The JAK/STAT pathway is activated in systemic sclerosis and is effectively targeted by tofacitinib

Rationale: Fibrosis leads to failure of the skin, lungs, and other organs in systemic sclerosis; accounts for substantial morbidity and mortality; and lacks effective therapy. Myofibroblast activation underlies organ fibrosis, but the key extracellular cues driving persistence of the process remain incompletely characterized. Objectives: The objectives were to evaluate activation of the IL6/JAK/STAT axis associated with fibrosis in skin and lung biopsies from systemic sclerosis patients and effects of the Food and Drug Administration–approved JAK/STAT inhibitor, tofacitinib, on skin and lung fibrosis in animal models. Methods: Bioinformatic analysis showed that IL6/JAK/STAT3 and tofacitinib gene signatures were aberrant in biopsies from systemic sclerosis patients in four independent cohorts. The results were confirmed by JAK and STAT3 phosphorylation in both skin and lung biopsies from patients with systemic sclerosis. Furthermore, treatment of mice with the selective JAK inhibitor tofacitinib not only prevented bleomycin-induced skin and lung fibrosis but also reduced skin fibrosis in TSK1/+ mice. Conclusion: These findings implicate the JAK/STAT pathway in systemic sclerosis skin and lung fibrosis and identify tofacitinib as a potential antifibrotic agent for the treatment of systemic sclerosis and other fibrotic diseases.

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Effects of nintedanib in patients with systemic sclerosis-associated ILD (SSc-ILD) and differing extents of lung fibrosis: the SENSCIS trial*

10.1055/s-0039-3403187 ◽

2020 ◽

Author(s):

R Wiewrodt ◽

G Raghu ◽

O Distler ◽

A Azuma ◽

KB Highland ◽

...

Keyword(s):

Systemic Sclerosis ◽

Lung Fibrosis

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The involvement of leucine-rich α-2 glycoprotein in the progression of skin and lung fibrosis in bleomycin-induced systemic sclerosis model

Modern Rheumatology ◽

10.1080/14397595.2021.1883841 ◽

2021 ◽

pp. 1-10

Author(s):

Hideki Nakajima ◽

Kimiko Nakajima ◽

Satoshi Serada ◽

Minoru Fujimoto ◽

Tetsuji Naka ◽

...

Keyword(s):

Systemic Sclerosis ◽

Lung Fibrosis

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Differences in Texture Analysis Parameters Between Active Alveolitis and Lung Fibrosis in Chest CT of Patients with Systemic Sclerosis

Academic Radiology ◽

10.1016/j.acra.2017.07.002 ◽

2017 ◽

Vol 24 (12) ◽

pp. 1596-1603 ◽

Cited By ~ 6

Author(s):

Christopher Kloth ◽

Anya C. Blum ◽

Wolfgang M. Thaiss ◽

Heike Preibsch ◽

Hendrik Ditt ◽

...

Keyword(s):

Systemic Sclerosis ◽

Texture Analysis ◽

Lung Fibrosis ◽

Chest Ct

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Knee myopericytoma-case report and literature review

MOJ Orthopedics & Rheumatology ◽

10.15406/mojor.2020.12.00534 ◽

2020 ◽

Vol 12 (6) ◽

pp. 127-128

Author(s):

Susana Rodrigues ◽

Catrine Ferreira ◽

Tiago Coelho ◽

Diogo Gaspar ◽

Jean Fallah ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Case Report ◽

Systemic Sclerosis ◽

Middle Age ◽

Subcutaneous Tissue ◽

Connective Tissue Diseases ◽

Systemic Lupus Erythematous ◽

Systemic Lupus ◽

Calcinosis Cutis ◽

Substantial Morbidity

Calcinosis cutis is a rare disorder characterized by of deposition of insoluble calcium salts in the skin and subcutaneous tissue. Five subtypes of calcinosis cutis are described: dystrophic, metastatic, idiopathic, iatrogenic, and calciphylaxis.1 Of these subtypes, dystrophic calcinosis (DC) is the most common, and it is the most frequently seen in association with underlying autoimmune connective tissue diseases.2 Dermatomyositis, systemic sclerosis and less commonly systemic lupus erythematous were described to be complicated by DC. However, DC associated with rheumatoid arthritis (RA) is extremely rare.2 The condition causes substantial morbidity and is associated with pain and limitation of movement when the process involves areas close to joints or when ulceration occurs.2 We report a middle age Sudanese woman with good controlled RA who developed dystrophic calcinosis cutis.

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BRD4 inhibition for the treatment of pathological organ fibrosis

F1000Research ◽

10.12688/f1000research.11339.1 ◽

2017 ◽

Vol 6 ◽

pp. 1015 ◽

Cited By ~ 17

Author(s):

Matthew S. Stratton ◽

Saptarsi M. Haldar ◽

Timothy A. McKinsey

Keyword(s):

Extracellular Matrix ◽

Pulmonary Fibrosis ◽

Small Molecule ◽

Regulatory Protein ◽

Medical Need ◽

Fibrotic Diseases ◽

Brd4 Inhibition ◽

Developed World ◽

Organ Fibrosis

Fibrosis is defined as excess deposition of extracellular matrix, resulting in tissue scarring and organ dysfunction. It is estimated that 45% of deaths in the developed world are due to fibrosis-induced organ failure. Despite the well-accepted role of fibrosis in the pathogenesis of numerous diseases, there are only two US Food and Drug Administration–approved anti-fibrotic therapies, both of which are currently restricted to the treatment of pulmonary fibrosis. Thus, organ fibrosis represents a massive unmet medical need. Here, we review recent findings suggesting that an epigenetic regulatory protein, BRD4, is a nodal effector of organ fibrosis, and we highlight the potential of small-molecule BRD4 inhibitors for the treatment of diverse fibrotic diseases.

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Tofacitinib Suppresses Several JAK-STAT Pathways in Rheumatoid Arthritis In Vivo and Baseline Signaling Profile Associates With Treatment Response

Frontiers in Immunology ◽

10.3389/fimmu.2021.738481 ◽

2021 ◽

Vol 12 ◽

Author(s):

Maaria Palmroth ◽

Krista Kuuliala ◽

Ritva Peltomaa ◽

Anniina Virtanen ◽

Antti Kuuliala ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

T Cells ◽

Treatment Response ◽

Peripheral Blood ◽

Janus Kinase ◽

Cytokine Signaling ◽

Stat3 Phosphorylation ◽

Stat Pathway

ObjectiveCurrent knowledge on the actions of tofacitinib on cytokine signaling pathways in rheumatoid arthritis (RA) is based on in vitro studies. Our study is the first to examine the effects of tofacitinib treatment on Janus kinase (JAK) - signal transducer and activator of transcription (STAT) pathways in vivo in patients with RA.MethodsSixteen patients with active RA, despite treatment with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), received tofacitinib 5 mg twice daily for three months. Levels of constitutive and cytokine-induced phosphorylated STATs in peripheral blood monocytes, T cells and B cells were measured by flow cytometry at baseline and three-month visits. mRNA expression of JAKs, STATs and suppressors of cytokine signaling (SOCS) were measured from peripheral blood mononuclear cells (PBMCs) by quantitative PCR. Association of baseline signaling profile with treatment response was also investigated.ResultsTofacitinib, in csDMARDs background, decreased median disease activity score (DAS28) from 4.4 to 2.6 (p < 0.001). Tofacitinib treatment significantly decreased cytokine-induced phosphorylation of all JAK-STAT pathways studied. However, the magnitude of the inhibitory effect depended on the cytokine and cell type studied, varying from 10% to 73% inhibition following 3-month treatment with tofacitinib. In general, strongest inhibition by tofacitinib was observed with STAT phosphorylations induced by cytokines signaling through the common-γ-chain cytokine receptor in T cells, while lowest inhibition was demonstrated for IL-10 -induced STAT3 phosphorylation in monocytes. Constitutive STAT1, STAT3, STAT4 and STAT5 phosphorylation in monocytes and/or T cells was also downregulated by tofacitinib. Tofacitinib treatment downregulated the expression of several JAK-STAT pathway components in PBMCs, SOCSs showing the strongest downregulation. Baseline STAT phosphorylation levels in T cells and monocytes and SOCS3 expression in PBMCs correlated with treatment response.ConclusionsTofacitinib suppresses multiple JAK-STAT pathways in cytokine and cell population specific manner in RA patients in vivo. Besides directly inhibiting JAK activation, tofacitinib downregulates the expression of JAK-STAT pathway components. This may modulate the effects of tofacitinib on JAK-STAT pathway activation in vivo and explain some of the differential findings between the current study and previous in vitro studies. Finally, baseline immunological markers associate with the treatment response to tofacitinib.

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