tofacitinib and Lung-Diseases--Interstitial

Topics: Autoantibodies; Dermatomyositis; Humans; Interferon-Induced Helicase, IFIH1; Lung Diseases, Interstitial; Piperidines; Pyrimidines

Interstitial lung diseases (ILDs) have been reported to be associated with myositis (including polymyositis and dermatomyositis). These myositis-associated ILDs carry significant morbidity and mortality. This review summarizes recent findings on myositis-associated ILD with a focus on pathogenesis and emerging treatment.. Recent advances in genetics have revealed 22 myositis-associated genome-wide loci, which were significantly enriched in regulatory regions in immune cells. An analysis of such disease-associated loci elucidated potential drug targets (e.g., TYK2 targeted by tofacitinib). In another study, an intronic variant in WDFY4 in association with clinically amyopathic dermatomyositis (CADM) had an effect for higher expression of a truncated WDFY4 isoform. Truncated WDFY4 markedly enhanced the MDA5-mediated NF-κB activation and cell apoptosis, indicating the dysregulated WDFY4-MDA5 pathway as a novel pathogenesis of CADM. As a novel strategy, tofacitinib treatment showed a promising improvement in survival and clinical features of CADM-associated ILD.. The genetic differences in the myositis-susceptible loci may explain the heterogeneous phenotypes and treatment responses in myositis-associated ILD. The understanding of pathogenesis with the genetic background as well as autoantibodies will enable the practice of personalized treatment in the management of the disease.

Topics: Apoptosis; Autoantibodies; Dermatomyositis; Humans; Interferon-Induced Helicase, IFIH1; Intracellular Signaling Peptides and Proteins; Lung Diseases, Interstitial; Molecular Targeted Therapy; Myositis; NF-kappa B; Phenotype; Piperidines; Polymyositis; Pyrimidines; Signal Transduction; TYK2 Kinase

Tofacitinib, a selective inhibitor of JAK1 and/or JAK3, is considered to alleviate the pulmonary condition of primary Sjögren's syndrome (pSS)-associated interstitial lung disease (ILD) through its anti-inflammatory and antifibrotic effects.. This is a single-center, prospective, randomized, open-label trial. The trial will compare a 52-week course of oral tofacitinib with traditional therapy cyclophosphamide (CYC) combined with azathioprine (AZA) in the treatment of pSS-ILD. A total of 120 patients will be randomly assigned into two treatment groups with a 1:1 ratio and followed for 52 weeks from the first dose. The primary endpoint of the study is the increase of forced vital capacity (FVC) at 52 weeks. Secondary endpoints include high-resolution computed tomography (HRCT), diffusion capacity for carbon monoxide of the lung (DLCO), the Mahler dyspnea index, the health-related quality of life (HARQoL) score, the cough symptom score, EULAR Sjögren's syndrome disease activity index (ESSDAI), and safety.. This study will be the first randomized controlled trial to investigate tofacitinib compared to the traditional regimen of CYC in combination with AZA in the treatment of pSS-ILD, which will provide data on efficacy and safety and further elucidate the role of the JAK-STAT signaling pathway in the development of pSS-ILD.. Before starting the experiment, the research proposal, informed consent (ICF) and relevant documents in accordance with the ethical principles of the Helsinki Declaration and the relevant requirements of the local GCP rules for ethical approval shall be submitted to the ethics committee of the hospital. The ethical approval of this study is reviewed by the Ethics Committee of Tongji Hospital and the ethical approval number is 2021-LCYJ-007. When the experiment is completed, the results will also be disseminated to patients and the public through publishing papers in international medical journals.. The study was registered on the Chinese Clinical Trial Registry, www.chictr.org.cn ; ID ChiCTR2000031389.

Topics: Azathioprine; Cyclophosphamide; Humans; Lung Diseases, Interstitial; Prospective Studies; Quality of Life; Randomized Controlled Trials as Topic; Review Literature as Topic; Sjogren's Syndrome

Topics: Adult; Autoantibodies; Dermatomyositis; Drug Therapy, Combination; Female; Glucocorticoids; Historically Controlled Study; Humans; Interferon-Induced Helicase, IFIH1; Janus Kinase Inhibitors; Lung Diseases, Interstitial; Male; Methylprednisolone; Middle Aged; Piperidines; Pyrimidines; Pyrroles

Anti-melanoma differentiation-associated gene 5 (MDA5) antibody is associated with clinically amyopathic dermatomyositis (CADM) with rapidly progressive interstitial lung disease (RP-ILD). Recently, several studies have reported that tofacitinib (TOF), a Janus kinase inhibitor, might be effective for cases of new or refractory RP-ILD in anti-MDA5 antibody-positive CADM; however, it is unknown whether TOF can also be effective for relapsed cases. We herein report a relapsed case of RP-ILD in anti-MDA5 antibody-positive CADM, which was successfully treated by combination therapy with TOF (5 mg twice daily). Our case suggests that TOF may also be a potential treatment option for relapsed cases of this disease.

Topics: Autoantibodies; Chronic Disease; Humans; Interferon-Induced Helicase, IFIH1; Lung Diseases, Interstitial; Recurrence

Topics: Autoantibodies; Humans; Lung Diseases, Interstitial; Melanoma; Piperidines; Pyrimidines

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.

Topics: Amino Acyl-tRNA Synthetases; Autoantibodies; Glycine-tRNA Ligase; Humans; Lung Diseases, Interstitial; Myositis; Respiratory Distress Syndrome

Anti-melanoma differentiation-associated protein 5 (MDA5) antibody-positive dermatomyositis (MDA5-DM) is frequently complicated with rapidly progressive-interstitial lung disease (RP-ILD). The prognosis of MDA5-DM with RP-ILD is mostly poor despite intensive treatment with a combination of high-dose glucocorticoids and single conventional immunosuppressants. It was reported that the triple therapy (high-dose glucocorticoids, cyclophosphamide and tacrolimus) was more effective than a combination of high-dose glucocorticoids and stepwise addition of immunosuppressants. In addition, the efficacy of tofacitinib 10 mg/day for MDA5-DM with RP-ILD refractory to the triple therapy was suggested. However, the effect of those therapies was evaluated only in comparison to the historical control. Moreover, more importantly, there are still refractory patients even if treated with those therapies. In this case series, we report six MDA5-DM cases with RP-ILD in which the dose of tofacitinib was increased from 10 mg to 20 mg/day due to poor response to the triple therapy, followed by tofacitinib 10 mg/day. Four of six patients improved after dose escalation of tofacitinib, while two non-responders died. All six patients developed at least one infection including five cases of cytomegalovirus reactivation, one pulmonary aspergillosis, one herpes zoster and one herpes simplex keratitis. These cases suggest that the dose escalation of tofacitinib can be an option for MDA5-DM patients refractory to 10 mg/day of tofacitinib and other immunosuppressants although the risk of infection is a concern. The risk-benefit balance of the dose escalation of tofacitinib should be carefully assessed in each case.

Topics: Dermatomyositis; Glucocorticoids; Humans; Immunosuppressive Agents; Lung Diseases, Interstitial

Anti-melanoma differentiation-associated protein-5 (MDA5) autoantibodies (Abs) are associated with rapidly progressive interstitial lung disease (RP-ILD) in dermatomyositis (DM). Because the addition of plasma exchange (PE) and rituximab (RTX) to triple therapy is inadequate in severe cases, we treat such cases with intensive induction therapy (IIT) combining all these options with tofacitinib (TOF). In this study, we investigated the poor prognostic factors and the efficacy and safety of IIT.. Thirty-three patients diagnosed with anti-MDA5 Ab-positive DM in our institution between 2014 and 2021 were included. The clinical characteristics of poor prognosis were retrospectively analysed using principal component analysis (PCA), and the outcomes of IIT were analysed in terms of survival, assessed using the Kaplan-Meier test, and adverse events.. Although triple therapy with RTX, PE, or intravenous immunoglobulin was administered before the introduction of IIT, eight of 12 RP-ILD cases with a ferritin level >400 ng/mL (mean, 2,342) died within a median of 2.5 months. PCA revealed distinct clusters for prognosis, and age and serum ferritin were leading predictors of the prognosis. IIT, consisting of combinations of triple therapy with higher doses of methylprednisolone, PE, RTX, and TOF, was applied to eight patients (mean ferritin, 3,558). Although two patients died even with these regimens, a significant improvement in survival was documented. Several IIT-related adverse events were observed, including viral and fungal infections and cytopenia.. IIT significantly improved the survival of patients with severe anti-MDA5 Ab-positive RP-ILD. Although infections are noted, their benefits outweigh the risks in younger patients with high serum ferritin levels.

Topics: Autoantibodies; Dermatomyositis; Disease Progression; Ferritins; Humans; Induction Chemotherapy; Interferon-Induced Helicase, IFIH1; Lung Diseases, Interstitial; Plasma Exchange; Retrospective Studies; Rituximab

Topics: Autoantibodies; Dermatomyositis; Humans; Interferon-Induced Helicase, IFIH1; Lung Diseases, Interstitial; Piperidines; Prognosis; Pyrimidines; Retrospective Studies

The oral Janus kinases inhibitor (JAKi) has improved the management of skin manifestations in systemic sclerosis (SSc), and our study aimed to explore the efficacy of non-selective JAKi tofacitinib in ameliorating interstitial lung disease (ILD) in the patients with SSc. The hospitalization data of the SSc-ILD patients from April 2019 to April 2021 were collected, and the changes of pulmonary function and the radiological findings in pulmonary high-resolution CT (HRCT) from the 9 patients who received tofacitinib for at least 6 months and a matched group of 35 SSc-ILD patients treated with conventional immunosuppressants or glucocorticoids, were compared and analyzed. There were no significant differences in demographic data and clinical characteristics between the tofacitinib-treated group (tofa-group) and the matched group. However, in the tofa-group, the changes in serum lactate dehydrogenase (LDH) concentration and serum interleukin-6 levels were significantly lower than those in the matched group. Moreover, the tofa-group showed amelioration in decreased diffusing capacity of the lung for carbon monoxide (DLCO) (62.05 ± 9.47 vs. 66.61 ± 12.39, p = 0.046), reductions in ground-glass attenuation involvement (1.00 ± 0.86 vs. 0.33 ± 0.50, p = 0.024) and irregular pleural thickening (1.33 ± 0.50 vs. 0.67 ± 0.51, p = 0.004) in pulmonary HRCTs, alleviated modified Rodnan skin score (mRSS) of skin sclerosis (9.22 ± 3.81 vs. 7.11 ± 3.92, p = 0.048), and reduced HRCT scores of pulmonary fibrosis (15.00 ± 3.87 vs. 12.66 ± 4.92, p = 0.009). Logistic regression analysis showed that the involvement of ground-glass attenuation (OR 11.43) and the add-on therapy of tofacitinib (OR 9.98) were the relevant factors in the amelioration of HRCT. Our results indicate that the use of JAKi (tofacitinib) may be relevant to significant improvement of the sclerosis and early radiological abnormalities in SSc-ILD patients. Further studies are needed to confirm these findings and to explore its efficacy more precisely. Key Points • The currently available therapies for SSc-ILD have limited therapeutic benefits. • The add-on therapy of the oral JAK inhibitor is available in the real world. • The tofacitinib was promising in the improvement of the sclerosis and early radiological abnormalities in SSc-ILD patients.

Topics: Humans; Janus Kinase Inhibitors; Lung; Lung Diseases, Interstitial; Retrospective Studies; Scleroderma, Systemic; Sclerosis

Anti-MDA5 antibody-positive dermatomyositis (DM) is a rare clinical autoimmune disease, and anti-MDA5-positive DM with interstitial lung disease (ILD) is the most important cause of death in DM patients. We reported the efficacy of the JAK1/3 inhibitor tofacitinib as an anti-MDA5-negative treatment option for patients with anti-MDA5-positive DM-ILD.. Here we report a 51-year-old female patient with cough, sputum, shortness of breath for 5 months, rash for 3 months, and muscle pain in the extremities for 1 month. After conventional immunosuppressive therapy plus hormone therapy, the remission was slow. Methylprednisolone was successfully reduced after we administered tofacitinib and tacrolimus. After 132 weeks of follow-up, anti-MDA5 antibody turned negative, clinical symptoms were relieved, and lung Imaging tests were successfully reversed.. There is currently no report of tofacitinib supplement therapy for anti-MDA5 positive to negative DM. With this case report, tofacitinib is an option for the treatment of anti-MDA5-positive DM-ILD, which deserves attention.

Topics: Autoimmune Diseases; Dermatomyositis; Female; Humans; Janus Kinase Inhibitors; Lung Diseases, Interstitial; Middle Aged

Juvenile dermatomyositis (JDM) is a chronic autoimmune disease. Some patients remain in an active state even though they were administrated with a combination of corticosteroid and methotrexate. Existing research has suggested that interferon and Janus kinase played an important role in pathogenesis. Existing research has suggested the efficacy of JAK inhibitors (JAKi). Our retrospective study aimed to investigate the efficacy of tofacitinib in refractory JDM patients.. A total of eighty-eight patients in China who had been diagnosed with JDM and subjected to tofacitinib therapy for over 3 months were retrospectively analyzed. Skin and muscle manifestations were assessed using the Cutaneous Assessment Tool-binary method (CAT-BM), Childhood Myositis Assessment Scale (CMAS), and kinase. Pulmonary function was assessed using a high-resolution CT (computerized tomography) scan and pulmonary symptoms. All patients were subjected to regular follow-up, and core measures were assessed every 3 months after initiation. Furthermore, the data were analyzed using the Wilcoxon single test, Mann-Whitney U test, and chi-square test.. Compared with the baseline data, skin and muscle manifestations were found significantly improved during the respective follow-up visit. At the most recent follow-up, nearly 50% of patients achieved a clinical complete response and six patients received tofacitinib monotherapy. Sixty percent of patients suffering from interstitial lung disease well recovered on high-resolution CT. Seventy-five percent of patients showed a reduction in the size or number of calcinosis, and 25% of patients showed completely resolved calcinosis.. In this study, the result suggested that tofacitinib therapy exerted a certain effect on skin manifestations, muscle manifestations, interstitial lung disease (ILD), calcinosis, as well as downgrade of medication. In-depth research should be conducted to focus on the correlation between the pathogenesis of JDM and JAKi.

Topics: Calcinosis; Child; Dermatomyositis; Humans; Janus Kinase Inhibitors; Lung Diseases, Interstitial; Retrospective Studies

Tofacitinib has an important role in pediatric rapidly progressive interstitial lung disease (ILD) associated with juvenile dermatomyositis (JDM), an otherwise potentially fatal condition. It may be useful in induction of remission and can be used safely to maintain remission. Serum ferritin and interleukin-18 are useful markers for tracking activity and response of JDM-associated ILD.

Topics: Child; Dermatomyositis; Humans; Janus Kinase Inhibitors; Lung Diseases, Interstitial; Male; Piperidines; Pyrimidines; Remission Induction

Clinically amyopathic dermatomyositis (CADM) patients often develop rapidly progressive interstitial lung disease (RP-ILD). A high level of anti-melanoma differentiation-associated gene 5 antibodies (anti-MDA5 Ab) before treatment is associated with RP-ILD development, a poor treatment response, and poor survival. The prognosis of CADM patients remains poor due to ILD even with combined intensive immunosuppressive therapy. Recently, several additional therapies, including tofacitinib (TOF) and plasma exchange (PE) therapy, have been reported to be effective. We herein report a case of CADM-ILD with a high level of anti-MDA5 Ab that was refractory to combined intensive immunosuppressive therapy including TOF, but successfully treated with PE. The following are possible reasons why TOF was ineffective: (1) cytokines that were not suppressed by TOF played an important role in RP-ILD; (2) TOF was administered later than previously reported; and (3) TOF did not suppress pathological substances such as antibodies. On the other hand, PE removes cytokines and various pathological substances. Therefore, PE may be a more reasonable additional therapy for intractable CADM-ILD.

Topics: Autoantibodies; Cytokines; Dermatomyositis; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Interferon-Induced Helicase, IFIH1; Lung Diseases, Interstitial; Piperidines; Plasma Exchange; Pyrimidines

Rheumatoid arthritis associated interstitial lung disease (RA-ILD) is a major concern in RA. These patients have been included in clinical trials and in the post-marketing setting of RA patients using tofacitinib. We aimed to assess the real-life efficacy and safety of tofacitinib in patients with RA-ILD.. RA patients with ILD diagnosis based on the HRCT images of the lungs from eight different centres recruited to study. As a control group, RA patients without ILD under tofacitinib were included. Demographic data, patients' characteristics, available pulmonary function tests regarding RA and RA-ILD at the visit in which tofacitinib was initiated and for the last follow-up visit under tofacitinib were recorded. Reasons for tofacitinib discontinuation were also recorded. Drug retention rates were compared by log-rank test. p-value <0.05 was considered statistically significant.. A total of 47(42.6% male) RA patients with RA-ILD and a control group of 387 (17.8% male) patients without RA-ILD were included in analysis. After the median of 12 (9-19) months follow-up, mean FEV1%; 82.1 vs. 82.8 (pre/post-treatment, respectively, p=0.08), mean FVC%; 79.8 vs. 82.8 (pre/post-treatment, respectively, p=0.014) were stable and worsening was observed in 2/18 (11.1%) patients. Retention rates were similar (p=0.21, log-rank). In RA-ILD group, most common cause of drug discontinuation was infections (6.3 vs. 2.4 per 100 patient-years).. Treatment strategy of RA-ILD patients is still based on small observational studies. A high rate of discontinuation due to infections was observed in RA-ILD patients under tofacitinib; however, RA-ILD patients were older than RA patients without ILD.

Topics: Arthritis, Rheumatoid; Female; Humans; Lung Diseases, Interstitial; Male; Piperidines; Pyrimidines

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.. 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.. 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.

Topics: Autoantibodies; Cholecystitis; Dermatomyositis; Humans; Interferon-Induced Helicase, IFIH1; Lung Diseases, Interstitial; Piperidines; Pyrimidines

The efficacy of tofacitinib (TOF) in the early diagnosis of melanoma differentiation-associated gene 5 (MDA5)-related interstitial lung disease (ILD) has been described. However, whether TOF exposure is associated with a reduced 1-year mortality rate remains undetermined.. Patients diagnosed with MDA5-ILD receiving TOF or tacrolimus (TAC) treatment were included. A Cox proportional hazards model, which was adjusted for age, sex, smoking history, anti-MDA5 antibody titers, and concurrent use of other steroid-sparing agents, was performed to compare all-cause mortality and to investigate the risk factors predicting 1-year mortality rates in the 2 treatment groups.. During the study period, 26 patients were treated with TOF and 35 were treated with TAC. The 6-month (38.5% vs 62.9%;. Our observational study showed that TOF use might have a potential effect on improving the outcomes of MDA5-ILD. Future clinical trials are needed to assess the long-term efficacy and tolerability of TOF.

Topics: Autoantibodies; Dermatomyositis; Humans; Interferon-Induced Helicase, IFIH1; Lung Diseases, Interstitial; Melanoma; Retrospective Studies; Tacrolimus

Anti-melanoma differentiation-associated protein 5 (MDA5)-positive rapidly progressive interstitial lung disease (RP-ILD) is associated with poor prognosis, and the most effective therapeutic intervention has not been established. Herein we report a case of a 45-year-old female patient who presented with myalgia, Gottron's papules with ulceration, and dyspnea on exertion which became aggravated within weeks. Laboratory examination and electromyography confirmed myopathy changes, and a survey of myositis-specific antibodies was strongly positive for anti-MDA5 antibody. High-resolution chest tomography suggested organizing pneumonia with rapidly progressive changes within the first month after diagnosis of the disease. Anti-MDA5-associated dermatomyositis with RP-ILD was diagnosed. Following combination therapy with rituximab, tofacitinib and pirfenidone, clinical symptoms, including cutaneous manifestation, respiratory conditions and radiographic changes, showed significant and sustainable improvement. To our knowledge, this is the first reported case of anti-MDA5-associated dermatomyositis with RP-ILD successfully treated with the combination of rituximab, tofacitinib, and pirfenidone.

Topics: Autoantibodies; Dermatomyositis; Female; Humans; Lung Diseases, Interstitial; Middle Aged; Piperidines; Pyridones; Pyrimidines; Rituximab

Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). Interstitial lung disease (ILD) is an extra-articular manifestation of RA. We investigated incidence rates of ILD in patients with RA, receiving tofacitinib 5 or 10 mg twice daily, and identified potential risk factors for ILD.. This post hoc analysis comprised a pooled analysis of patients receiving tofacitinib 5 or 10 mg twice daily or placebo from 2 phase (P)1, 10 P2, 6 P3, 1 P3b/4, and 2 long-term extension studies. Interstitial lung disease events were adjudicated as "probable" (supportive clinical evidence) or "possible" (no supportive clinical evidence) compatible adverse events. Incidence rates (patients with events per 100 patient-years) were calculated for ILD events.. Of 7061 patients (patient-years of exposure = 23,393.7), 42 (0.6%) had an ILD event; median time to ILD event was 1144 days. Incidence rates for ILD with both tofacitinib doses were 0.18 per 100 patient-years. Incidence rates generally remained stable over time. There were 17 of 42 serious adverse events (40.5%) of ILD; for all ILD events (serious and nonserious), 35 of 42 events (83.3%) were mild to moderate in severity. A multivariable Cox regression analysis identified age 65 years or older (hazard ratio 2.43 [95% confidence interval, 1.13-5.21]), current smokers (2.89 [1.33-6.26]), and Disease Activity Score in 28 joints-erythrocyte sedimentation rate score (1.30 [1.04-1.61]) as significant risk factors for ILD events.. Across P1/2/3/4/long-term extension studies, incidence rates for ILD events were 0.18 following tofacitinib treatment, and ILD events were associated with known risk factors for ILD in RA.

Topics: Aged; Antirheumatic Agents; Arthritis, Rheumatoid; Humans; Incidence; Lung Diseases, Interstitial; Piperidines; Pyrimidines; Pyrroles; Treatment Outcome

Anti-melanoma differentiation-associated gene 5 (MDA-5) antibodies have widely known to be associated with amyopathic dermatomyositis with rapidly progressive interstitial lung disease (ILD). Although the triple combination therapy with high-dose glucocorticoids, cyclophosphamide, and a calcineurin inhibitor has been used to treat anti-MDA-5 antibody-positive rapidly progressive ILD, the prognosis of these patients remains poor despite this intensive therapy. Recently, several investigators have shown that combination therapy with tofacitinib might be potentially efficacious in those patients. We herein report a case of anti-MDA-5 antibody-positive dermatomyositis and associated ILD who had not responded to the triple therapy and tofacitinib 10 mg/day but markedly responded after increasing the dose of tofacitinib to 20 mg/day.

Topics: Autoantibodies; Dermatomyositis; Dose-Response Relationship, Drug; Humans; Interferon-Induced Helicase, IFIH1; Lung Diseases, Interstitial; Male; Middle Aged; Piperidines; Pyrimidines; Recurrence; Treatment Outcome

Anti-melanoma differentiation-associated gene 5 juvenile dermatomyositis (anti-MDA5 JDM) is associated with high risk of developing rapidly progressive interstitial lung disease (RP-ILD). Here we report an 11-year-old girl with anti-MDA5 JDM and RP-ILD which led to a fatal outcome, further aggravated by SARS-CoV-2 infection. She was referred to our hospital after being diagnosed with anti-MDA5 JDM and respiratory failure due to RP-ILD. On admission, fibrobronchoscopy with bronchoalveolar lavage (BAL) revealed

Topics: Adenosine Monophosphate; Alanine; Anti-Bacterial Agents; Antibodies, Monoclonal, Humanized; Antiviral Agents; Autoantibodies; Bronchoscopy; Child; COVID-19; COVID-19 Nucleic Acid Testing; Cyclophosphamide; Dermatomyositis; Disease Progression; Fatal Outcome; Female; Humans; Hydroxychloroquine; Immunocompromised Host; Immunoglobulins, Intravenous; Immunologic Factors; Immunosuppressive Agents; Interferon-Induced Helicase, IFIH1; Lung; Lung Diseases, Interstitial; Lymphohistiocytosis, Hemophagocytic; Mediastinal Emphysema; Methylprednisolone; Piperidines; Pneumonia, Pneumocystis; Pneumothorax; Pyrimidines; Respiratory Insufficiency; Shock, Septic; Subcutaneous Emphysema; Tomography, X-Ray Computed; Trimethoprim, Sulfamethoxazole Drug Combination

Topics: Autoantibodies; Dermatomyositis; Humans; Interferon-Induced Helicase, IFIH1; Lung Diseases, Interstitial; Piperidines; Pyrimidines

Topics: Adult; Autoantibodies; Dermatomyositis; Humans; Interferon-Induced Helicase, IFIH1; Lung Diseases, Interstitial; Male; Mediastinal Emphysema; Piperidines; Pyrimidines

STING-associated vasculopathy with onset in infancy (SAVI) is a new rare auto-inflammatory disease. The purpose of this study is to report new cases and summarize the manifestations and outcome of SAVI.. We made a retrospective analysis of three pediatric patients diagnosed with SAVI between March 2016 and July 2018 in Beijing Children's Hospital.. Three patients comprised one boy and two girls. The median age of onset was 4 months. All patients had the same de novo heterozygous mutation (c.463G>A, p. V155M) of TMEM173. All patients presented with interstitial lung disease and one coexisted with diffuse alveolar hemorrhage. Rashes were presented in two patients. Other clinical manifestations include febrile attacks, failure to thrive, arthritis, myositis, cerebrovascular involvement, ureteral calculus, gastroesophageal reflux, and malnutrition. Ground-glass opacities were the most common features of chest computed tomography, followed with cysts and reticular opacities. Transbronchial lung biopsy was performed in one patient revealing pulmonary vasculitis. Skin biopsy was performed in one patient with changes of vasculitis. All patients were treated with corticosteroids and two patients received combined treatment of tofacitinib. The therapeutic effects of tofacitinib were limited on interstitial lung disease in both patients and were poor on rashes in one patient. One patient under the treatment of tofacitinib died.. New clinical aspect of diffuse alveolar hemorrhage is first reported to be associated with SAVI. Unsatisfactory therapeutic effects of tofacitinib are observed in this study and further evaluations are needed.

Topics: Child, Preschool; Female; Hemorrhage; Humans; Infant; Inflammation; Lung; Lung Diseases, Interstitial; Male; Membrane Proteins; Mutation; Piperidines; Pyrimidines; Retrospective Studies; Skin; Vascular Diseases

Topics: Autoantibodies; Dermatomyositis; Female; Humans; Interferon-Induced Helicase, IFIH1; Lung Diseases, Interstitial; Middle Aged; Piperidines; Protein Kinase Inhibitors; Pyrimidines

Janus kinase (JAK) inhibitors (also termed Jakinibs) constitute a family of small drugs that target various isoforms of JAKs (JAK1, JAK2, JAK3 and/or tyrosine kinase 2 (Tyk2)). They exert anti-inflammatory properties linked, in part, to the modulation of the activation state of pro-inflammatory M1 macrophages. The exact impact of JAK inhibitors on a wider spectrum of activation states of macrophages is however still to be determined, especially in the context of disorders involving concomitant activation of pro-inflammatory M1 macrophages and profibrotic M2 macrophages. This is especially the case in autoimmune pulmonary fibrosis like scleroderma-associated interstitial lung disease (ILD), in which M1 and M2 macrophages play a key pathogenic role. In this study, we directly compared the anti-inflammatory and anti-fibrotic effects of three JAK inhibitors (ruxolitinib (JAK2/1 inhibitor); tofacitinib (JAK3/2 inhibitor) and itacitinib (JAK1 inhibitor)) on five different activation states of primary human monocyte-derived macrophages (MDM). These three JAK inhibitors exert anti-inflammatory properties towards macrophages, as demonstrated by the down-expression of key polarization markers (CD86, MHCII, TLR4) and the limited secretion of key pro-inflammatory cytokines (CXCL10, IL-6 and TNFα) in M1 macrophages activated by IFNγ and LPS or by IFNγ alone. We also highlighted that these JAK inhibitors can limit M2a activation of macrophages induced by IL-4 and IL-13, as notably demonstrated by the down-regulation of the M2a associated surface marker CD206 and of the secretion of CCL18. Moreover, these JAK inhibitors reduced the expression of markers such as CXCL13, MARCO and SOCS3 in alternatively activated macrophages induced by IL-10 and dexamethasone (M2c + dex) or IL-10 alone (M2c MDM). For all polarization states, Jakinibs with inhibitory properties over JAK2 had the highest effects, at both 1 μM or 0.1 μM. Based on these in vitro results, we also explored the effects of JAK2/1 inhibition by ruxolitinib in vivo, on mouse macrophages in a model of HOCl-induced ILD, that mimics scleroderma-associated ILD. In this model, we showed that ruxolitinib significantly prevented the upregulation of pro-inflammatory M1 markers (TNFα, CXCL10, NOS2) and pro-fibrotic M2 markers (Arg1 and Chi3L3). These results were associated with an improvement of skin and pulmonary involvement. Overall, our results suggest that the combined anti-inflammatory and anti-fibrotic properties of

Topics: Animals; Anti-Inflammatory Agents; Cell Differentiation; Chemokine CXCL13; Female; Gene Expression Regulation; Hypochlorous Acid; Janus Kinase 1; Janus Kinase 2; Janus Kinase 3; Lung; Lung Diseases, Interstitial; Macrophage Activation; Macrophages; Mice; Mice, Inbred C57BL; Nitriles; Piperidines; Primary Cell Culture; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Pyrroles; Receptors, Immunologic; Scleroderma, Systemic; Suppressor of Cytokine Signaling 3 Protein

Topics: Disease Progression; Humans; Lung Diseases, Interstitial; Male; Middle Aged; Myositis; Piperidines; Pyrimidines; Time Factors

Dermatomyositis (DM) can be complicated by calcinosis and interstitial lung disease (ILD). Calcinosis can be severely debilitating or life-threatening and to date there is no treatment with proven efficacy. In DM type I interferon contributes to pathophysiology by inducing the expression of proinflammatory cytokines and the JAK-STAT (signal transducer and activator of transcription) pathway may be involved in the regulation of mitochondrial calcium store release, a process potentially important for calcification in DM. JAK-inhibition may therefore be an attractive therapy in DM complicated by calcifications.. We report on the fast and persistent response of extensive and rapidly progressive DM-associated calcifications in two patients treated with the JAK-inhibitor tofacitinib. During the 28-week observation period in both patients no new calcifications formed and existing calcifications were either regressive or stable. Furthermore, concomitant life-threatening DM-associated ILD (acute fibrinous and organizing pneumonia; AFOP) in one patient rapidly responded to tofacitinib monotherapy. Both patients were able to taper concomitant glucocorticoids. Tofacitinib was well tolerated and safe.. The results of our study support the role of JAK/STAT signaling in the development of calcinosis and ILD in DM. Tofacitinib may be an effective and safe treatment for calcinosis in DM and potentially for other connective tissue disease complicated by calcinosis.

Topics: Calcinosis; Dermatomyositis; Female; Humans; Lung Diseases, Interstitial; MAP Kinase Kinase 4; Middle Aged; Piperidines; Pyrimidines; Pyrroles

Rheumatoid arthritis-associated interstitial lung disease (RA-ILD) is a sometimes life-threatening complication in RA patients. SKG mice develop not only arthritis but also an ILD resembling RA-ILD. We previously reported that tofacitinib, a JAK inhibitor, facilitates the expansion of myeloid-derived suppressor cells (MDSCs) and ameliorates arthritis in SKG mice. The aim of this study was to elucidate the effect of tofacitinib on the ILD in SKG mice.. We assessed the effect of tofacitinib on the zymosan (Zym)-induced ILD in SKG mice histologically and examined the cells infiltrating the lung by flow cytometry. The effects of lung MDSCs on T cell proliferation and Th17 cell differentiation were assessed in vitro. We also evaluated the effects of tofacitinib on MDSCs and dendritic cells in vitro.. Tofacitinib significantly suppressed the progression of ILD compared to the control SKG mice. The MDSCs were increased, while Th17 cells, group 1 innate lymphoid cells (ILC1s), and GM-CSF+ILCs were decreased in the lungs of tofacitinib-treated mice. MDSCs isolated from the inflamed lungs suppressed T cell proliferation and Th17 cell differentiation in vitro. Tofacitinib promoted MDSC expansion and suppressed bone marrow-derived dendritic cell (BMDC) differentiation in vitro.. Tofacitinib facilitates the expansion of MDSCs in the lung and ameliorates ILD in SKG mice.

Topics: Animals; Cell Differentiation; Cell Proliferation; Dendritic Cells; Disease Models, Animal; Immunity, Innate; Lung Diseases, Interstitial; Male; Mice; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Th17 Cells

We aimed to determine the outcome of combination therapy with tofacitinib (TOF) in a case series of refractory rapidly progressive interstitial lung disease (ILD) associated with anti-melanoma differentiation-associated 5 gene (MDA5) antibody-positive (Ab+) DM. Patients who had poor prognostic factors and failed to respond to immunosuppressive therapy were selected for TOF treatment.. Five patients with anti-MDA5 Ab+ DM-ILD who failed to respond to triple therapy with high dose glucocorticoids, CSA and CYC were given additional TOF (10 mg/day). To identify the poor prognostic factors, data from 15 consecutive patients (seven survived and eight died) with anti-MDA5 Ab+ DM-ILD before induction of TOF were analysed.. Three poor prognostic factors were identified: serum ferritin level >1000 ng/ml before therapy; ground-glass opacities in all six lung fields before therapy; and worsening of pulmonary infiltrates during therapy. All six patients who had all of the three factors and received triple therapy died before TOF therapy. There were five patients who had all of the three prognostic factors and failed to respond to triple therapy, but were able to receive the combination therapy with TOF; among them, three survived and two died. The survival rate of patients who received TOF was significantly better than that of the historical controls with immunosuppressive therapy before TOF. The patients who received TOF experienced complicated adverse events, particularly viral infection.. Combination therapy with TOF might have the potential to control refractory anti-MDA5 Ab+ DM-ILD.

Topics: Adult; Aged; Dermatomyositis; Drug Therapy, Combination; Female; Ferritins; Glucocorticoids; Humans; Interferon-Induced Helicase, IFIH1; Lung; Lung Diseases, Interstitial; Male; Middle Aged; Piperidines; Prognosis; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Survival Rate; Treatment Outcome