Efficacy of cyclophosphamide in treating connective tissue disease-related interstitial lung diseases.

Interstitial lung diseases (ILDs) are some of the first and most serious complications of connective tissue diseases (CTDs). However, the pathogenesis of CTD-related ILDs (CTD-ILDs) is still unclear and their treatment often depends on functional and radiographic disease progression as well as on patient age and comorbidities. It can be difficult to manage CTD-ILDs due to their heterogeneous nature, the lack of robust therapeutic data, and the few well-defined outcome measures. This review focuses on cyclophosphamide due to its crucial role in the treatment of systemic sclerosis-related ILD, particularly in the case of patients with progressive ILD. This narrative review was performed using PubMed, Medline, and Cochrane Library databases to retrieve English language papers published between 2000 and April 2020 concerning the treatment of CTD-ILDs with cyclophosphamide.

The effect of drugs used in rheumatology for treating SARS-CoV2 infection.

INTRODUCTION: SARS-CoV-2 is a novel coronavirus that was first isolated from a group of patients hospitalized with pneumonia in China at the end of 2019, and, in February 2020, the syndrome it caused was named coronavirus disease 2019 (COVID-19) by the World Health Organization. In the absence of specific antiviral treatments capable of neutralizing the etiological agent, one therapeutic approach is to control the cytokine storm responsible for the most severe forms of the disease. The characteristic cytokine profile of severely affected patients is increased levels of interleukin (IL)-1ß, IL-2, IL-6, IL-7, IL-8, and tumor necrosis factor alpha (TNF-α). AREAS COVERED: This article discusses the pathogenesis of COVID-19 as a rationale for using the biological and targeted synthetic drugs used in rheumatology (anti-TNF, anti-IL-1 and anti-IL-6 agents and baricitinib) to treat the disease, and provides key information concerning their potential benefits and adverse effects. EXPERT OPINION: Interleukin inhibition seems to be a promising means of treating COVID-19 patients when respiratory function declines (or even earlier) if there are laboratory data indicating the presence of a cytokine storm because the interleukins are key drivers of inflammation. However, it is important to consider the risks and benefits of biological agents carefully, and critically analyze the evidence concerning their use in COVID-19 patients.

Concerns about the safety of anti-TNF agents when treating rheumatic diseases.

INTRODUCTION: More than 15 years after its introduction, there is still no agreement as to whether anti-TNF treatment increases the risk of developing infections, cardiovascular or neurological diseases, or auto-antibodies. Anti-TNF drugs reduce inflammation and sub-clinical atherosclerosis in rheumatoid arthritis (RA) patients, but they also alter their lipid profiles and can lead to the development of severe infections. Furthermore, as they increase the risk of developing demyelinating diseases, are not recommended in patients with multiple sclerosis or related disorders. The authors searched the Medline database for English language articles concerning the adverse events of anti-TNF drugs published between 1998 and December 2019, and have summarized their contents relating to infections, malignancies, cardiovascular diseases, autoimmunity and neurological diseases. Patients should be fully informed of the increased risks associated with anti-TNF drugs, and physicians should know how to treat them. AREAS COVERED: This review considers these safety concerns, their possible underlying causes, and other aspects that are important in clinical practice. EXPERT OPINION: Growing concern about the safety of anti-TNF drugs underlines the need to ensure that all clinicians are capable of taking appropriate preventive and therapeutic action.

Adverse events, clinical considerations and management recommendations in rheumatoid arthritis patients treated with JAK inhibitors.

BACKGROUND: A new class of oral synthetic drugs has been developed for the treatment of rheumatoid arthritis (RA) with the aim of blocking the Janus kinase/signal transducer and activator of transcription (JAK-STAT) system. Tofacitinib and baricitinib have been approved for the treatment RA patients who inadequately respond to methotrexate or anti-tumor necrosis factor drugs. The aim of this narrative review is to summarize the data concerning the drugs' basic mechanisms and clinical trial results in order to inform clinicians about the serious and non-serious adverse events associated with JAK inhibitors. Areas covered: The mechanisms, adverse events, and clinical trial data associated with the use of JAK inhibitors in RA patients were reviewed by searching the PubMed, Medline, and Cochrane Library databases for papers published between 1999 and April 2018 using combinations of words or terms. Articles not written in English were excluded. Expert commentary: Management of the adverse events of JAK inhibitors is challenging because of the lack of robust treatment data used and the heterogeneity of the events themselves. Treatment decisions are often made clinically on the basis of age and the burden of comorbidities, and require the multidisciplinary collaboration of rheumatologists and other specialists.

Association between cortisol levels and pain threshold in systemic sclerosis and major depression.

Pain perception and threshold show complex interactions with the inflammatory, psychiatric and neuroendocrine stimuli. This study aims to test whether lower serum cortisol levels are associated with lower pain thresholds and higher degree of depression in systemic sclerosis (SSc) and major depression with atypical features (MD-AF) patients compared to controls. 180 female subjects (SSc = 60, MD-AF = 60, healthy controls = 60) participated in this observational, cross-sectional, parallel group study. Pressure pain threshold (PPT) was assessed in three anatomical sites: nail bed (NB), metacarpophalangeal joint (MCP) and quadriceps muscle (QDR). Depressive symptoms were evaluated using the Beck Depression Inventory (BDI) scale and morning serum cortisol levels were collected. In SSc patients, quality of life was measured through the Health Assessment Questionnaire (HAQ-DI) and the scleroderma-specific visual analogue scales (scleroderma-VAS). Lower PPT scores (NB 4.42 ± 1.6; MCP 4.66 ± 1.4; QDR 4.79 ± 1.5) were observed in SSc patients compared to both MD-AF (NB 7.33 ± 2.2; MCP 6.01 ± 1.9; QDR 6.31 ± 1.6; p < 0.005) and controls (NB 9.57 ± 2; MCP 7.9 ± 2.1 and QDR 8.43 ± 2.1; p < 0.0001), while MD-AF patients had lower PPT scores compared to controls (p < 0.0001). SSc patients had also lower serum cortisol levels compared to MD-AF patients (8.78 vs 13.6 µg/dl; p < 0.05). A direct correlation was observed between serum cortisol and PPT scores both in SSc (r 2 for NB 0.29; for MCP 0.25; for QDR 0.27) and in MD-AF (r 2 for NB 0.34; for MCP 0.25; for QDR 0.47; p < 0.05), while depressive symptoms negatively correlated with serum cortisol (r 2 for NB 0.34; for MCP 0.17; for QDR 0.15) and in MD-AF (r 2 for NB 0.19; for MCP 0.31; for QDR 0.30; p < 0.05). Among SSc patients, those with serum cortisol levels below the normal range (n = 16) had higher BDI scores (15, 6-21 vs 9, 2-15; p < 0.005), lower PPTs (NB 4 ± 1.4 vs 4.9 ± 0.9; MCP 4.1 ± 0.8 vs 4.8 ± 0.9; QDR 4.1 ± 1.2 vs 5 ± 0.9; p < 0.005) and higher HAQ-DI (1.25, 0.25-2 vs 0.75, 0-1.25; p < 0.05) and scleroderma-VAS scores (VAS overall severity 7, 5.5-9.5 vs 4.5, 2.5-6; p < 0.05). The effect of cortisol serum levels upon pain mechanism, in chronic inflammatory conditions warrants longitudinal studies to detect treatable variations in pain thresholds, depressive symptoms and to improve quality of life.

Mastocytosis and systemic sclerosis: a clinical association.

BACKGROUND: Systemic sclerosis (SSc) is a complex autoimmune disease characterized by vascular alterations and autoimmune activation leading to widespread organ fibrosis. At the early stage of disease when organ involvement and extent of disease are emerging, mast cells may have some role, as implied by both symptoms and histologic evidence. CASE PRESENTATION: A female patient diagnosed with cutaneous mastocytosis experienced the onset of systemic sclerosis after 15 years followed by the switch of mastocytosis to the systemic phenotype. A literature review on the evidences related to mast-cells activation in systemic sclerosis is presented below. CONCLUSIONS: For clinicians, more attention must be paid to the potential association between systemic sclerosis and cancer. This case suggests that a proliferative disease in the mast cell compartment-though representing a rare association-may not be completely unexpected in SSc and perhaps excess mast cell activity can serve a pathogenic role in promoting fibrotic disease.

Propylthiouracil prevents cutaneous and pulmonary fibrosis in the reactive oxygen species murine model of systemic sclerosis.

INTRODUCTION: Recent advances suggest that the cellular redox state may play a significant role in the progression of fibrosis in systemic sclerosis (SSc). Another, and as yet poorly accounted for, feature of SSc is its overlap with thyroid abnormalities. Previous reports demonstrate that hypothyroidism reduces oxidant stress. The aim of this study was therefore to evaluate the effect of propylthiouracil (PTU), and of the hypothyroidism induced by it, on the development of cutaneous and pulmonary fibrosis in the oxidant stress murine model of SSc. METHODS: Chronic oxidant stress SSc was induced in BALB/c mice by daily subcutaneous injections of hypochlorous acid (HOCl) for 6 weeks. Mice (n = 25) were randomized into three arms: HOCl (n = 10), HOCl plus PTU (n = 10) or vehicle alone (n = 5). PTU administration was initiated 30 minutes after HOCl subcutaneous injection and continued daily for 6 weeks. Skin and lung fibrosis were evaluated by histologic methods. Immunohistochemical staining for alpha-smooth muscle actin (α-SMA) in cutaneous and pulmonary tissues was performed to evaluate myofibroblast differentiation. Lung and skin concentrations of vascular endothelial growth factor (VEGF), extracellular signal-related kinase (ERK), rat sarcoma protein (Ras), Ras homolog gene family (Rho), and transforming growth factor (TGF) ß were analyzed by Western blot. RESULTS: Injections of HOCl induced cutaneous and lung fibrosis in BALB/c mice. PTU treatment prevented both dermal and pulmonary fibrosis. Myofibroblast differentiation was also inhibited by PTU in the skin and lung. The increase in cutaneous and pulmonary expression of VEGF, ERK, Ras, and Rho in mice treated with HOCl was significantly prevented in mice co-administered with PTU. CONCLUSIONS: PTU, probably through its direct effect on reactive oxygen species or indirectly through thyroid function inhibition, prevents the development of cutaneous and pulmonary fibrosis by blocking the activation of the Ras-ERK pathway in the oxidant-stress animal model of SSc.

Bone mineral density, bone turnover markers and fractures in patients with systemic sclerosis: a case control study.

OBJECTIVE: The aim of our study was to elucidate the pathophysiology of systemic sclerosis-related osteoporosis and the prevalence of vertebral fragility fracture in postmenopausal women with systemic sclerosis (SSc). METHODOLOGY: Fifty-four postmenopausal women with scleroderma and 54 postmenopausal controls matched for age, BMI, and smoking habits were studied. BMD was measured by dual energy-x-ray absorptiometry at spine and femur, and by ultrasonography at calcaneus The markers of bone turnover included serum osteocalcin and urinary deoxypyridinoline. All subjects had a spine X-ray to ascertain the presence of vertebral fractures. RESULTS: bone mineral density at lumbar spine (BMD 0.78±0.08 vs 0.88±0.07; p<0,001), femoral neck (BMD: 0.56±0.04 vs 0.72±0.07; p<0,001) and total femur (BMD: 0.57±0.04 vs 0.71±0.06; p<0,001) and ultrasound parameter at calcaneus (SI: 80.10±5.10 vs 94.80±6.10 p<0,001) were significantly lower in scleroderma compared with controls; bone turnover markers and parathyroid hormone level were significantly higher in scleroderma compared with controls, while serum of 25(OH)D3 was significantly lower. In scleroderma group the serum levels of 25(OH)D3 significantly correlated with PTH levels, BMD, stiffness index and bone turnover markers. One or more moderate or severe vertebral fractures were found in 13 patients with scleroderma, wherease in control group only one patient had a mild vertebral fracture. CONCLUSION: Our data shows, for the first time, that vertebral fractures are frequent in subjects with scleroderma, and suggest that lower levels of 25(OH)D3 may play a role in the risk of osteoporosis and vertebral fractures.

Simvastatin attenuates the development of pulmonary and cutaneous fibrosis in a murine model of systemic sclerosis.

OBJECTIVE: The antifibrotic effect of simvastatin has been demonstrated in human lung fibroblasts. This study aimed to measure the effects of simvastatin in the development of pulmonary and cutaneous fibrosis in a murine model of SSc and to explore the mechanisms of these effects. METHODS: Chronic oxidant stress SSc was induced in BALB/c mice by daily s.c. injections of HOCl for 6 weeks. Mice were randomized in three arms: treatment with HOCl, HOCl plus simvastatin or vehicle alone. Statin treatment was initiated 30 min after HOCl s.c. injection and continued daily for 6 weeks. Skin and lung fibrosis were evaluated by histological methods. Immunohistochemical staining for α-smooth muscle actin in cutaneous and pulmonary tissues was performed to evaluate myofibroblast differentiation. Lung and skin concentrations of VEGF, extracellular signal-related kinase (ERK), rat sarcoma protein (Ras), Ras homologue gene family (Rho) and TGF-ß were analysed by western blot. RESULTS: Injections of HOCl induced cutaneous and lung fibrosis in BALB/c mice. Simvastatin treatment prevented both skin thickness and pulmonary fibrosis. Myofibroblast differentiation was also inhibited by simvastatin in the skin and in the lung. Increased cutaneous and pulmonary expression of VEGF, ERK, Ras and Rho in mice treated with HOCl was significantly lower in mice treated with HOCl plus simvastatin. CONCLUSION: Simvastatin reduces the development of pulmonary fibrosis, potentially modulating adverse lung remodelling, as shown by the reduced deposition of collagen in alveolar septae. Simvastatin also reduces skin thickness in this model.

Remission of Behcet's disease with anti-tumor necrosis factor monoclonal antibody therapy: a case report.

BACKGROUND: Behcet's disease (BD) is a chronic relapsing multisystem inflammatory disorder with mucocutaneous, ocular, articular, vascular, gastrointestinal and central nervous system manifestations. Tumor necrosis factor (TNF)-alpha is believed to play a pivotal role in BD. Therapeutic blockade of the activity of TNF has been successfully given in a short course of therapy with favorable effects in patients with BD refractory to conventional immunosuppressive drugs. We aimed to find out whether a 12-month treatment with infliximab, a chimeric monoclonal antibody to TNF-alpha, had any beneficial effect in reducing relapses of a patient with long-standing BD refractory to conventional immunosuppressive drugs. CASE PRESENTATION: A 54 year-old-woman with a 35-year history of BD with orogenital ulcerations, arthritis in the right knee and retinal lesions compatible with vasculitis received infliximab, 5 mg/kg by a two-hour intravenous infusion. Symptoms improved within 24 hours and eight days later the genital and oral ulcers healed as well as the arthritis in the right knee subsided. The retinal infiltrates completely resolved within 10 days. The infusions were repeated at weeks 2, 6, 14, 22 and then every 8 weeks. The patient was able to return to her domestic daily life. No exacerbation of the mucocutaneous ocular or arthritic symptoms occurred during the treatment period. CONCLUSIONS: Previous studies have suggested that infliximab given in a short course of treatment is effective in inducing remission of severe mucocutaneous, gastrointestinal and ocular manifestations of BD. Our patient received a 12-month infliximab treatment showing a favorable effect on remission of BD manifestations. The long-term infliximab treatment appears as a new therapeutic option for patients with active BD who failed to respond to conventional immunosuppressive agents.