. RESULTS: Nine patients with anti-MDA5-ILD were seen during the study period, of whom 4 developed anti-MDA5-ILD between August and October 2021, approximately 6 to 12 weeks after vaccination with a COVID-19 mRNA vaccine and a few months after the rapid mRNA COVID-19 vaccination campaign in Japan. None of the 4 patients had evidence of SARS-CoV-2 infection. The difference in the annual number of anti-MDA5-ILD cases before vs after the COVID-19 vaccination campaign (1.25 ± 0.96 cases/yr vs 4.0 cases/yr) was not statistically significant (P = 0.08). CONCLUSION: We encountered 4 cases of anti-MDA5-ILD after COVID-19 vaccination. Further large population studies are needed to clarify the relationship between anti-MDA5-ILD and vaccination with COVID-19 mRNA vaccines.

Rapidly Progressive Interstitial Lung Disease Associated with Melanoma Differentiation-Associated Gene 5 Antibody.

Anti-melanoma differentiation-associated gene-5 (MDA-5) antibody is an autoantibody found in patients with dermatomyositis. These antibody-positive patients are clinically characterized by complications of rapidly progressive interstitial pneumonia resistant to treatment and with poor prognosis. We describe herein a patient with MDA-5 antibody-positive interstitial lung disease, which progressed rapidly to death after a period of slow progress. Recently, attention has been paid to the similarities in clinical courses and CT images between MDA-5 antibody-positive interstitial lung disease and coronavirus disease 2019 (COVID-19)-associated pneumonia. Patients with MDA-5 antibody do not always have diffuse and evenly distributed bilateral opacities at the time of first presentation. This patient had significant laterality of such opacities. It should be considered that MDA-5 antibody-positive patients with such laterality in opacities might progress rapidly. Chest physicians, dermatologists, and dermatologists need to be aware of the characteristics of the disease for optimal treatment choices.

Pregnancy Considerations for Patients With Interstitial Lung Disease.

Advances in our understanding of interstitial lung disease (ILD) pathophysiology and natural history have led to the development of guidelines for the diagnosis and management of several of these complex diseases. The demographics of patients with ILD indicate the disease is not restricted to older adults. Connective tissue disease-associated ILD, familial pulmonary fibrosis, and post-COVID-19 fibrosis may affect women of child-bearing age. Recent trials have excluded pregnant women, thereby limiting the applicability of contemporary therapeutic advances to these patients. This review synthesizes the current knowledge of pregnancy outcomes in those with ILD, with a focus on connective tissue disease-associated ILD, and potential treatment implications for patients with ILD who are pregnant or considering pregnancy. Pregnancy considerations for patients with ILD include the need for preconception counseling and planning to ensure disease stability, medication and vaccination optimization, and multidisciplinary involvement of a patient's pulmonologist, obstetrician, and, when indicated, rheumatologist and genetic counselor. Evidence to date suggests that women with ILD can have safe and healthy pregnancies but that complications may occur in those with severe ILD.

Multidisciplinary clinical guidance on trastuzumab deruxtecan (T-DXd)-related interstitial lung disease/pneumonitis-Focus on proactive monitoring, diagnosis, and management.

Trastuzumab deruxtecan (T-DXd; DS-8201) is an antibody-drug conjugate targeting human epidermal growth factor receptor 2. Interstitial lung disease (ILD)/pneumonitis is an adverse event associated with T-DXd; in most cases, it is low grade (grade ≤ 2) and can be treated effectively but may develop to be fatal in some instances. It is important to increase patient and provider understanding of T-DXd-related ILD/pneumonitis to improve patient outcomes. Drug-related ILD/pneumonitis is a diagnosis of exclusion; other possible causes of lung injury/imaging findings must be ruled out for an accurate diagnosis. Symptoms can be nonspecific, and identifying early symptoms is challenging; therefore, diagnosis is often delayed. We reviewed characteristics of patients who developed T-DXd-related ILD/pneumonitis and its patterns, produced multidisciplinary guidelines on diagnosis and management, and described areas for future investigation. Ongoing studies are collecting data on T-DXd-related ILD/pneumonitis to further our understanding of its clinical patterns and mechanisms. SEARCH STRATEGY AND SELECTION CRITERIA: References were identified based on the guidelines used by the authors in treating interstitial lung disease and pneumonitis. Searches of the authors' own files were also completed. A search of PubMed with the search terms (trastuzumab deruxtecan) AND (interstitial lung disease) AND (guidelines) was conducted on November 1, 2021, with no restrictions based on publication date, and the two articles yielded by the search were included.

COVID-19 outcomes in patients with Dermatomyositis: A registry-based cohort analysis.

BACKGROUND: Patients with rheumatic diseases (RDs) like DM are known to be vulnerable towards various types of infections due to aggressive disease activity mandating high dose immunosuppressive therapy. The severity of COVID-19 in RDs is limited in literature due to the heterogeneous nature of the condition. Therefore, specific details on mortality is essential to navigate any precautions required in the treatment. OBJECTIVES: To determine outcomes of COVID-19 in DM as compared to controls, and identify the risk association of gender, race, interstitial lung disease, neoplasms, and use of immunosuppressant. METHODS: Retrospective data of individuals with DM and COVID-19 and the general population with COVID-19 between January 2020 to August 2021 was retrieved from the TriNetX database. 1:1 Propensity Score matching was used to adjust for confounders. We assessed COVID-19 outcomes such as mortality, hospitalisation, ICU admission, severe COVID-19, mechanical ventilation (MV), acute kidney injury (AKI), venous thromboembolism (VTE), ischemic stroke, acute respiratory distress syndrome (ARDS), renal replacement therapy (RRT) and sepsis. Subgroup analyses included gender, race, ILD, cancer patients, disease-modifying rheumatic drugs (DMARDs) use, and glucocorticoids (GC) use. RESULTS: We identified 5,574 DM patients with COVID-19, and 5,574 general population with COVID-19 (controls). DM with COVID-19 had a lower risk of mortality in comparison to controls [RR 0.76], hospitalisation [RR 0.8], severe COVID-19 [RR 0.76], AKI [RR 0.83], and sepsis [RR 0.73]. Males and African Americans were more likely to develop AKI [RR 1.35, 1.65], while African Americans had higher odds for severe COVID-19 [RR 1.62] and VTE [RR 1.54]. DM with ILD group also experienced higher odds for severe COVID-19 infection [RR 1.64], and VTE [RR 2.06]. DM patients receiving DMARDs and glucocorticoids had higher odds for hospitalisation [RR 1.46, 2.12], and sepsis [RR 3.25, 2.4] Subgroup analysis of 5-year neoplasm history amongst DM patients with COVID-19 was inadequate for meaningful comparison. CONCLUSION: Dermatomyositis patients without comorbities have reasonable COVID-19 outcomes including mortality and hospitalisation. Black race, male gender, ILD, DMARDS and glucocorticoid users, are associated with poor outcomes.

Neurovascular and infectious disease phenotype of acute stroke patients with and without COVID-19.

BACKGROUND: The infectious disease phenotype of acute stroke associated with COVID-19 has been poorly characterized. OBJECTIVE: We investigated the neurovascular and infectious disease phenotype of stroke patients with and without COVID-19 infection, and their effect on in-hospital mortality. METHODS: This is a retrospective cohort study of consecutive patients with acute stroke, admitted to any ward of a hub hospital for stroke in Lombardy, Italy, during the first wave of COVID-19. Demographic, neurovascular, infectious disease, and respiratory characteristics were collected. The effect of clinical variables on survival was evaluated using logistic regression models. RESULTS: One hundred thirty-seven patients with acute stroke were recruited; 30 (21.9%) patients had COVID-19 and represented 2.5% of the 1218 COVID-19 patients hospitalized in the study period. Demographics, comorbidities, stroke type, stroke severity, and etiology did not differ between COVID + stroke patients and non-COVID stroke patients, except for an excess of multi-embolic ischemic stroke in the COVID + group. Most COVID + stroke patients had symptomatic infection (60%) and interstitial pneumonia (70%). COVID + stroke patients required more frequently respiratory support (77% versus 29%; p < 0.0001) and had higher in-hospital mortality (40% versus 12%; p = 0.0005) than non-COVID stroke patients. Mortality was independently associated with symptomatic interstitial pneumonia (aOR 6.7; 95% CI 2.0-22.5; p = 0.002) and, to a lesser extent, with NIHSS on admission (aOR 1.1; 95% CI 1.03-1.2; p = 0.007) and recanalization therapies (aOR 0.2; 95% CI 0.04-0.98; p = 0.046). CONCLUSION: Symptomatic interstitial pneumonia was the major driver of in-hospital mortality in COVID + stroke patients.

Treatment of MDA5-positive dermatomyositis complicated by gangrenous cholecystitis with tofacitinib.

BACKGROUND: Dermatomyositis is a rare idiopathic inflammatory disease with diverse presentations that can have varying degrees of cutaneous and systemic involvement. This phenotypic heterogeneity makes DM a therapeutic challenge. Some therapeutic drugs, such as hormones and immunosuppressants, have poor therapeutic effects. In recent years, tofacitinib has been reported to be effective in the treatment of dermatomyositis. CASE PRESENTATION: We report a case of anti-MDA5 antibody-positive dermatomyositis that was relieved after treatment with tofacitinib, during which gallbladder gangrene and suppurative cholecystitis occurred. After cholecystectomy, we continued to use tofacitinib and achieved a good therapeutic effect. CONCLUSIONS: Tofacitinib is effective in the treatment of anti-MDA5 antibody-positive dermatomyositis, but the risk of infection is increased. It can still be used after infection control. Close follow-up should be performed during the use of tofacitinib.

Risk factors for pneumonitis in advanced extrapulmonary cancer patients treated with immune checkpoint inhibitors.

BACKGROUND: Immune-mediated pneumonitis has a high mortality rate; however, information regarding the related risk factors remains limited. This study aimed to analyze risk factors for pneumonitis, including smoking and lung metastasis (LM), in patients with extrapulmonary primary tumors. METHODS: Data of 110 patients treated with immune checkpoint inhibitors (ICIs) (nivolumab/pembrolizumab) for treating extrapulmonary primary tumors at the Shiga University of Medical Science Hospital between January 2015 and December 2019 were retrospectively collected. The association between the onset of pneumonitis and treatment-related factors was analyzed by logistic regression. The severity of pneumonitis was graded according to the Common Terminology Criteria for Adverse Events version 5.0. Risk factors, such as the absence or presence of interstitial lung disease (ILD) and LM, or other clinical factors, including smoking status before ICI administration, were analyzed. RESULTS: Multivariate analyses indicated that the amount of smoking was significantly associated with an increase in the development of all-grade pneumonitis types (odds ratio (OR) = 20.33, 95% confidence interval (CI) = 20.03-20.66; p = 0.029). LM and ILD were significantly related to an increase in the development of symptomatic pneumonitis (≥ Grade 2) (OR = 10.08, 95% CI = 1.69-199.81; p = 0.076, and OR = 6.76, 95% CI = 1.13-40.63; p = 0.037, respectively). CONCLUSIONS: Pre-screening for ILD and LM and recognizing patients' smoking history is important for determining the risk of ICI-induced pneumonitis and allowing safe ICI administration.