Maria Chiara Ditto

Standard and pocket-size lung ultrasound devices can detect interstitial lung disease in rheumatoid arthritis patients

OBJECTIVES Interstitial lung disease (ILD) is a frequent extra-articular manifestation of RA associated with increased mortality. High-resolution CT (HRCT) is used for diagnosis and follow-up, but its accuracy is counterbalanced by high costs and radiological risk. In the presence of ILD, lung US (LUS) detects vertical artefacts called B-lines. The aims of the present study were to evaluate the accuracy of LUS in the diagnosis of ILD in RA and to validate the use of a pocket-size US device (PS-USD) as a screening tool. METHODS LUS was performed with standard equipment by a trained physician through longitudinal scans following anatomical lines: 72 segments were considered (28 anteriorly and 44 posteriorly) and B-lines were counted in each segment. A B-lines score >10 identified a positive examination (presence of ILD). A second LUS session for positive/negative judgment was performed by a short-trained physician using a PS-USD. RESULTS Thirty-nine patients were studied. The sensitivity and specificity of standard LUS vs HRCT were 92% and 56%, respectively. The B-line score was significantly correlated with HRCT score (r = 0.806). A total of 29 patients were studied with a PS-USD. Sensitivity and specificity for PS-USD vs HRCT were 89% and 50%. CONCLUSION The sensitivity of LUS in the detection of ILD supports its use as a screening test for ILD in RA patients, even in the ambulatory setting with a PS-USD. The strong correlation between echographic and HRCT scores indicates LUS is a valid tool for grading and follow-up of ILD.

Investigating the potential side effects of anti-TNF therapy for rheumatoid arthritis: cause for concern?

There are now five anti-TNF drugs available for clinical use, and it will not be long before they are joined by biosimilar drugs. Some patients treated with selective TNF drugs may develop adverse events such as infections, malignancies, acute infusion and injection reactions, autoimmunity and cardiovascular effects. Registry data consistently show that, particularly during the first 6 months, anti-TNF drugs slightly increase the risk of serious infections of the skin, soft tissues and joints, but it does not seem to increase the risk of cancer other than nonmelanoma skin cancers. A number of studies have shown that the administration of biological agents can lead to the formation of neutralizing and nonneutralizing antibodies. Lipid levels increase, but the atherogenic index remains stable and qualitative changes to lipid particles may reduce the risk of cardiovascular diseases. Patients treated with anti-TNF drugs therefore need to be monitored regularly.

The Microbiome in Connective Tissue Diseases and Vasculitides: An Updated Narrative Review

Objective To provide a narrative review of the most recent data concerning the involvement of the microbiome in the pathogenesis of connective tissue diseases (CTDs) and vasculitides. Methods The PubMed database was searched for articles using combinations of words or terms that included systemic lupus erythematosus, systemic sclerosis, autoimmune myositis, Sjögrens syndrome, undifferentiated and mixed CTD, vasculitis, microbiota, microbiome, and dysbiosis. Papers from the reference lists of the articles and book chapters were reviewed, and relevant publications were identified. Abstracts and articles written in languages other than English were excluded. Results We found some evidence that dysbiosis participates in the pathogenesis of systemic lupus erythematosus, systemic sclerosis, Sjögrens syndrome, and Behçets disease, but there are still few data concerning the role of dysbiosis in other CTDs or vasculitides. Conclusions Numerous studies suggest that alterations in human microbiota may be involved in the pathogenesis of inflammatory arthritides as a result of the aberrant activation of the innate and adaptive immune responses. Only a few studies have explored the involvement of dysbiosis in other CTDs or vasculitides, and further research is needed.

Measurement of Serum Klotho in Systemic Sclerosis

Background The aim of our study was to evaluate the serum concentration of klotho in a cohort of systemic sclerosis (SSc) patients compared to that of healthy controls and to correlate its levels with the degree and the kind of organ involvement. Methods Blood samples obtained from both patients and controls were collected and analysed by an ELISA test for the determination of human soluble klotho. Scleroderma patients were evaluated for disease activity through clinical, laboratory, and instrumental assessment. Results Our cohort consisted of 81 SSc patients (74 females, mean age 63.9 ± 13.1 years) and 136 healthy controls (78 females, mean age 50.5 ± 10.7 years). When matched for age, serum klotho concentration significantly differed between controls and patients (p < 0.001). However, in SSc patients, we did not find any significant association between serum klotho and clinical, laboratory, and instrumental findings. Lower serum levels of klotho were detected in 4 patients who were anticitrullinated peptide antibody (ACPA) positive (p = 0.005). Conclusions Our data show a lower concentration of klotho in the serum of SSc patients compared to that of healthy controls, without any significant association with clinical manifestations and laboratory and instrumental findings. The association between serum klotho and ACPA positivity requires further investigation.

Psoriatic Arthritis Registries.

The introduction of new biological drugs for the treatment of rheumatoid arthritis and spondyloarthritis has led to the creation of a number of registries in Europe and the United States. Most of them are sponsored by national rheumatology societies, and provide information that is useful in clinical practice concerning the clinical characteristics, efficacy, and safety of all licensed biological drugs. Their findings also help to improve our understanding of the quality of life and working ability of patients receiving biological drugs, and suggest methods for allocating resources. However, there are only a few registries for psoriatic arthritis, and efforts should be made to increase their number to obtain further reliable and useful data.

Certainties and uncertainties concerning the contribution of pericytes to the pathogenesis of systemic sclerosis

The role of pericytes in systemic sclerosis (SSc) is unclear because of the difficulty in phenotyping them. They are mainly distributed in the pre-capillary, capillary and post-capillary abluminal side of non-muscular micro-vessels, express platelet-derived growth factor receptors (PDGFRs), and preside over vascular integrity and regeneration. By establishing close contact with many endothelial cells, a single pericyte can regulate ion influx, mechanical stress, leukocyte diapedesis, and platelet activation. Moreover, under pathological conditions such as SSc, pericytes may acquire a contractile phenotype and respond to various stimuli, including endothelin, angiotensin II and reactive oxygen species. The pericytes of SSc patients share some molecular patterns with myofibroblasts or fibroblasts, including A disintegrin and metalloproteinase domain 12 (ADAM-12), α-smooth muscle actin (α-SMA), the extra domain A (ED-A) variant of fibronectin, and Thy-1. Following stimulation with PDGF-β or transforming growth factor-β (TGF-β), pericytes may acquire a myofibroblast phenotype, and produce extracellular matrix or indirectly promote fibroblast activation. They may also contribute to fibrosis by means of epigenetic regulation. The pericyte plasmalemma is particularly rich in caveolae containing caveolin-1, a deficit of which has been associated with defective vessel tone control and lung fibrosis in mice. Consequently, dysfunctional pericytes may underlie the microangiopathy and fibrosis observed in SSc patients. However, given its variability in biological behaviour and the lack of a pan-pericyte marker, the exact role of these cells in SSc warrants further investigation.

The Immunogenicity of Branded and Biosimilar Infliximab in Rheumatoid Arthritis According to Th9-Related Responses

Our objective was to evaluate the immunogenicity of branded and biosimilar infliximab by detecting changes in T-helper-9 (Th9) percentages induced by an in vitro stimulation test. Methods: Peripheral blood mononuclear cells collected from 55 consecutive rheumatoid arthritis (RA) outpatients (15 drug free, 20 successfully treated with branded infliximab, 20 branded infliximab inadequate responders) and 10 healthy controls were cultured, with or without 50 μg/mL of infliximab originator (Remicade®) or 50 μg/mL of infliximab biosimilar (Remsima®) for 18 h. Th9 lymphocytes were identified by means of flow cytometry as PU.1 and IRF4-expressing, IL-9-secreting CD4+ T cells. Furthermore, the markers CCR7 and CD45RA were used to distinguish naïve from memory IL-9 producer cells. Results: Under unstimulated conditions, the drug-free RA patients had the highest percentages of Th9 lymphocytes. Following stimulation with branded infliximab, the percentages of PU.1 and IRF4-expressing Th9 cells, CCR7+, CD45RA− (central memory) and CCR7−, CD45RA− (effector memory) cells significantly increased in the group of inadequate responders, but no significant variation was observed after exposure to the biosimilar of infliximab. Conclusions: Th9 cells seem to be involved in the immune response to the epitopes of branded, but not biosimilar, infliximab, and this may depend on the recall and stimulation of both central and effector memory cells.

AB0413 Induction and progression of subcutaneous nodulosis in rheumatoid arthritis patients treated with tocilizumab

Background Tocilizumab (TCZ) is a monoclonal antibody (moAb) directed against the IL-6 receptor approved for moderate-to severe rheumatoid arthritis (RA) treatment. Some authors have reported a beneficial effect of TCZ in preventing lung and subcutaneous nodulosis in RA patients. On the contrary, to our knowledge no data concerning the acceleration of subcutaneous nodulosis under TCZ therapy are currently available. Objectives We report a small case series of 5 RA patients experimenting an evident worsening of subcutaneous nodulosis during the treatment with intravenous tocilizumab. Methods Our cohort included 5 patients (1 male and 4 females, mean age ± Standard Deviation (SD) 64±10.6 years, mean disease duration ± SD 21.8±10.9 years). Four patients were rheumatoid factor and anti-citrullinated peptide antibodies positive. Each patient had been previously treated with several conventional and biologic drugs. At the time of observation, three subjects were practicing methotrexate (MTX), two patients were taking hydroxychloroquine (HCQ) and one patient was taking prednisone. Intravenous tocilizumab 8 mg/kg every 4 weeks was administered for a mean ± SD of 43.4±32.4 months, with a good disease control in 3 cases. All the patients had a previous history of subcutaneous nodulosis that considerably worsened during the treatment with tocilizumab. Patients experimented the development of new subcutaneous nodules localized at the fingers, elbows or the inframammary fold, tending to ulceration. The management of this medical event included the tapering of MTX, the administration of steroids, the addition of HCQ, the use of antibiotics and surgery. However, neither pharmacological nor surgical treatment was completely effective, as nodules tended to recur and to increase in number and dimensions. Results To our knowledge this is the first report describing an accelerated subcutaneous nodulosis in a small cohort of RA patients treated with tocilizumab. Disclosure of Interest None declared

AB0389 The immunogenicity of branded and biosimilar infliximab in rheumatoid arthritis according to th9-related responses

Background There are many evidences that Th9 lymphocytes take part to the pathogenesis of rheumatoid arthritis (RA), however it is unclear whether these cells are implicated in the immunogenicity of biologic agents. Objectives We aimed to evaluate the immunogenicity of branded and biosimilar infliximab by detecting changes in Th9 percentages following an “in vitro” stimulation test. Methods PBMCs from 55 consecutive RA outpatients (15 drug-free, 20 successfully treated with branded infliximab and 20 failing branded infliximab) and from 10 healthy controls were collected. PBMCs were cultured with/without 50 μg/mL infliximab originator (Remicade®) or 50 μg/mL infliximab biosimilar (Remsima®), 50 μg/mL Human IgG1kappa and 50 μg/mL recombinant Human IgG Fc for 18 hours. Th9 lymphocytes were identified by means of flow cytometry as PU.1+, IRF4+, IL9+ CD4+ cells. Furthermore, the markers CCR7 and CD45RA were used to distinguish naive from memory IL-9-producer cells. Results In unstimulated condition, RA patients showed the highest percentages of Th9 lymphocytes. Following stimulation with branded infliximab, the percentage of PU.1+, IRF4+ Th9 cells, CCR7+, CD45RA- central memory and CCR7-, CD45RA- effector memory IL-9 producer cells significantly increased in the group of infliximab non responder RA patients. On the contrary, no significant variation was observed after biosimilar exposure. Figures 1,2,3,4 resume the results. Conclusions According to our results, Th9 cells seem to be involved in the immune response against the epitopes of branded but not biosimilar infliximab and this condition could rely on the recall and the stimulation of both central and effector memory cells. Further studies are indeed needed to confirm these data. Disclosure of Interest None declared

AB0635 Measurement of Serum Alpha-Klotho in Systemic Sclerosis Patients: Results from A Pivotal Study

Background Systemic sclerosis (SSc) is a connective tissue disease characterized by microangiopathy and fibrosis involving skin and inner organs. Furthermore, an aberrant activation of the immune system may contribute, at least in part, to the pathogenesis of the disease. Klotho, expressed both as transmembrane and soluble protein, contributes to prevent ageing, hyperphosphatemia, fibrosis, arteriosclerosis, inflammation, and cancer development. Mice lacking klotho gene expression develop an accelerated ageing, with different phenotypes ranging from atherosclerosis and hyperphosphatemia to skin atrophy and emphysema. A deficiency in klotho expression could be responsible for microangiopathy, calcinosis and fibrosis, which represent common characteristics of systemic sclerosis (fig. 1). Objectives To evaluate the serum concentration of a-klotho in a group of SSc patients compared to healthy controls and to correlate its levels with the degree and the kind of organs involvement, assessed through Mesdgers scale score. Methods We enrolled 69 patients affected by SSc, according to ACR/EULAR 2013 criteria, and 77 matched HC. Blood samples obtained from both patients and controls were collected and analysed by an ELISA test for the determination of human soluble a-klotho by using an anti-human Klotho Mouse IgG (My Biosource, CA, USA). Scleroderma patients were assessed for disease activity through Mesdgers scale. Moreover, modified Rodnan Skin Score (mRSS), pulmonary function tests, 2D echocardiography, chest high resolution computerized tomography, serum creatinine level, ESR, and CRP were also assessed. Subjects suffering from uncontrolled diabetes, lung obstructive diseases or renal impairment not depending on systemic sclerosis were excluded. Results Our cohort consisted of 69 SSc patients (61 females, mean age 64.5±12.5 years, mean disease duration 9.1±6.7 years) and 77 healthy controls (28 females, mean age 49,7±10,2 years). Demographic data are reported in tab.1. Patients were treated with calcium channels blockers (21 cases), i.v.prostanoids (all), immunosuppressive drugs (prednisone in 22 cases; hydroxychloroquine in 14 cases; mofetilmycophenolate in 3 cases; methotrexate in 6 cases; cyclosporin A in 1 case; azathyoprine in 5 cases). Overall, SSc patients have lower serum klotho concentration than healthy controls (0.45 + 0.43 ng/ml vs 0.59 + 0.39 ng/ml; p=0.023197; fig.2). However, in SSc patients Spearman test did not reveal a significant association between the serum concentration of klotho and Mesdgers scores. Furthermore, we did not find any association among klotho levels and mRSS, DLCO/AV, serum creatinine, disease duration, age of the patients, ESR and CRP. Conclusions To our knowledge, this is the first study aiming to investigate the serum concentration of klotho in SSc patients. Our data showed a lower concentration of klotho in the serum of SSc patients compared to healthy controls. However, klotho levels were not related to the severity of the disease, assessed through Mesdger scale, neither to lung or kidney functional impairment, skin fibrosis or systemic inflammation. Disclosure of Interest None declared