Interferon-induced versus chemokine transcripts as lupus biomarkers

Compelling support for a central role for interferon-alpha in lupus pathogenesis has led to a new focus on the role of innate immune system activation in the generation of pathogenic mediators. These insights have been extended in translational studies of patients with well-characterized disease activity and clinical manifestations in order to identify informative molecular biomarkers. Chemokines are among the interferon-inducible genes, and new data support an association between the expression of chemokines and both lupus disease activity and organ damage. Longitudinal studies that relate molecular biomarkers to disease activity will be needed to validate these promising data and establish a sensitive measure of change for interventional studies and patient care

Belimumab or anifrolumab for systemic lupus erythematosus? A risk-benefit assessment

Treatment of systemic lupus erythematosus (SLE) currently employs agents with relatively unselective immunosuppressive properties. However, two target-specific biological drugs have been approved: belimumab (anti-B-cell-activating factor/BAFF) and anifrolumab (anti-interferon alpha receptor-1/IFNAR1). Here, we performed a comparative risk-benefit assessment for both drugs based on the role of BAFF and IFNAR1 in host defense and the pathogenesis of SLE and by considering the available data on safety and efficacy. Due to differences in target expression sites, anti-IFNAR1, but not anti-BAFF, might elicit organ-specific effects, consistent with clinical efficacy data. The IFNAR1 is specifically involved in innate and adaptive antiviral immunity in most cells of the body. Consistent with this observation, the available safety data obtained from patients negatively selected for LN and neuropsychiatric SLE, primary immunodeficiencies, splenectomy and chronic HIV, HBV, HCV infections suggest an increased risk for some viral infections such as varicella zoster and perhaps influenza. In contrast, BAFF is mainly involved in adaptive immune responses in lymphoid tissues, thus anti-BAFF therapy modulates SLE activity and prevents SLE flares without interfering with local innate host defense mechanisms and should only marginally affect immune memory to previous pathogen exposures consistent with the available safety data from SLE patients without chronic HIV, HBV or HCV infections. When using belimumab and anifrolumab, careful patient stratification and specific precautions may minimize risks and maximize beneficial treatment effects for patients with SLE

Plasmacytoid dendritic cells promote systemic sclerosis with a key role for TLR8

Systemic sclerosis (SSc) is a multisystem life-threatening fibrosing disorder that lacks effective treatment. The link between the inflammation observed in organs such as the skin and profibrotic mechanisms is not well understood. The plasmacytoid dendritic cell (pDC) is a key cell type mediating Toll-like receptor (TLR)-induced inflammation in autoimmune disease patients, including lupus and skin diseases with interface dermatitis. However, the role of pDCs in fibrosis is less clear. We show that pDCs infiltrate the skin of SSc patients and are chronically activated, leading to secretion of interferon-α (IFN-α) and CXCL4, which are both hallmarks of the disease. We demonstrate that the secretion of CXCL4 is under the control of phosphatidylinositol 3-kinase δ and is due to the aberrant presence of TLR8 on pDCs of SSc patients, which is not seen in healthy donors or in lupus pDCs, and that CXCL4 primarily acts by potentiating TLR8-but also TLR9-induced IFN production by pDCs. Depleting pDCs prevented disease in a mouse model of scleroderma and could revert fibrosis in mice with established disease. In contrast, the disease was exacerbated in mice transgenic for TLR8 with recruitment of pDCs to the fibrotic skin, whereas TLR7 only partially contributed to the inflammatory response, indicating that TLR8 is the key RNA-sensing TLR involved in the establishment of fibrosis. We conclude that the pDC is an essential cell type involved in the pathogenesis of SSc and its removal using depleting antibodies or attenuating pDC function could be a novel approach to treat SSc patients

PROMIS CAT in SLE Personal non-commercial use only

ABSTRACT. Objective. The aims of this study were to assess the construct validity and the test-retest reliability of Patient Reported Outcomes Measurement Information System (PROMIS) computerized adaptive tests (CAT) in patients with systemic lupus erythematosus (SL

2017 American College of Rheumatology/American Association of Hip and Knee Surgeons Guideline for the Perioperative Management of Antirheumatic Medication in Patients With Rheumatic Diseases Undergoing Elective Total Hip or Total Knee Arthroplasty

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/137753/1/acr23274.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/137753/2/acr23274_am.pd

2017 American College of Rheumatology/American Association of Hip and Knee Surgeons Guideline for the Perioperative Management of Antirheumatic Medication in Patients With Rheumatic Diseases Undergoing Elective Total Hip or Total Knee Arthroplasty

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/137769/1/art40149.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/137769/2/art40149_am.pd

Anti-interferon alpha treatment in SLE

Abstract Several studies in the last decade have highlighted the role of the type I interferon (IFN-I) pathway, and particularly interferon alpha (IFNα) in SLE pathogenesis. As a result, a multitude of potential treatments targeting IFNα have emerged in the last few years, a few of which have already completed phase II clinical trials. Some of the treatment strategies have focused on blocking IFNα or its receptor and others the plasmacytoid dendritic cell (pDC), which is the principal IFNα producing cell. In this review, we will discuss the evidence supporting a pathogenic role of IFNα and pDC in SLE, provide an update on the current status of these therapeutic strategies, and discuss the potential advantages and disadvantages of each therapeutic approach