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Abdominal X-ray image of an SSc patient with SIBO. The storage of gas in the intestinal tract is observed throughout the abdomen. SSc: systemic sclerosis; SIBO: small intestinal bacterial overgrowth.
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Systemic sclerosis (SSc) is a connective tissue disease, the pathogenesis of which is thought to involve interleukin-6 (IL-6), an inflammatory cytokine. This is based on findings of its concentration in patient serum, the results of an IL-6 suppression experiment in an animal model, and the results of a pilot study using IL-6 receptor antibody. How...
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Systemic sclerosis (SSc) is a connective tissue disease of unknown etiology. SSc causes damage to the skin and various organs including the lungs, heart, and digestive tract, but the extent of the damage varies from patient to patient. The pathology of SSc includes ischemia, inflammation, and fibrosis, but the degree of progression varies from case...
Citations
... Finally, since the synthesis of IL-6 by Topo 1-specific T cells in SSc patients is of key importance for the effective activation and production of anti-Topo 1 by autologous B cells [66], it can be assumed that a decrease in the level of anti-Topo 1 during RTX treatment may be associated with depletion of B cells synthesizing IL-6 [67,68]. It should be recalled that IL-6 exhibits a pronounced profibrotic activity [69], and its inhibition is considered a promising method of therapy for SSc [70,71]. ...
The aim of our study was to assess the relationship between the changes of antinuclear autoantibodies (ANAs) and autoantibodies to topoisomerase 1 (anti-Topo 1) in systemic sclerosis (SSs) patients on rituximab (RTX) therapy. The prospective study included 88 patients (73 women) with a mean age of 47 (17-71) years. The mean disease duration was 5.9 ± 4.8 years. The mean follow-up period was more than 2 years (27 (12-42) months). We documented a statistically significant change in skin score, the disease activity index, improvement of pulmonary function and reduction of mean dose of prednisolone after RTX treatment. There was a significant decrease in the number of patients with high levels of ANA and overall decrease of the ANA and anti-Topo 1 levels. A moderate positive statistically significant correlation was found between ANA and anti-Topo 1 (r = 0.403). In the group of patients positive for anti-Topo 1 there were a more pronounced depletion of B lymphocytes, significantly higher increase in forced vital capacity and diffusion capacity, decrease in the disease activity index, compared with patients negative for anti-Topo 1. We observed the decline in the level of ANA and anti-Topo 1 in SSc patients after RTX therapy, and it was correlated by an improvement of the main outcome parameters of the disease. Therefore, anti-Topo 1 positivity could be considered as a predictor of a better response to RTX treatment, especially in SSc patients with hyperproduction of anti-Topo 1.
... In addition, increased secretion of IL-6 from skin and lung biopsy samples of SSc patients has been shown to be associated with the proliferation and accumulation of B lymphocytes, particularly during the early stages of the disease (within 6 years of diagnosis). [17][18][19][20] Based on these findings, a phase III RCT with tocilizumab was conducted in patients with early dSSc and increased levels of inflammatory markers. 21,22 Although the primary endpoint regarding skin involvement was not achieved in this study, treatment with tocilizumab in patients with early dSSc did stabilize the pulmonary condition as measured by forced vital capacity. ...
Systemic sclerosis (SSc) is a chronic immune-mediated disease characterized by microangiopathy, immune dysregulation, and progressive fibrosis of the skin and internal organs. Though not fully understood, the pathogenesis of SSc is dominated by microvascular injury, endothelial dysregulation, and immune response that are thought to be associated with fibroblast activation and related fibrogenesis. Among the main clinical subsets, diffuse SSc (dSSc) is a progressive form with rapid and disseminated skin thickening accompanied by internal organ fibrosis and dysfunction. Despite recent advances and multiple randomized clinical trials in early dSSc patients, an effective disease-modifying treatment for progressive skin fibrosis is still missing, and there is a crucial need to identify new targets for therapeutic intervention. Eotaxin-2 (CCL24) is a chemokine secreted by immune cells and epithelial cells, which promotes trafficking of immune cells and activation of pro-fibrotic cells through CCR3 receptor binding. Higher levels of CCL24 and CCR3 were found in the skin and sera of patients with SSc compared with healthy controls; elevated levels of CCL24 and CCR3 were associated with fibrosis and predictive of greater lung function deterioration. Growing evidence supports the potency of a CCL24-blocking antibody as an anti-inflammatory and anti-fibrotic modulating agent in multiple preclinical models that involve liver, skin, and lung inflammation and fibrosis. This review highlights the role of CCL24 in orchestrating immune, vascular, and fibrotic pathways, and the potential of CCL24 inhibition as a novel treatment for SSc.
... Наконец, поскольку у пациентов с ССД синтез ИЛ-6 Топо 1-специфичными Т-клетками имеет ключевое значение для эффективной активации и продукции анти-Топо 1 аутологичными В-клетками [66], можно предположить, что снижение уровня анти-Топо 1 на фоне лечения РТМ может быть связано с деплецией В-клеток, синтезирующих ИЛ-6 [67,68]. Следует напомнить, что ИЛ-6 обладает выраженной профибротической активностью [69], а его ингибиция рассматривается как перспективный метод терапии ССД [70,71]. Таким образом, у пациентов с ССД применение РТМ приводит к снижению титров АНФ и анти-Топо 1, ассоциирующемуся с клинической эффективностью терапии. ...
The aim of our study was to assess the relationship between the changes of antinuclear autoantibodies (ANA) and autoantibodies to topoisomerase 1 (anti-Topo 1) in systemic sclerosis (SSc) patients on rituximab (RTX) therapy. Materials and methods. The prospective study included 88 patients (73 women) with a mean age of 47 (17– 71) years. The mean disease duration was 5.9±4.8 years. The mean follow-up period was more than 2 years (27 (12–42) months). Results. We documented a statistically significant change in skin score, the disease activity index, improvement of pulmonary function and reduction of mean dose of prednisolone after RTX treatment. There was a significant decrease in the number of patients with high levels of ANA and overall decrease of the ANA and anti-Topo 1 levels. A moderate positive statistically significant correlation was found between ANA and anti-Topo 1 (r=0.403). In the group of patients positive for anti-Topo 1 there were a more pronounced depletion of B lymphocytes, significantly higher increase in forced vital capacity and diffusion capacity, decrease in the disease activity index, compared with a patients negative for anti-Topo 1. Conclusions. We observed the decline in the level of ANA and anti-Topo 1 in SSc patients after RTX therapy and it was correlated by an improvement of the main outcome parameters of the disease. Therefore, anti-Topo 1 positivity could be considered as a predictor of a better response to RTX treatment, especially in SSc patients with hyperproduction of anti-Topo 1.
... Denton et al. [153] confirmed that IL-6 blockades could reverse TGF-β pathway activation in dermal fibroblasts to suppress skin fibrosis. However, Shima Y. et al. [154] unveiled that SSc patients with high IL-13 serum levels abrogated the influence of IL-6 on tissue fibrosis. Recently, Iorio et al. [155] suggested that anti-IL-6 therapy should be considered against inflamm-aging in the elderly. ...
Systemic sclerosis (SSc) is a chronic connective tissue disorder characterized by immune dysregulation, chronic inflammation, vascular endothelial cell dysfunction, and progressive tissue fibrosis of the skin and internal organs. Moreover, increased cancer incidence and accelerated aging are also found. The increased cancer incidence is believed to be a result of chromosome instability. Accelerated cellular senescence has been confirmed by the shortening of telomere length due to increased DNA breakage, abnormal DNA repair response, and telomerase deficiency mediated by enhanced oxidative/nitrative stresses. The immune dysfunctions of SSc patients are manifested by excessive production of proinflammatory cytokines IL-1, IL-6, IL-17, IFN-α, and TNF-α, which can elicit potent tissue inflammation followed by tissue fibrosis. Furthermore, a number of autoantibodies including anti-topoisomerase 1 (anti-TOPO-1), anti-centromere (ACA or anti-CENP-B), anti-RNA polymerase enzyme (anti-RNAP III), anti-ribonuclear proteins (anti-U1, U2, and U11/U12 RNP), anti-nucleolar antigens (anti-Th/T0, anti-NOR90, anti-Ku, anti-RuvBL1/2, and anti-PM/Scl), and anti-telomere-associated proteins were also found. Based on these data, inflamm-aging caused by immune dysfunction-mediated inflammationexists in patients with SSc. Hence, increased cellular senescence is elicited by the interactions among excessive oxidative stress, pro-inflammatory cytokines, and autoantibodies. In the present review, we will discuss in detail the molecular basis of chromosome instability, increased oxidative stress, and functional adaptation by deranged immunome, which are related to inflamm-aging in patients with SSc.
... Similarly, an SSc-induced increase in COL1A1 synthesis resulted in significantly attenuated HPMECs exposed to sera of iloprost-treated SSc patients, suggesting collagen synthesis activation as a potential target of the loprost therapeutic effect ( Figure 1D). A possible explanation of the iloprost treatment's beneficial effect might be the ability to decrease the levels of circulating pro-oxidant and pro-fibrotic factors, which has been reported as increased in the SSc sera [28,[34][35][36][37][38]. In this context, consonant with our data, multiple lines of evidence indicate the ability of Iloprost to modulate oxidative markers at systemic levels [25,[39][40][41]. ...
Endothelial cell injury is an early event in systemic sclerosis (SSc) pathogenesis and several studies indicate oxidative stress as the trigger of SSc-associated vasculopathy. Here, we show that circulating factors present in sera of SSc patients increased reactive oxygen species (ROS) production and collagen synthesis in human pulmonary microvascular endothelial cells (HPMECs). In addition, the possibility that iloprost, a drug commonly used in SSc therapy, might modulate the above-mentioned biological phenomena has been also investigated. In this regard, as compared to sera of SSc patients, sera of iloprost-treated SSc patients failed to increased ROS levels and collagen synthesis in HPMEC, suggesting a potential antioxidant mechanism of this drug.
... 21 Tocilizumab also showed good efficacy and safety in the treatment of juvenile SSc and significantly improved the lung function of patients. 22 It was an immunoglobulin G antibody that could bind to IL-6 receptor, 26 thereby blocking the IL-6/STAT3/Smad3 axis trans-signaling pathway, which may reduce lung inflammation and fibrosis. 27 The CCL2 was a chemokine produced by endothelial cells, monocytes, type II alveolar cells and other cells, 20 and is the main chemokine and activator of monocytes and T cells. ...
Objectives: This study aims to analyze gene expression in lung tissue and lung fibroblasts of patients with systemic sclerosis-associated interstitial lung disease (SSc-ILD) to identify potential biomarkers and therapeutic targets and to examine its possible role in the pathogenesis of SSc-ILD.
Patients and methods: We obtained datasets from Gene Expression Omnibus (GEO) database, and used Robust Rank Aggregation to calculate the co-expressed differentially-expressed-genes (DEGs) in three chips, then analyzed the function, signaling pathways and the protein-protein interaction network of the DEGs. Finally, we verified the DEGs related to SSc-ILD by three databases of Comparative Toxicogenomics Database (CTD), GENE, and DisGeNET, respectively.
Results: There were 16 co-expressed DEGs related to SSc-ILD in three GEO series, of which six genes were upregulated, and 10 genes were downregulated. The CTD included 29,936 genes related to SSc, and the GENE and DisGeNET databases had 429 genes related to SSc.
Conclusion: The results of gene differential expression analysis suggest that interleukin-6, chemokine ligand 2, intercellular adhesion molecule 1, tumor necrosis factor alpha-induced protein 3, pentraxin 3, and cartilage oligomeric matrix protein may be implicated in the pathogenesis of SSc-ILD and are expected to be potential biomarkers and therapeutic targets for SSc-ILD.
... 33.3% of PAH patients in our study were SSc, and 40% were RA. A study reported that serum IL-6 and IL-13 levels increased in SSc patients with PAH [22]. In our study, while there was no significant relation between PAH and cytokines, there was a positive correlation with the inflammatory HRCT score. ...
Objective
Interstitial lung disease (ILD) is one of the most severe complications which is associated with connective tissue disease (CTD) and causes to morbidity and mortality. So, we aimed to determine serum levels of interleukin-6 (IL-6), IL-13, and IL-17, to investigate whether these cytokines are related to CTD-ILD, and to find their possible contribution to determining the prognosis of the disease.MethodsA total of 150 participants, 80 patients diagnosed with CTD-ILD (mean age, 58.21 ± 12.36) and 70 healthy controls (mean age, 57.07 ± 9.60) were recruited from the rheumatology department between January 2016 and June 2019 in the study. High-resolution computed tomography (HRCT) findings were scored as similarly to previous studies. Serum IL-6, IL 13, and IL-17 levels were measured by ELISA test kits.ResultsThe levels of IL-6, IL-13, and IL-17 in CTD patients were significantly higher than the healthy individuals (p < 001), but the HRCT score’s relation were not determined. IL-6 was associated with disease duration and disease activity scores of DAS28, ESDAII, and dSSc. There was a significant relation between dSSc, HCRT fibrosis, and total score.CRP, hemoglobin, and platelets were associated with the HRCT inflammation pattern.Conclusion
At the study, it has been observed that serum IL-13, IL-6 and IL-17 levels are increased in patients with CTD-ILD. Besides, IL-6 was associated with disease activity scores of DAS28, ESDAII, and dSSc. Also, HRCT fibrosis score is associated with dSSc. Further and comprehensive studies are needed to understand better the complex intersection of lung disease with systemic autoimmunity.
Key Points
• Serum IL-13, IL-6, and IL-17 levels are increased in patients with CTD-ILD.
• IL-6 was associated with disease activity scores of DAS28, ESDAII, and diffuse skin involvement.
• HRCT fibrosis score is associated with diffuse skin involvement in patients with SSc-ILD.
• HRCT inflammation score is associated with PAH.
... Additional path was aiming the receptor of cytokine instead of the cytokine itself, using a humanized anti IL-6Rα "Tocilizumab". The hopeful findings supported the continual progress of tocilizumab in the treatment of SSc, which is being explored in a phase 3 trial [32,33]. Measurement of serum IL-6 in Egyptian SSc patients and its association with different clinical presentation helps to identify potential subgroup of patients that can benefit from this new treatment modality and to assess their response to it. ...
... Interleukin (IL)-6 is shown to play a role in pathogenesis of systemic sclerosis. It was found to be present in the higher concentration in serum of systemic sclerosis patients comparing to healthy controls [15][16][17]. Given that IL-6 is thought to play a role in pathophysiologic mechanisms in systemic sclerosis, it has been considered a potential treatment target for patients who are refractory to conventional therapy including steroids and DMARDs. ...
... Tocilizumab (TCZ) is an IgG antibody capable of inhibiting the binding of IL-6 to the IL-6 receptor [15]. The efficacy and safety of TCZ in adult patients have been studied in a few recent studies [16][17][18][19][20][21]. The currently approved pediatric indication for TCZ usage includes systemic and polyarticular juvenile idiopathic arthritis [22,23]. ...
... The median age at the study was 17.7 years (11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21), at the disease onset 10.8 years (6)(7)(8)(9)(10)(11)(12)(13)(14)(15) and at the diagnosis 12 years (7.5-17). The total disease duration was 6.9 years (3)(4)(5)(6)(7)(8)(9)(10)(11). ...
To evaluate the efficacy and safety of anti-interleukin (IL)-6 receptor antibody tocilizumab (TCZ) as a treatment option of juvenile systemic sclerosis (JSS). Nine JSS patients were assigned to a TCZ, additionally to conventional treatment (steroids, methotrexate, mycophenolate-mofetil). The modified Rodnan skin score (mRSS), carbon-monoxide diffusion capacity (DLCO), thorax high-resolution tomography (HRCT), patient global assessment (PGA) and Juvenile Systemic Sclerosis Severity (J4S) score were used to explore the efficacy of treatment. Nine JSS patients were treated with TCZ with a median treatment duration of 10 (1–21) months. Nine patients (77.8%) had radiologically confirmed improvement on thorax HRCT, 7 (77.8%) had decreased PGA (mean pre-treatment PGA 3.7 vs. 2.3 post-treatment PGA 2), 6 (66.7%) had increased DLCO (mean pre-treatment DLCO 69.14% vs. post-treatment DLCO 79.50%) after the TCZ treatment. In all patients mRSS and the J4S decreased: 26.1 vs. 19.7 and 8.2 vs. 4.7, respectively. Changes in mRSS, DLCO, PGA and J4S were statistically significant: p = 0.012, 0.04, 0.026 and 0.007, respectively. All patients tolerated well TCZ treatment. JSS is a rare condition characterized with skin fibrosis and internal organ involvement. Tocilizumab represents a potential treatment option for patients unresponsive to conventional treatment. Long-term prospective studies with higher number of patients are needed to provide more relevant data.
... Причины отсутствия значимых различий по основному показателю эффективности (чаще всего плотность кожи по модифицированному кожному счету Роднана) анализируются и объясняются, с одной стороны, недостаточной адекватностью данного параметра, с другой -редкостью и гетерогенностью заболевания (когда, например, в группе плацебо у нескольких пациентов развивается спонтанное улучшение), что не позволяет подобрать достаточно однородную группу больных. Применительно к ТЦЗ было высказано предположение, что при ССД ответ на ТЦЗ зависит не только от превалирования воспалительных реакций на ранней стадии, но и от выраженности и стадии органной патологии, в частности поражения легких [45]. Проведенное ранее исследование уровня цитокинов в сыворотке больных ССД показало, что концентрация ИЛ-6 повышена на ранней стадии болезни и при развитии ИЗЛ. ...
... Возможно, что при прогрессировании легочного фиброза уровень провоспалительного ИЛ-6 снижается, но повышается уровень профиброзного ИЛ-13. Тогда с повышением уровня ИЛ-13 участие в патогенезе заболевания ИЛ-6 уменьшается, и пациенты теряют чувствительность к ТЦЗ [45]. Нельзя также исключить, что в коже и легких фиброзирующие процессы могут протекать с разной скоростью и выраженностью. ...
A significant progress has been made in recent years in management of severe systemic scleroderma (SSD) manifestations, such as Raynaud’s phenomenon, renal crisis, and pulmonary arterial hypertension, subsequently improving survival and quality of life. At the same time, treatment algorithms for interstitial lung damage in SSD have not yet been developed. The review provides relevant information on therapeutic efficacy of drugs with various mechanisms of action, including immunosuppressive drugs (cyclophosphamide, mycophenolate mofetil, etc.), and high-dose chemotherapy followed by autologous hematopoietic stem cell transplantation. New drugs with antifibrotic activity, including recently marketed in Russia nintedanib for treatment of interstitial lung diseases in SSD, as well as perspectives for potential use of biologics (rituximab, tocilizumab, etc.), and lung transplantation are considered separately.
