Search

Elevated concentrations of soluble urokinase plasminogen activator receptor (suPAR) predict progression to severe respiratory failure (SRF) or death among patients with COVID-19 pneumonia and guide early anakinra treatment. As suPAR testing may not be routinely available in every health-care setting, alternative biomarkers are needed. We investigated the performance of C-reactive protein (CRP), interferon gamma-induced protein-10 (IP-10) and TNF-related apoptosis-inducing ligand (TRAIL) for predicting SRF or death in COVID-19.Two cohorts were studied; one discovery cohort with 534 patients from the SAVE-MORE clinical trial; and one validation cohort with 364 patients from the SAVE trial including also 145 comparators. CRP, IP-10 and TRAIL were measured by the MeMed Key® platform in order to select the biomarker with the best prognostic performance for the early prediction of progression into SRF or death.IP-10 had the best prognostic performance: baseline concentrations 2000 pg/ml or higher predicted equally well to suPAR (sensitivity 85.0 %; negative predictive value 96.6 %). Odds ratio for poor outcome among anakinra-treated participants of the SAVE-MORE trial was 0.35 compared to placebo when IP-10 was 2,000 pg/ml or more. IP-10 could divide different strata of severity for SRF/death by day 14 in the validation cohort. Anakinra treatment decreased this risk irrespective the IP-10 concentrations.IP-10 concentrations of 2,000 pg/ml or higher are a valid alternative to suPAR for the early prediction of progression into SRF or death the first 14 days from hospital admission for COVID-19 and they may guide anakinra treatment.gov, NCT04680949 and NCT04357366.

Rheumatoid arthritis is a systemic autoimmune disease resulting in joint destruction and deformities, but also associated with extraarticular and systemic manifestations. The later devastating conditions, such as the development of rheumatoid vasculitis, are more frequently encountered in seropositive patients and their incidence has been attenuated after the introduction of biologic disease modifying drugs, such as anti-tumor necrosis factor alpha (TNFa) agents, which generally have considerably contributed to the better control and long-term outcomes of the disease. Interestingly, autoimmune syndromes may, rarely, present in patients without a positive history after the initiation of treatment. We present a rare case of a woman with seronegative rheumatoid arthritis who developed pyoderma gangrenosum whistle on treatment with golimumab, a fully humanized anti TNFa antibody. The recording of this as well as analogous paradoxical autoimmune syndromes in association with the individual patient characteristics will render treating physicians aware of potential adverse reactions and assist in the understanding of the cytokine driven pathophysiological mechanisms underlying these disorders.

Nephritis represents a frequent, severe complication of systemic lupus erythematosus. Autoantibodies appear to be fundamental in the pathogenesis of lupus nephritis. Several hypotheses are currently experimentally tested to further elucidate the direct induction of inflammation through interaction of the pathological autoantibodies with intrinsic glomerular components and the triggering of a complement-driven autoinflammatory cascade. B-cells have, in the last decade, emerged as a promising new therapeutic target, as biological treatments successfully attempting B-cell depletion, inhibition of B-cell proliferation and differentiation, or modulation of B-cell function have become bioengineered. Clinical trials have so far proved controversial regarding the efficacy of these new agents. Thus, despite the short and long-term side effects associated with immunosuppressive treatment alternative emerging treatments are still regarded “rescue” regimens in refractory patients. In an effort to accurately evaluate the potential of these therapies in lupus nephritis, several issues have been raised mainly in terms of patient selection criteria and trial duration. This review aims to expand on the proposed pathophysiologic mechanisms implicating the B-cell pathway in the pathogenesis of lupus nephritis and summarize current knowledge obtained from clinical trials introducing these biologics in its treatment. Finally, it will elaborate on potential applications of currently available biologic agents and forthcoming treatment options.

Parvovirus B19 infection has been associated with a variety of rheumatic manifestations/diseases, mainly rheumatoid arthritis, vasculitis and systemic lupus erythematosus (SLE). B19 infection may simulate both clinical and laboratory features of SLE, presenting either as a potential first time diagnosis of SLE or as an exacerbation of previously established disease. The similarities in both clinical and serological features of parvovirus infection and SLE at presentation may hinder the differential diagnosis between these two conditions. Hence, parvovirus B19 infection mimicking SLE usually fulfils

The B-cell-activating factor (BAFF), a member of the tumor necrosis factor (TNF) family, has recently attracted attention as a potent cytokine, involved in B-cell stimulation and survival of autoimmune cells. Despite its significance in the pathogenesis of autoimmune diseases, data is limited and inconclusive regarding its expression in different stages of rheumatoid arthritis (RA). The aim of this study was to assess BAFF in biologic-naïve RA patients with early versus established disease and monitor its levels in response to anti-TNF treatment in seronegative- and seropositive patients. Based on our results, B-cell-activating factor (BAFF) did not appear to be overexpressed or differentially expressed early (≤2 years duration) in comparison to established rheumatoid arthritis (RA). Moreover, tumor necrosis factor (TNF) blockade did not appear to affect BAFF levels in either seropositive or seronegative RA patients, despite the association of anti-TNF treatment with the development of autoantibodies and the known anti-apoptotic effects of BAFF. As expected, BAFF became induced after B-cell depletion. Investigation of the effect of different biologics on the expression of BAFF and other cytokines will help elucidate the interconnecting immune pathways involved in the initiation and perpetuation of the inflammatory process.

The issue of fertility and fecundity in female patients with chronic inflammatory arthitides involves, besides sexual dysfunction [1], a higher rate of gynaecological disease, metrorrhagias, ovaria...

Vascular disease, either as a direct complication of the disease or developing as an accompanying comorbidity impairs significantly the quality of life of patients with SLE and represents the most frequent cause of death in established lupus. This paper aims to give an overview of the prevalence of the different forms of vasculopathy that can be encountered in a lupus patient, describe their pathogenesis, and address their impact on disease severity and outcome.

Chronic viral infections, such as chronic hepatitis C, are major causes of disease worldwide. They represent model systems for the study both of sophisticated ways to elute host defense mechanisms, and of mechanisms to sustain inflammation, potentially leading to autoimmune manifestations as a side effect. Cytokines are central inducers and regulators of both immune-mediated virus clearance and of immunopathology. This review describes the potential implications of TNFa in the development and clinical progression of chronic hepatitis C infection. The frequency of chronic hepatitis C, its usually indolent course, and the current application of these biological agents for the management of continuously expanding therapeutic indices, renders the study of the molecular effects and safety of TNFa antagonists in chronic HCV carriers of particular clinical significance.

Objective: Rituximab is used to deplete B cells and control disease activity, mainly in patients with rheumatoid arthritis (RA) who have not responded to anti-tumor necrosis factor (TNF) therapy. Response rates and time to relapse vary significantly among treated individuals. The objective of this study was to monitor the response of seropositive and seronegative RA patients to rituximab and correlate relapse with B-cell markers in the two groups. Methods: Seventeen RA patients (eight seropositive for rheumatoid factor [RF+] and nine seronegative [RF-]) were treated with two cycles of rituximab. After treatment, all patients were re-evaluated at the outpatient clinic, and rituximab was readministered when disease relapse was confirmed by clinical-laboratory measures (Disease Activity Score [DAS]-28). CD20+ cells and CD20 receptor expression levels were estimated at initiation, relapse, and re-evaluation timepoints, and were compared between the two groups. Results: Seropositive patients responded favorably to treatment compared with the seronegative group. The mean time to relapse was 337.5±127.0 days for the RF+ patients versus 233.3 ± 59.6 days for the RF-patients (p = 0.043), despite more aggressive concomitant treatment in the seronegative group. The DAS28 decrease 3 months after treatment was 1.695 ± 1.076 in seropositive patients versus 0.94±1.62 in seronegative patients. At relapse, CD20 receptor expression (molecules/cell) was higher in RF+ patients than in their RF-counterparts, despite a significantly lower percentage of CD20+ cells. Conclusion: Rituximab treatment is efficient in both seropositive and seronegative RA. However, seropositive RA patients tend to respond favorably compared with seronegative patients. The differential CD20 receptor expression in the two groups at relapse potentially suggests a different pathogenetic mechanism of relapse and merits further investigation.

The therapeutic use of tumor necrosis factor a (TNFa) antagonists has added a highly effective treatment in the field of inflammatory musculoskeletal, skin, and bowel diseases. Most of the side effects of these very potential agents, like infections or skin reactions, were predictable; the development of psoriatic lesions was not, as they are very successfully used to treat psoriasis and psoriatic arthritis, too. There is a number of cases of anti-TNFa-induced psoriatic lesions in the literature, some of them developing with the use of two agents in the same patient, clearly suggesting a class effect. We report an additional series of 12 cases from a total of 300 patients (>800 patient years) and hypothesize on several mechanisms for the explanation of this paradoxical phenomenon namely, local action of TNF, dysregulation of regulatory T cells, or, finally, imbalance between TNF and interferon-a locally. Further studies are needed to elucidate the exact pathogenesis of these manifestations, so that the use of these agents will not only have changed the course of diseases like rheumatoid arthritis or ankylosing spondylitis but may also aid our in depth understanding of the underlying process of disease.

Background Impaired macrovascular function is typically encountered in rheumatoid arthritis. Systemic inflammation and autoimmune-mediated atherosclerosis inherent in rheumatoid arthritis are considered to play a primary role in the development of macrovascular disease. On the contrary, the impact of rheological properties on macrovascular function in patients with rheumatoid arthritis remains substantially understudied. Objectives The aim of the present study was to investigate whether an association exists between macrovascular function and rheological parameters independent of inflammatory burden in a population of patients suffering from rheumatoid arthritis. Methods Consecutive patients with rheumatoid arthritis attending the Rheumatology Outpatient Clinic of our Department were included in the study. Blood sampling was performed for the measurement of biochemical and inflammatory markers. To evaluate macrovascular function, carotid ultrasound was used for the measurement of mean carotid intima-media thickness (cIMT). The non-invasive plethysmography technique of impedance cardiography was applied to all patients to detect the properties of the blood flow in the thorax and specifically measure hemodynamic parameters including stroke index (SI), cardiac index (CI), thoracic fluid content index (TFCI), and systemic vascular resistance index (SVRI). Results A total of 81 patients, 17 males and 64 females aged 61.8±12.2 years, with mean duration of 14.1±12.7 years of rheumatoid arthritis and a mean DAS28 score of 3.78±0.98 were included in the study. Mean body mass index (BMI) of the participants was 26.6±4.8 and mean systolic/diastolic blood pressure was 124.3±15.0/75.0±9.3 mmHg. Median erythrocyte sedimentation rate (ESR) was 16 (IQR: 10 – 29), median C-reactive protein (CRP) was 3.19 (IQR: 3.19 – 6.38) and total cholesterol levels were 205.0±34.4 mg/dl. Mean cIMT of the participants was 0.70±0.12 mm. Mean SI was 48.9±12.4 ml/m2, mean CI was 3.4±0.8 l/min/m2, mean TFCI was 18.2±3.5 l/kOhm/m2, and mean SVRI was 2063.5±669.3 dyn s cm-5m2. In the univariate analysis, only SVRI and CI among rheological parameters significantly correlated with cIMT (r=0.374, p=0.001 and r= -0.283, p=0.014, respectively). A significant association was observed between cIMT and ESR (r=0.304, p=0.024), but neither with DAS28 nor CRP. After adjustment for other parameters (age, sex, BMI, ESR, systolic blood pressure, cholesterol levels) in the multiple regression model, SVRI remained a significant independent predictor of cIMT (p=0.023). Conclusions Using non-invasive, easily applicable, low-cost technology, the present study demonstrates for the first time that impaired carotid vascular wall appears to be associated with hemodynamic parameters in rheumatoid arthritis patients, independent of inflammation and other factors potentially interfering. Whether appropriate pharmacological modification of hemodynamic parameters might result in an improvement of macrovascular function in patients with rheumatoid arthritis, and vice versa, warrants future studies. Disclosure of Interest None declared

Chronic infections, such as hepatitis C, in the setting of rheumatic disorders pose a potential hindrance to optimal management because of possible complications linked to the institution of immune suppression, as well as the high incidence of hepatotoxicity associated with many of the disease-modifying antirheumatic drugs included in the conventional therapeutic regimens. In the setting of hepatitis C, however, the effect of TNFalpha blockade may be potentially beneficial because TNFalpha appears to be involved in the pathogenesis of liver fibrosis through the stimulation of apoptotic pathways. Data related to this subject are, unfortunately, still limited and without detailed information regarding the clinical progression of the rheumatic disorder. We report the cases of two patients, one with ankylosing spondylitis and one with psoriatic arthritis, who were efficiently treated long-term with anti-TNF agents for their rheumatic disease without any evidence of reactivation or flaring of their hepatitis C infection or deterioration of their liver function. Our results indicate that TNFalpha blockade is a highly efficient and uncompromising therapy in hepatitis C-affected individuals with connective tissue disorders. However, systematic, large-scale studies addressing the issue of safety of these new efficient drugs, i.e., monoclonal antibodies targeted against TNFalpha, in patients with chronic hepatitis C will be needed to properly assess the risks and benefits of this treatment in analogous cases.

Background Scleroderma is a disease hallmarked by microangiopathy; the extensive avascular areas developing in the course of the disease are clinically associated with severe tissue hypoxia and the formation of digital ulcers. Tissue oxygenation is further impaired through the development of tissue fibrosis. The proangiogenic factor VEGF is upregulated in all stages of the disease with little effect on efficient neovascularization. Surprisingly, no correlation between the expression of VEGF and HIF-1a could be documented in scleroderma skin biopsies in previous reports. Objectives The aim of this study was to investigate expression of HIF-1a and VEGF in naive scleroderma patients, and correlate histochemical findings with the capillaroscopic pattern and clinical manifestations. Methods Skin biopsies from 9 patients with scleroderma (diffuse/ limited) were analysed and compared to 10 normal skin biopsies. Patients were informed prior to the biopsy and gave their consent. Mean age of the patients was 52,22±14,37 yrs, and median duration of the symptoms 28 months [4-120]. Autoantibody profile, capillaroscopic pattern and clinical manifestations, e.g. digital ulcerations, was recorded. Paraffin sections of 3μm were stained with Abs against HIF-1a and VEGF according to standardized protocols. Results In the normal skin, there were rare immunoreactivecells for HIF-1a. In the dermis there was immunoreactivity of follicular keratinocytes of sweat and sebaceous glands and endothelial cells, in accordance with previously reported data. All skin biopsies from scleroderma patients were HIF-1a-positive. The staining was nuclear and it was observed throughout the keratinocytes of the epidermis. Nuclear expression of HIF-1a was also seen in sweat and sebaceous glands and in dermal inflammatory foci with distinct staining of endothelial cells and scattered staining of lymphocytes. In the normal skin, immunostaining for VEGF was mainly observed in suprabasal keratinocytes. In the dermis there was immunoreactivity of endothelial cells. In patients with scleroderma, immunostaining of epidermal keratinocytes was seen in all cases. The immunoreactivity was cytoplasmic. Immunostaining was also observed in endothelial cells of the dermis. No statistically significant differences in the expression of HIF-1a and VEGF, estimated semiquantitatively by immunohistochemistry, were recorded in patients at different stages at diagnosis according to capillaroscopic and clinical criteria. Conclusions To date, and despite low pO2 values measured in the skin of patients with systemic sclerosis, no pathophysiological connection could be proven between clinical hypoxia and increased levels of the oxygen-sensitive alpha-subunit of HIF-1. Our study is the first to show potent constitutive expression and accumulation of HIF-1a in the skin of scleroderma patients, even in early stages of the disease. The patients included in this study were treatment-naive, i.e. had not been previously exposed to any immuno- or vasomodulatory treatment. This observation contributes to the understanding of the pathophysiology of the disease. Further studies are needed in order to characterize downstream modulatory factors, which may interfere with efficient tissue neovascularization. Disclosure of Interest None Declared

We read with great interest the article by Genovese et al 1 on the effect of the B-cell activating factor (BAFF) antagonist tabalumab in rheumatoid arthritis patients with inadequate response to tumour necrosis factor (TNF)a blockade. The results of this study indicated a moderate effect of tabalumab early (week 6/week 9) after initiation of therapy, both in terms of clinical as well as laboratory markers of disease activity, which however was not significantly sustained later on in the course of treatment (week 16). In the previous decade, biological therapies that target the B cell have become established in the treatment of rheumatoid …