Treatment Of Interstitial Lung Disease Research Articles

POSITIVE ENVISIA GENOMIC CLASSIFIER RESULT PREDICTS CLINICAL PROGRESSION IN FIBROTIC INTERSTITIAL LUNG DISEASE

POSITIVE ENVISIA GENOMIC CLASSIFIER RESULT PREDICTS CLINICAL PROGRESSION IN FIBROTIC INTERSTITIAL LUNG DISEASE

Pulmonary hypertension in patients with interstitial lung disease: a tool for early detection.

Pulmonary hypertension (PH) complicates the treatment of interstitial lung disease (ILD) patients resulting in poor functional status and worse outcomes. Early recognition of PH in ILD is important for initiating therapy and considering lung transplantation. However, no standard exists regarding which patients to screen for PH‐ILD or the optimal method to do so. The aim of this study was to create a risk assessment tool that could reliably predict PH in ILD patients. We developed a PH‐ILD Detection tool that incorporated history, exam, 6‐min walk distance, diffusion capacity for carbon monoxide, chest imaging, and cardiac biomarkers to create an eight‐component score. This tool was analyzed retrospectively in 154 ILD patients where each patient was given a score ranging from 0 to 12. The sensitivity (SN) and specificity (SP) of the PH‐ILD Detection tool and an area‐under‐the‐curve (AUC) were calculated. In this cohort, 74 patients (48.1%) had PH‐ILD. A score of ≥6 on the PH‐ILD Detection tool was associated with a diagnosis of PH‐ILD (SN: 86.5%; SP: 86.3%; area‐under‐the‐curve: 0.920, p < 0.001). The PH‐ILD Detection tool provides high SN and SP for detecting PH in ILD patients. With confirmation in larger cohorts, this tool could improve the diagnosis of PH in ILD and may suggest further testing with right heart catheterization and earlier intervention with inhaled treprostinil and/or lung transplant evaluation.

P14 Challenges in treating anti-melanoma differentiation associated gene 5 (MDA5) antibody positive juvenile dermatomyositis (JDM) with interstitial lung disease (ILD) complicated by pneumocytis jirovecii pneumonia (PCP): a case report

Introduction/BackgroundWe describe a case of MDA5 antibody positive JDM associated with ILD who developed worsening in breathing effort requiring oxygen support. We highlight the challenges associated with the risk of rapidly progressing ILD (RPILD) versus infection as the patient deteriorated when her oral prednisolone was tapered. Whilst investigating for other potential causes of RPILD, immunosuppression was intensified. A suboptimal response to treatment prompted extensive opportunistic infection screening identifying pneumocystis pneumonia (PCP). Here, we describe the clinical course of this patient, outline the management, and ask whether immunosuppressed JDM patients with ILD should be prophylactically treated for fungal disease.Description/MethodA 12-year-old girl presented with a 4 months history of oral ulcers, exercise intolerance, joint stiffness, and erythematous palmar rash. On examination, she had a weak swallowing with swelling and restriction in her joints, Gottron’s papules, vasculitic rash with skin ulceration and dilated nailfold capillaries. Manual muscle testing (MMT)-8 and Childhood Muscle Assessment Scale (CMAS) scores were 54/80 and 42/52 respectively. Based on this clinical presentation and further tests she was diagnosed with MDA5 positive JDM.She developed symptoms suspicious of pulmonary embolism, prompting a CT pulmonary angiogram. This identified coincidental scattered areas of ground-glass consolidation with atelectasis consistent with ILD. Lung function testing (LFT) was normal (FEV1 2.89L (100.2%), FVC 2.94L (89.9%), DLCO 87%, KCO 98.4%).She was treated with pulses of IV methylprednisolone (IVMP), IV immunoglobulin (IVIG), methotrexate, and rituximab. Methotrexate was stopped as she developed transaminitis and switched to ciclosporin. She was discharged with prednisolone and ciclosporin.She presented 6 weeks later with dyspnoea, fatigue and new skin rashes, but had no cough. Examination found reduced breath sounds and crackles.Investigations showed CRP <5, ESR 80mm/hour, WCC 15.45 (x10*9/L), ALT 43 (U/L), AST 80 (U/L), CK 21 (U/L), LDH 639 (U/L). Chest radiograph on admission was reported as normal and CT thorax showed non-specific patchy mild ground-glass opacification. LFT showed worsening restrictive picture with decreased diffusing capacity with FEV1 1.56L (53%), FVC 1.79L (54%), DLCO 46%, and KCO 73%. Progression of ILD was suspected thus she was pulsed with IVMP and given IV cyclophosphamide.Fever with worsening respiratory distress ensued requiring PICU admission, prompting an extensive infection screen. PCP PCR and β -D glucan were positive, thus she was treated for PCP with co-trimoxazole and caspofungin. She made good recovery and was discharged well.Discussion/ResultsJuvenile dermatomyositis (JDM) is a rare systemic autoimmune condition in childhood. It primarily affects the proximal muscles and skin but may also affect the heart, respiratory, GI system, joint and other organs. It is a complex condition and is potentially life threatening if treated inadequately. The emergence of myositis specific antibodies (MSA) have enhanced our understanding of both the clinical and laboratory features of JDM. The phenotype of children with anti-MDA5 autoantibodies has yet to be clearly established unlike their adult counterpart however there have been increased recognition that it is associated with risk of developing ILD. In our case, MDA5-associated ILD was diagnosed at presentation and she was treated aggressively with immunosuppressants. She developed deterioration in her respiratory symptoms 6 weeks later whilst on weaning course of steroids triggering the possibility of worsening ILD. This has led to her receiving a course of intravenous cyclophosphamide in addition to on-going immunosuppressants. However, as she worsened despite optimal treatment for ILD, she was screened for opportunistic infections and was positive for PCP. This highlights challenges faced by clinicians in identifying the cause of worsening respiratory function in a children with established ILD who are immunosuppressed. It maybe multi-factorial however opportunistic infections such as PCP should always be considered in these children to ensure it is treated appropriately to prevent further complications.Key learning points/ConclusionAnti-MDA5 positive ILD represents a cohort of children requiring a more aggressive immunosuppressive therapies to optimise and prevent further deterioration in their clinical respiratory function. However, since there are no proven biomarkers able to differentiate indolent ILD from RPILD, it may be favourable to assume RPILD and treat aggressively.Balancing the risks and benefits caused by aggressive immunosuppression in these children continues to be a challenge. Therefore, clinicians should be cognisant of opportunistic infections such as PCP when faced with children with underlying ILD whose respiratory function deteriorates. Chemoprophylaxis with co-trimoxazole is generally well tolerated with minimal side effects and therefore should be considered in these children at diagnosis.

Multidisciplinary teams in the clinical care of fibrotic interstitial lung disease: current perspectives.

Multidisciplinary team (MDT) meetings, involving the integrated collaboration of healthcare professionals, are increasingly used in clinical practice to inform the diagnosis and treatment of interstitial lung diseases (ILDs). Over time, the assessment of patients with ILD has transitioned from discussions among clinicians, radiologists and pathologists to the inclusion of a broader range of clinical data and specialist expertise. Studies have shown that a multidisciplinary approach can have many benefits for the clinical care of patients with ILD by improving the diagnostic confidence for different ILDs and guiding treatment decisions. The utility of MDT discussions for diagnosis, monitoring disease progression and management decisions, will need to be considered based on how it is best positioned in the diagnostic and therapeutic process, as well as the practicality and challenges of its use. There are also uncertainties and heterogeneity concerning the optimal practices of MDT meetings in ILD care. In this review, we describe recent developments refining the approach to MDTs in clinical practice, including who should be involved in the MDTs, when it is most needed, their use in patient management, challenges in their implementation, and ongoing controversies in the field that need further research.

Human MIKO-1, a Hybrid Protein That Regulates Macrophage Function, Suppresses Lung Fibrosis in a Mouse Model of Bleomycin-Induced Interstitial Lung Disease.

Although interstitial lung disease (ILD) is a life-threatening pathological condition that causes respiratory failure, the efficiency of current therapies is limited. This study aimed to investigate the effects of human MIKO-1 (hMIKO-1), a hybrid protein that suppresses the abnormal activation of macrophages, on murine macrophage function and its therapeutic effect in a mouse model of bleomycin-induced ILD (BLM-ILD). To this end, the phenotype of thioglycolate-induced murine peritoneal macrophages co-cultured with hMIKO-1 was examined. The mice were assigned to normal, BLM-alone, or BLM + hMIKO-1 groups, and hMIKO-1 (0.1 mg/mouse) was administered intraperitoneally from day 0 to 14. The mice were sacrificed on day 28, and their lungs were evaluated by histological examination, collagen content, and gene expression levels. hMIKO-1 suppressed the polarization of murine macrophages to M2 predominance in vitro. The fibrosis score of lung pathology and lung collagen content of the BLM + hMIKO-1 group were significantly lower than those in the BLM-alone group. The expression levels of TNF-α, IL-6, IL-1β, F4/80, and TIMP-1 in the lungs of the BLM + hMIKO-1 group were significantly lower than those in the BLM-alone group. These findings indicate that hMIKO-1 reduces lung fibrosis and may be a future therapeutic candidate for ILD treatment.

Modern principles and prospects for drug therapy of interstitial lung diseases in children

The article discusses the principles of therapy and prospects for the treatment of interstitial lung diseases in children. Many of interstitial lung diseases occur with progressive fibrosis, so the use of new antifibrotic drugs is especially relevant now. These drugs include pirfenidone and nintedanib. Therapy of interstitial lung diseases using antifibrotic drugs in children is a promising new direction.

Vitamin d deficiency and effect of its supplementation on interstitial lung disease (ILD): a randomized clinical trial

Background: Vitamin D is a steroid hormone that affects the immune system, lung remodeling, and bone health. Aim of the work: to assess serum vitamin D level in non-connective tissue disease-associated interstitial lung diseases (ILD), and to evaluate the impact of vitamin D supplementation. Patients and methods: One hundred and four patients with different types of ILD were randomly assigned to either; Group 1 (intervention): included 52 patients who received vitamin D for 3 months besides their standard treatment, and Group 2 (control): included 52 patients who received only the standard treatment of ILD. Follow up after 3 months. All patients were subjected to; dyspnea scoring, spirometry, six minutes walk test (6-MWT), and measurement of serum vitamin D at the time of enrollment and after 3 months for the intervention group. Results: The mean serum vitamin D level was (8.53 ± 6.29) ng/ml. After 3 months of supplementation; it significantly increased [5.7 to 18.5 (ng/ml), p &lt; 0.001], dyspnea score significantly decreased, significant increase of forced vital capacity (FVC)% and forced expiratory volume in the first second (FEV1)% (P=0.004 &amp; 0.02), with improvement of six minute walk distance (6-MWD) and oxygen saturation.

Targeted nanotherapy with everolimus reduces inflammation and fibrosis in scleroderma-related interstitial lung disease developed by PSGL-1 deficient mice.

Interstitial lung disease (ILD) is the main cause of mortality in systemic sclerosis (SSc), and current therapies available are of low efficacy or high toxicity. Thus, the identification of innovative less toxic and high efficacy therapeutic approaches to ILD treatment is an urgent need. The interaction of P-selectin glycoprotein ligand-1 (PSGL-1) with P-selectin initiates leukocyte extravasation and deletion of the corresponding gene (Selplg) induces a SSc-like syndrome with high incidence of ILD in aged mice. Aged PSGL-1 KO (Selplg-/- ) mice were used to assess the therapeutic effects of nanotherapy with everolimus, included in liposomes decorated with high MW hyaluronic acid (LipHA+Ev) and administered intratracheally to specifically target CD44-expressing lung cells. PSGL-1 KO mice had increased numbers of CD45+ and CD45- cells, including alveolar and interstitial macrophages, eosinophils, granulocytes and NK cells, and myofibroblasts in bronchoalveolar lavage (BAL). CD45+ and CD45- cells expressing pro-inflammatory and pro-fibrotic cytokines were also increased. Lungs from PSGL-1 KO mice showed increased immune cell infiltration and apoptosis and exacerbated interstitial and peribronchial fibrosis. Targeted nanotherapy with LipHA+Ev decreased the myofibroblasts in BAL, cells producing proinflammatory and profibrotic cytokines, and the degree of lung inflammation at histology. LipHA+Ev treatment also decreased the severity of peribronchial and interstitial lung fibrosis, from moderate to mild levels. In PSGL-1 KO mice, targeted nanotherapy with LipHA+Ev was an effective treatment for SSc-ILD, reducing the number of inflammatory and fibrotic cells in BAL and reducing inflammation and fibrosis in lungs.

Current perspective of progressive-fibrosing interstitial lung disease.

Interstitial lung disease (ILD) is a parenchymal lung disease and restrictive disorder that presents as diffuse infiltrative shadows. The initial diagnosis of ILD is important because management strategies depend on the disease pathogenesis. Connective-tissue disease (CTD)-associated ILD including rheumatoid arthritis (RA), systemic sclerosis (SSc) requires a thorough evaluation of chronic respiratory symptoms such as non-productive cough and exertional dyspnea, as well as physical findings. Moreover, myeloperoxidase-positive anti-neutrophilic cytoplasmic antibody (MPO-ANCA)-associated vasculitis with ILD also shows disease progression. In CTD-associated ILD, the first-line treatment is anti-inflammatory drugs such as prednisolone or immunosuppressants. In hypersensitivity pneumonitis (HP), detailed environmental history-taking is crucial. Therefore, systematic standardized questionnaires are needed. However, the causative antigens are often not identified in daily clinical practice. When an antigen is identified or suspected, the first action is avoidance. If antigen avoidance does not contribute to clinical improvement, anti-inflammatory drugs such as prednisolone might be introduced. Regarding sarcoidosis, while most patients do not require treatment for lung involvement, some need anti-inflammatory drugs or immunosuppressants. Additionally, steroid treatment should be considered for the critical status of extrapulmonary sarcoidosis including cardiac, neurogenic and ocular sarcoidosis. Once starting treatment for ILD, multi-dimensional approaches are applied, including symptom tracking, chest imaging, pulmonary function test (PFT), and 6-min walking test. Recently, the concept of progressive-fibrosing interstitial lung disease (PF-ILD) has been proposed as a new disease entity. The definition of PF-ILD includes symptom progression, PFT decline, and extension of chest high-resolution computed tomography (HRCT) findings. This mini-review describes the background, definition, clinical characteristics, management, and challenges of PF-ILD.

Ageing with Interstitial lung disease: preserving health and well being.

Ageing, the accrual of molecular and cellular damage over a lifetime confers progressive physiologic dysfunction of bodily systems, leaving the body in a heightened state of vulnerability to biophysical and psychosocial stressors. The inflection point is frailty which easily leads to disability and death. Interstitial lung disease (ILD) creates biophysical and psychosocial stresses difficult for even optimally fit patients to cope with. With evolving ILD treatment pathways, people with ILD are living longer. ILD and ageing are bi-directionally influential: ILD, its treatments, complications, and collateral systemic extra-pulmonary damage (hypoxic and oxidative stress) wear on the ageing person and ageing impacts a person's tolerance of ILD. ILD extent may proportionally accelerate age-related vulnerabilities. ILD related to inflammatory systemic diseases, e.g. connective tissue diseases or sarcoidosis, exert an even more complex biophysical impact on the body. The present review stresses goals of preventing frailty in ILD and preserving general health and well being of people living with ILD of any age, from time of diagnosis and as they age. The development of a prediction score is proposed to classify those at risk of frailty and guide interventions that preserve successful ageing for all levels of ILD severity. http://links.lww.com/COPM/A32.

Treating Autoimmune-Related Interstitial Lung Disease With B Cell Depletion.

Autoimmune rheumatic diseases may affect vital organs with lung involvement being severe and difficult to treat manifestation. Systemic sclerosis (SSc) commonly affects the lung in the form of interstitial lung disease (ILD). ILD may be also seen in patients with rheumatoid arthritis (RA), Sjögren's syndrome (SS), systemic lupus erythematosus (SLE), inflammatory myositis (IM), antisynthetase syndrome (AS), and the ANCA-associated vasculitides (AAV). Rituximab (RTX) is an anti-CD20 B lymphocyte depleting mAb, often administered in the treatment of autoimmune rheumatic diseases. Although RTX is an off-label treatment for CTD–ILD, there are numerous reports providing data that is effective in improving both pulmonary function tests (PFTs) and chest computed tomography findings consistent with ILD. There are retrospective uncontrolled studies that assess RTX as a treatment of ILD in autoimmune diseases. These studies, apart from one, do not include patients with AAV-ILD. In SSc-ILD, in particular, there are both controlled and uncontrolled studies displaying encouraging results following B cell depletion. In addition, a number of retrospective uncontrolled studies and fewer prospective studies evaluate RTX in connective tissue diseases CTD–ILD. Although RTX is an approved treatment for AAV there are scarce only data focusing on patients with AAV-ILD specifically. The results of a handful of studies comparing treatment of CTD-ILD with RTX to treatment with other agents are in favor of RTX. Results from large, still ongoing controlled trials are awaited to ascertain RTX effects in ILD encountered in autoimmune rheumatic diseases. We review herein the results of the different RTX trials in patients with autoimmune disease–associated with ILD. Despite the heterogeneity of these studies, RTX may be considered an alternative and safe but still off-label treatment for patients with refractory CTD–ILD.

Surgical lung biopsy for interstitial lung diseases-a single center study of 129 patients.

BackgroundAccording to guidelines for the diagnosis and treatment of interstitial lung diseases (ILDs), a diagnostic surgical lung biopsy should be used to obtain the differential diagnosis of an ILD in patients with ILDs, which are difficult to distinguish clinically. However, the risk of developing postoperative complications such as postoperative pulmonary fistula or acute exacerbation is a concern. The purpose of this study was to evaluate the safety of surgical lung biopsy for the differential diagnosis of ILDs.MethodsFrom October 2007 to July 2019, 129 patients thought to have ILD underwent a surgical lung biopsy at Toho University Omori Medical Center. We conducted a retrospective study on the diagnosis and safety of surgical lung biopsy for patients with ILD.ResultsThe 30- and 60-day mortality was 0%. Postoperative complications occurred in 13 of 129 (10.1%) patients. The complications included pneumothorax in 8 (6.2%) patients after removal of the chest tube, postoperative pneumonia in 2 (1.0%), and acute exacerbation in 1 (0.8%). Postoperative pneumothorax was observed in 4 of 13 patients (30.7%) who underwent a biopsy of the apex of the lung (right S1, left S1+2), which was a significantly higher rate of postoperative pneumothorax than seen for patients undergoing biopsy at other sites (P=0.0086).ConclusionsSurgical lung biopsy for the differential diagnosis of an ILD was performed safely. However, biopsy sites for ILDs need to be carefully selected to avoid postoperative complications.

AB0705 Changes of lung function and skin fibrosis in patients with interstitial lung disease associated with systemic sclerosis on rituximab therapy - comparison of the efficacy of biosimilar Acellbia and Mabthera

BackgroundRituximab (RTX) has shown itself as an effective option in treatment of interstitial lung disease associated with systemic sclerosis (ILD-SSc). However, there is not enough data on the effect of rituximab biosimilars in patients (pts) with SSc. Biosimilars could reduce price and increase pts access to expensive, but more efficient biologic therapy. The RTX biosimilar Acellbia (ACB) was registered in Russian Federation for all indications consistent with RTX.ObjectivesTo study changes of lung function and skin fibrosis in pts with ILD-SSc on ACB therapy in comparison with original RTX (Mabthera (MBT) during 1 year of follow-up.MethodsThis prospective study included 62 pts received RTX as an addition to previous therapy, when it was ineffective. The mean follow-up period was 12.9±2.2 months. 31 pts received MBT (group 1) and 31 pts received ACB (group 2). All pts had ILD. In group 1 the mean age was 42.2±12.3 years, female-25 pts (81%), the diffuse cutaneous subset of the disease had 21 pts (68%). The mean disease duration was 5.3±3.5years. 91% of pts were positive for ANA and 77% of them were positive for antitopoisomerase-1. All pts received prednisolone at a dose of 11.2±3.9 mg/day, immunosupressants (IS) at inclusion received 39% of them. The cumulative mean dose of RTX was 1.5±0.5g. In group 2 the mean age was 48.7±11.3 years, female-23 pts (74%), the diffuse cutaneous subset of the disease had 16 pts (52%). The mean disease duration was 6.2±7.1years. 88% of pts were positive for ANA, 36% of them were positive for antitopoisomerase-1. All pts received prednisolone at a dose of 10.6±4.5mg/day, IS at inclusion received 42% of them. The cumulative mean dose of RTX was 1.4±0.5g. The results are presented in the form of mean values and standard deviations, delta(Δ)-difference between the baseline parameter and follow up point, median, lower quartile and upper quartile.ResultsThere was an improvement of all evaluated parameters in both groups: decrease of Rodnan skin score (mRSS) and activity index(EScSG-AI), increase of forced vital capacity % predicted (FVC), diffusion capacity for carbon monoxide % predicted (DLCO) and 6-minute walk distance (Table 1). Both groups managed to reduce the mean dose of prednisolone. B-lymphocyte depletion persisted in both groups. When we compared changes (Δ) of the parameters between groups - no significant difference was obtained (Table 1).Table 1.Changes of the main parameters at RXT therapy in delta (Δ); median; lower quartile; upper quartile.ParametersGroup 1Pfor Group 1 (between baseline and follow-up point)Group 2Pfor Group 2 (between baseline and follow-up point)Pbetween group 1 and 2Δ mRSS4.7±5.6[2; 0; 10]0.00014.3±4.1[3; 0; 8]0.0001NSΔ FVC, % pred4.9±5.6[5.8; 1.8; 7.8]0.00014.7±5.5[3.1; 0.9; 7]0.0002NSΔ DLCO, % pred2.3±5.1[1.4; -0.6; 5.5]0.032.5±3.8[2; 0.8; 4.9]0.001NSΔ Activity Index (EScSG-AI)2±1.9[2; 0; 3.5]0.00011.8±1.5[2; 1; 2]0.0001NSΔ B-lymphocyte, absolute count0,221±0,16[0.185; 0.09; 0.33]0.00010,216±0,17[0.135; 0.09; 0.34]0.0001NSΔ 6-minute walk distance, m60.4±67.5[42.5; 10; 91]0.00855.1±42.6[52.5; 13; 90]0.0003NSΔ Prednisolone, mg/day2.03±2.1[2.5; 0; 5]0.00062.1±2.7[2.5; 0; 5]0.0004NSCumulative mean dose of RTX, g, M±σ1.5±0.5-1.4±0.5-NSConclusionOur prospective study showed the similar effectiveness of АСB in comparison with MBT in ILD-SSc. There was a significant improvement of lung function tests and decrease of skin fibrosis. RTX has been shown the positive effect even at low doses (less than 2 g). ACB has shown a good efficacy for therapy ILD-SSc, but studies with a large number of patients are required.Disclosure of InterestsNone declared

AB0728 Comparative results of long-term (for 36 months) use of rituximab and immunosuppressants in patients with systemic scleroderma with interstitial lung disease in real clinical practice

BackgroundImmunosuppressants (IS) is considered as a drug of choice for the treatment of interstitial lung disease (ILD) in the patients with systemic sclerosis (SSc). However, the IS use leads to rather limited and transient improvement of the pulmonary fibrosis. In this context the search for novel, more efficacious agents have been continued, such as attracting much attention rituximab (RTM).ObjectivesTo compare the dynamics of pulmonary function parameters and skin fibrosis in patients with SSc associated with ILD, who received RTM and IS for 3 years in real clinical practice.Methods158 pts with the SSс-ILD were enrolled into the study. All pts received low- and moderate-dose glucocorticoids regimens. Group A (n=100) received IS’s (31/31% mycophenolate mofetil, 27/27% cyclophosphamide, 15/15% methotrexate; 27/27% other drugs; the patient’s average age was 49.5±12.2 years, with female proportion 87%; SSc duration 8.6±7.2 years; diffused/localized forms 1/ 2.8). Group B (n=58) received RTM a total dose 3.0±1.2 g, 22 patients received RTM in combination with ISs (11/19% mycophenolate mofetil, 11/19% cyclophosphamide; average age 48.0±13.2 years, female proportion 86%, SSc duration 6.4±4.9 years, diffused/localized forms 1.5/1). The therapy duration in both groups was 36 months. The time courses of forced vital capacity (FVC), diffusive lung capacity (DLC), modified skin count (mRss, points), activity index (EScSG, points), HAQ were assessed in the study.ResultsIn Groups A and B the therapy was associated with significant decrease in mRss and stabilization of the diffusive lung capacity. During the follow-up period in Groups A no change of the other studied parameters was observed.In Groups B the therapy was associated with significant decrease in HAQ and EScSG.Evaluation of FVC time course in Group B revealed significant FVC increase with median increment about 5.6%. In Group B 10% FVC increase was found in the third of the patients thus exceeding respective parameter in Group B (16%). The patient percentage with FVC decrease by ≥10% in group B was less common compared to group A.During RTM therapy it was possible to significantly reduce the dose of glucocorticoids.RTM and immunosuppressants administration for 36 months in the patients with SSc and ILD effectively alleviated skin induration and stabilized DLCO.Table 1.ParametersGroup Аn=100Group Вn=58рFVC1 M ± SD95.2±17.0Р=0.376.8±20.7P=0.0003FVC1 M ± SD96.5±18.983.8±22.2Δ FVC %, SD’S [25%’S; 75%’S]-0.7 [-5.8; 7,9]5.6 [-1.9;14.8]0.008DLCO 1, M ± SD62.6±19.9Р=0.0846.4±18.3P=0.6DLCO 2, M ± SD60.1±17.447.1±17.6Δ DLCO %-1.7 [-5.9;3.3]1.25 [-4; 7.05]0.15mRss, 1 M ± SD5.6±5.3P=0.00311.3±10.2P=0.000013mRss, 2 M ± SD4.3±3.75.5±4.8Δ mRss, SD’S [25%’S; 75%’S]0 [-2;0]-3 [-11;0]0.000031HAQ10.86±0.5P=0.91.14±0.8P=0.01HAQ20.86±0.60.9±0.8EScSG 1, M ± SD1.64±1.2P=0.42.6±P=0.0005EScSG 2,M ± SD1.8±1.31.4±Dose of glucocorticoids 1, mg8.8±4.8P=0.1611.4±4.0P=0.002Dose of glucocorticoids 2, mg8.1±3.79.1±2.9FVC increment by ≥10%, n/%16/1617/29.30.04FVC decrement by ≥10% n/%14/144/6.70.18DLCO increment by ≥10%, n/%6/65/8.60.5DLCO decrement by ≥10% n/%14/145/8.60.31 = before treatment, 2 = after treatment; M ± SD = mean value and standard deviation; * = significant difference between the vales measured before and after the treatmentConclusionOnly RTM significantly improved FVC and the patient’s quality of life and decreased of the activity index. RTM demonstrated a steroid-saving effect. The study findings substantiate potential use of RTM as a first-line agent for the treatment ILD progressive phenotype in SSc. The immunosuppressants use as a single-agent therapy is more preferable in patients with less pronounced ILD.Disclosure of InterestsNone declared

Therapeutic options for the treatment of interstitial lung diseases in systemic rheumatic diseases – systemic sclerosis as an example

Therapeutic options for the treatment of interstitial lung diseases in systemic rheumatic diseases – systemic sclerosis as an example

Rituximab in the Treatment of Interstitial Lung Diseases Related to Anti-Melanoma Differentiation-Associated Gene 5 Dermatomyositis: A Systematic Review.

ObjectiveThe effectiveness of rituximab in anti-melanoma differentiation-associated gene 5 (MDA5) dermatomyositis (DM) with interstitial lung disease (ILD) has been explored only in isolated case reports and small series. This paper aims to review the current evidence regarding rituximab (RTX) use in the treatment of ILD related to anti-MDA5 DM (anti-MDA5 DM-ILD).MethodsWe conducted a review by searching PubMed, Web of Science, Embase, and Cochrane for articles with information on patients with anti-MDA5 DM and RTX treatment, published until August 2021, in English language. The selected studies listed variation in chest high-resolution computed tomography (HRCT) and/or pulmonary function test (PFT) as a primary outcome, in patients with anti-MDA5 DM-related ILD after using RTX.ResultsOf the 145 potentially eligible articles, 17 were selected. The information gathered from a total of 35 patients with anti-MDA5 DM-ILD was reviewed, including 13 men and 22 women. Patient age at onset was 47.60 ± 13.72 years old. A total of 11.43% (4/35) of the patients were found to have chronic ILD (C-ILD) and 88.57% (31/30) exhibited rapidly progressive ILD (RP-ILD). Most patients (29/30) had typical DM rashes. Prior to RTX administration, the majority of patients (27/35) were treated with medium- or high-dose glucocorticoids and at least one additional immunotherapeutic agent. With regard to RTX efficacy for ILD in anti-MDA5 DM, 71.43% (25/35) of the patients responded to treatment. Skin rash also improved in more than half of the patients after RTX treatment. The most common side effects were infections, reported by 37.14% (13/35) of the patients after using RTX.ConclusionAs a CD20 targeting drug, RTX is a promising therapeutic tool for anti-MDA5 DM-ILD, although the risk of infections should be considered before treatment. Further prospective controlled studies are required to evaluate the optimal RTX treatment regimen.Systematic Review Registration https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021289714, identifier CRD42021289714.

Biologika bei Kollagenosen und Vaskulitiden

Despite therapy with glucocorticoids (GC) and conventional immunosuppressants, patients with connective tissue diseases and vasculitides often develop functionally relevant and prognostically unfavourable internal organ damage. Based on new pathogenetic insights, biologics and small molecules have recently been studied as targeted therapies for collagen vascular diseases and vasculitides. The B lymphocyte stimulator antagonist belimumab has been used for the treatment of systemic lupus erythematosus (SLE) for several years and has recently also been approved as an add-on therapy for lupus nephritis. Anifrolumab, an antibody against the type‑1 interferon receptor, has also been shown to be effective in phaseIII trials for the treatment of SLE. The interleukin (IL)-6-antagonist tocilizumab showed efficacy in the treatment of interstitial lung disease (ILD) in systemic sclerosis (SSc) and thus has been approved in the USA, although the phaseIII trial had anegative primary endpoint. In Europe the tyrosine inhibitor nintedanib is approved for progressive ILD in SSc. Tocilizumab is approved for the treatment of giant cell arteritis and reduces both the risk of recurrence and the cumulative GC requirement. The B‑lymphocyte depleting antibody rituximab is approved for induction and maintenance therapy of granulomatosis with polyangiitis and microscopic polyangiitis (MPA) and is currently also being investigated for the treatment of eosinophilic granulomatosis with polyangiitis (EGPA). In patients with EGPA, the IL‑5 antibody mepolizumab leads to improved disease control and reduces GC requirements. AphaseIII trial of the small molecule antagonist avacopan targeting the complement C5a receptor as areplacement for high-dose GC in induction therapy of GPA and MPA met its primary endpoints. Various other biologics and small molecule antagonists are currently in clinical development for several type of vasculitis and collagen vascular diseases, some of them at advanced stages.

Interstitial lung diseases associated with mutations of poly(A)-specific ribonuclease: A multicentre retrospective study.

Poly(A)-specific ribonuclease (PARN) mutations have been associated with familial pulmonary fibrosis. This study aims to describe the phenotype of patients with interstitial lung disease (ILD) and heterozygous PARN mutations. We performed a retrospective, observational, non-interventional study of patients with an ILD diagnosis and a pathogenic heterozygous PARN mutation followed up in a centre of the OrphaLung network. We included 31 patients (29 from 16 kindreds and two sporadic patients). The median age at ILD diagnosis was 59 years (range 54 to 63). In total, 23 (74%) patients had a smoking history and/or fibrogenic exposure. The pulmonary phenotypes were heterogenous, but the most frequent diagnosis was idiopathic pulmonary fibrosis (n=12, 39%). Haematological abnormalities were identified in three patients and liver disease in two. In total, 21 patients received a specific treatment for ILD: steroids (n=13), antifibrotic agents (n=11), immunosuppressants (n=5) and N-acetyl cysteine (n=2). The median forced vital capacity decline for the whole sample was 256 ml/year (range -363 to -148). After a median follow-up of 32 months (range 18 to 66), 10 patients had died and six had undergone lung transplantation. The median transplantation-free survival was 54 months (95% CI 29 to ∞). Extra-pulmonary features were less frequent with PARN mutation than telomerase reverse transcriptase (TERT) or telomerase RNA component (TERC) mutation. IPF is common among individuals with PARN mutation, but other ILD subtypes may be observed.

Coexistence of anti-topoisomerase I and anticentromere antibodies in a patient with systemic sclerosis. Efficacy of treatment combining rituximab and nintedanib. A case report

In the diagnostic of systemic sclerosis (SSc), both anti-centromere (ACA) and anti-topoisomerase I (ATA) antibodies are considered mutually exclusive, though their coexistence has been also reported in some patients. Notably, nintedanib has been approved for the treatment of interstitial lung disease associated to SSc. Herein, we present the clinical case of a 41-year-old woman with SSc who shows an immunological seroconversion (from ACA positivity to a coexistence of ACA and ATA antibodies) together with changes in her clinical phenotype. Besides, the patient responds positively to the treatment of her lung involvement with a combination of immunomodulators and antifibrotic agents.

Immunomodulatory treatment of interstitial lung disease.

Interstitial lung diseases (ILDs) other than idiopathic pulmonary fibrosis (IPF) have an array of immunomodulatory treatment options compared with IPF, due to their inflammatory component. However, there is a relative paucity of guidance on the management of this heterogeneous group of diseases. In ILDs other than IPF, immunosuppression is the cornerstone of therapy, with varying levels of evidence for different immunomodulatory agents and for each specific ILD. Classification of ILDs is important for guiding treatment decisions. Immunomodulatory agents mainly include corticosteroids, mycophenolate mofetil (MMF), azathioprine, methotrexate, cyclophosphamide and rituximab. In this review, the available evidence for single agents in the most common ILDs is first discussed. We then reviewed practical therapeutic approaches in connective tissue disease–related ILD and interstitial pneumonia with autoimmune features, scleroderma-related ILD, vasculitis and dermatomyositis with hypoxemic respiratory failure, idiopathic non-specific interstitial pneumonia, hypersensitivity pneumonitis sarcoidosis, fibrosing organizing pneumonia and eosinophilic pneumonia. The treatment of acute exacerbations of ILD is also discussed. Therapy augmentation in ILD is dictated by the recognition of progression of disease. Criteria for the evaluation of progression of disease are then discussed. Finally, specific protocol and measures to increase patients’ safety are reviewed as well, including general monitoring and serologic surveillance, Pneumocystis jirovecii prophylaxis, patients’ education, genetic testing for azathioprine, MMF serum levels and cyclophosphamide administration protocols. Immunomodulatory therapies are largely successful in the management of ILDs and can be safely managed with the application of specific protocols, precautions and monitoring.