Personalized Medicine and Machine Learning: A Roadmap for the Future

In the last ten years, many advances have been made in the treatment and diagnosis of immune-mediated diseases [...]

Combination Therapy with Nintedanib and Sarilumab for the Management of Rheumatoid Arthritis Related Interstitial Lung Disease

Rheumatoid arthritis (RA) is a chronic, systemic, inflammatory disease characterized by joint and extra-articular involvement. Among them, interstitial lung disease (ILD) is one of the most common and severe extra-articular manifestations, with a negative impact on both therapeutic approach and overall prognosis. ILD can occur at any point of the natural history of RA, sometimes before the appearance of joint involvement. Since no controlled studies are available, the therapeutic approach to RA-ILD is still debated and based on empirical approaches dependent on retrospective studies and case series. Here, we report the case of a 75-year-old patient affected by RA complicated by ILD successfully treated with a combination therapy of an antifibrotic agent, nintedanib, and an inhibitor of IL-6 receptor, sarilumab. We obtained a sustained remission of the joint involvement and, simultaneously, a stabilization of the respiratory symptoms and function, with a good safety profile. To date, this is the first report describing a combination therapy with nintedanib and a disease-modifying antirheumatic drug (DMARD) for the management of RA complicated by ILD. Future prospective studies are needed to better define efficacy and safety of this approach in the treatment of these subjects

COST ANALYSIS RELATED TO SUBCUTANEOUS IMMUNOGLOBULINS IN PATIENTS WITH INFLAMMATORY MYOPATHIES AND IMMUNE-MEDIATED CHRONIC NEUROPATHIES. RESULTS OF AN OPEN LABEL STUDY

Background: Intravenous Immunoglobulins (IVIg) represent a relevant treatment option in various immune-mediated disorders such as idiopathic inflammatory muscle diseases (IIMD), immune-mediated chronic neuropathies (IMCN), hematologic autoimmune diseases, Still disease, Felty syndrome, systemic lupus erythematosus, vasculitis, some organ-specific autoimmune disease, and atopic diseases. The IVIg treatment is expensive and need of hospital-based assistance for administration; the recent avaibility of home-therapy with subcutaneous immunoglobulins (SCIg) may significantly reduce costs and improve the patient's quality of life. Objectives: The primary objective was to perform an analysis of costs of SCIg administration in patients affected by IIMD or IMCN compared to that of previous IVIg treatments. Methods: We prospectively evaluated 6 consecutive patients (3 males and 3 females, mean age 65,3 years, range 63 - 77), 2 affected by IIMD in the context of polymiositis and 4 by IMCN, 3 in the context of vasculitis and 1 in the context of undifferentiated connective tissue disease. All patients were previously treated with IVIg at the dosage of 2g/Kg monthly, (mean monthly dosage 143 g, range 98 – 160, average patient weight 71,5 kg, range 49 - 80), with good clinical and humoral response. After a mean therapy duration of 49.8 months (range 12 – 125) all patients were shifted to SCIg at the dosage of 10 g twice a week (80 g monthly). Each patient was followed-up by humoral and clinical evaluation, including Medical Research Council (MRC) score to quantify muscle strength and INCAT Sensory Score to evaluate sensory symptoms. The costs of the two therapeutic strategies were also compared, excluding indirect costs (absences from work and productivity losses, transport and parking, health care sector costs). Results: In 5/6 patients, we observed the maintenance of clinical and humoral status after a mean follow-up of 21 months (range 4 - 51), in particular we observed a stability in MRC score in patients presenting loss of strenght and INCAT score in patients presenting sensory symptoms. Furthermore, the treatment with SCIg was well-accepted and preferred to IVIg by all patients. In one patient SCIg were discontinued after 2 weeks, because of the appearance of a haemorrhagic lesions nearby the injection site (in the same patient IVIg have been stopped because of a hypertensive crisis during the infusion). Direct cost associated to IVIg amount to 252€ for 5 g of immunoglobulins (7,056€ monthly, considering a protocol of 2 g/kg/monthly and a patient-weight of 70kg), while direct costs associated to SCIg (20g weekly) amount to 6,400€/monthly, with a saving of 656€/monthly and 7,872€/yearly. In our case-series the annual saving was 9,686.40€/patient (from 86,486.40€ to 76,800€, for IVIg and SCIg, respectively). Conclusions: Our experience suggests that the shift to SCIg from IVIg in patients affected by IIMD and IMCN is feasible, cost-effective, safe and well-accepted by patients. Further studies are needed to evaluate the effectiveness of SCIg in first-line therapy of these diseases

Carotidynia Possibly due to Localized Vasculitis in a Patient with Latent Mycobacterium tuberculosis Infection.

Carotidynia is a syndrome characterized by tenderness of the carotid artery near the bifurcation due to numerous, heterogeneous causes. Here we reported the case of a 31-year-old Moroccan woman with right-sided neck pain and tenderness with irradiation to ipsilateral ear, eye, and occipital region. Clinical symptoms and imaging findings were suggestive of primary variant of carotidynia syndrome. In particular, color-Doppler ultrasonography revealed a concentric wall thickening of the distal common carotid artery, while thoracic magnetic resonance showed localized perivascular enhancement of the soft tissue in the right medial-distal common carotid artery in T1-weighted images, without intraluminal diameter variation. Moreover, careful clinicoserological and imaging investigations (cranial, cervical, and thoracic angiocomputed tomography and magnetic resonance) excluded well-known disorders potentially responsible for carotidynia syndrome. The patient was scarcely responsive to nonsteroidal anti-inflammatory drugs, but clinical symptoms resolved after three months. Of interest, the patient showed latent Mycobacterium tuberculosis infection (positive tuberculosis interferon-gamma release assay; QuantiFERON-TB Gold); this finding suggested a possible triggering role of mycobacterial antigens in the immune-mediated mechanism responsible for localized carotid injury

Treatment of Rheumatoid Arthritis-Associated Interstitial Lung Disease: Lights and Shadows

Rheumatoid arthritis (RA) is a chronic and systemic inflammatory disease affecting 0.5-1% of the population worldwide. Interstitial lung disease (ILD) is a serious pulmonary complication of RA and it is responsible for 10-20% of mortality, with a mean survival of 5-8 years. However, nowadays there are no therapeutic recommendations for the treatment of RA-ILD. Therapeutic options for RA-ILD are complicated by the possible pulmonary toxicity of many disease modifying anti-rheumatic drugs (DMARDs) and by their unclear efficacy on pulmonary disease. Therefore, joint and lung involvement should be evaluated independently of each other for treatment purposes. On the other hand, some similarities between RA-ILD and idiopathic pulmonary fibrosis and the results of the recent INBIULD trial suggest a possible future role for antifibrotic agents. From this perspective, we review the current literature describing the pulmonary effects of drugs (immunosuppressants, conventional, biological and target synthetic DMARDs and antifibrotic agents) in patients with RA and ILD. In addition, we suggest a framework for the management of RA-ILD patients and outline a research agenda to fill the gaps in knowledge about this challenging patient cohort

Therapeutic Options for the Treatment of Interstitial Lung Disease Related to Connective Tissue Diseases. A Narrative Review

Interstitial lung disease (ILD) is one of the most serious pulmonary complications of connective tissue diseases (CTDs) and it is characterized by a deep impact on morbidity and mortality. Due to the poor knowledge of CTD-ILD's natural history and due to the difficulties related to design of randomized control trials, there is a lack of prospective data about the prevalence, follow-up, and therapeutic efficacy. For these reasons, the choice of therapy for CTD-ILD is currently very challenging and still largely based on experts' opinion. Treatment is often based on steroids and conventional immunosuppressive drugs, but the recent publication of the encouraging results of the INBUILD trial has highlighted a possible effective and safe use of antifibrotic drugs as a new therapeutic option for these subjects. Aim of this review is to summarize the available data and recent advances about therapeutic strategies for ILD in the context of various CTD, such as systemic sclerosis, idiopathic inflammatory myopathy and Sjogren syndrome, systemic lupus erythematosus, mixed connective tissue disease and undifferentiated connective tissue disease, and interstitial pneumonia with autoimmune features, focusing also on ongoing clinical trials

Radiomics to predict the mortality of patients with rheumatoid arthritis-associated interstitial lung disease: A proof-of-concept study

OBJECTIVES: Patients with rheumatoid arthritis (RA) and interstitial lung disease (ILD) have increased mortality compared to the general population and factors capable of predicting RA-ILD long-term clinical outcomes are lacking. In oncology, radiomics allows the quantification of tumour phenotype by analysing the characteristics of medical images. Using specific software, it is possible to segment organs on high-resolution computed tomography (HRCT) images and extract many features that may uncover disease characteristics that are not detected by the naked eye. We aimed to investigate whether features from whole lung radiomic analysis of HRCT may alone predict mortality in RA-ILD patients. METHODS: High-resolution computed tomographies of RA patients from January 2012 to March 2022 were analyzed. The time between the first available HRCT and the last follow-up visit or ILD-related death was recorded. We performed a volumetric analysis in 3D Slicer, automatically segmenting the whole lungs and trachea via the Lung CT Analyzer. A LASSO-Cox model was carried out by considering ILD-related death as the outcome variable and extracting radiomic features as exposure variables. RESULTS: We retrieved the HRCTs of 30 RA-ILD patients. The median survival time (interquartile range) was 48 months (36–120 months). Thirteen out of 30 (43.33%) patients died during the observation period. Whole line segmentation was fast and reliable. The model included either the median grey level intensity within the whole lung segmentation [high-resolution (HR) 9.35, 95% CI 1.56–55.86] as a positive predictor of death and the 10th percentile of the number of included voxels (HR 0.20, 95% CI 0.05–0.84), the voxel-based pre-processing information (HR 0.23, 95% CI 0.06–0.82) and the flatness (HR 0.42, 95% CI 0.18–0.98), negatively correlating to mortality. The correlation of grey level values to their respective voxels (HR 1.52 95% CI 0.82–2.83) was also retained as a confounder. CONCLUSION: Radiomic analysis may predict RA-ILD patients’ mortality and may promote HRCT as a digital biomarker regardless of the clinical characteristics of the disease

PAP-TEST FEATURES IN A COHORT OF SYSTEMIC SCLEROSIS PATIENTS

Background: Increased incidence of malignancies was frequently reported in systemic sclerosis (SSc), as well as for other autoimmune diseases. Besides the previously observed association with lung cancer1 and the increased risk for breast cancer2, no association with cancer of the cervix has been described in literature. However, cervical uterus malignancy is one of the most frequent cancer in women so that public health programs of screening have been established in several countries worldwide. In Italy, the pap cytology test is recommended every 3 years for all women between 25 and 64 years old. Objectives: To investigate pap-test features in SSc patients. Methods: We retrospectively evaluated a cohort of 80 consecutive female SSc patients (mean age 51.2±12SD years, disease duration 7.9±5.8SD years, limited/diffuse skin subsets 72/8), who underwent to pap cytology tests as screening for cancer of the cervix, during the period between January 1st, 2008 and December 31th, 2014. All patients came from the same geographical area (province of Modena, Northern Italy). Clinical, serological, and instrumental data of SSc patients were collected and related to cytological findings. Results: At gynaecological and pap test evaluations, 55 (68.7%) patients were negative, while 20 (25%) presented inflammatory alterations (i.e. chronic cervicitis); while atypical cells related to cancer or pre-cancerous lesions were found in 5 (6.2%) cases. Namely, 2 women showed cervix cancer (one of them in situ), 1 a vulvar melanoma, 1 a vulvar intraepithelial neoplasia, and 1 an endocervical polyp with immature squamous metaplasia at histology. The frequency of cervix cancer in our series seems to be clearly higher in comparison to the incidence registered in the same geographical area and in the same years (standardized rate 8, 95%IC 5.2-10.7 cases out of 100,000 subjects). At statistical analysis, the atypical cytological findings correlated with serum anti-Scl70 autoantibodies (4/5 vs. 19/75; p=0.022); moreover, the patients with these alterations tended to be older (median 65, range 46-67), if compared to the whole series (p=0.052). No statistical correlations with skin or visceral involvements, smoking history, treatment with immunosuppressors were found. Conclusions: In our SSc patients' series, we found a relatively high frequency of cancerous lesions of the cervix by means of pap test. A significant correlation with anti-Scl70 autoantibodies was also found. These preliminary findings need to be verified in larger controlled epidemiological studies