Role of IL-6 and IL-6 targeted therapy in systemic lupus erythematosus.

Interleukin-6 (IL-6) is one of the cytokines implicated in murine and human SLE. Only a few small studies have investigated IL-6 inhibition in human SLE. Currently, there are no studies registered in clinicaltrials.gov to assess the IL-6 targeted therapy in SLE, yet its role in the future remains to be defined. This narrative review analyses these and potential areas of future studies with IL-6 targeted therapy in SLE.

Giant Cell Arteritis and Polymyalgia Rheumatica: Treatment Approaches and New Targets.

Prolonged glucocorticoid tapers have been the standard of care for giant cell arteritis (GCA) and polymyalgia rheumatica (PMR), but recent advancements have improved outcomes for patients with GCA while reducing glucocorticoid-related toxicities. Many patients with GCA and PMR still experience persistent or relapsing disease, and cumulative exposure to glucocorticoids for both diseases remains high. The objective of this review is to define current treatment approaches as well as new therapeutic targets and strategies. Studies investigating inhibition of cytokine pathways, including interleukin-6, interleukin-17, interleukin-23, granulocyte-macrophage colony-stimulating factor, Janus kinase-signal transduction and activator of transcription, and others, will be reviewed.

Unintentional unblinding in rheumatic disease trials.

The practice of blinding treatment assignment in randomised controlled trials mitigates important biases in observational studies. Unblinding, whereby study participants or investigators become aware of treatment assignments, is an important threat to the validity of trial results. Rheumatology studies might be particularly susceptible to unblinding because rheumatic disease therapies often cause high rates of idiosyncratic side-effects and frequently rely on subjective endpoints. Despite this susceptibility, the degree to which unblinding occurs in randomised controlled trials in rheumatic diseases has rarely been assessed during trials or acknowledged as a limitation. Rheumatologists should be aware of this important threat to the validity of trial results, assessments of unblinding should be undertaken, and strategies to prevent unblinding should be deployed when feasible.

Comparative Efficacy Randomized Controlled Trials in Rheumatology Guidelines.

BACKGROUND: Comparative efficacy randomized controlled trials (RCTs) compare two active interventions in a head-to-head design. They are useful for informing clinical practice guidelines, but the degree to which such trials inform clinical practice guidelines in rheumatology is unknown. METHODS: The American College of Rheumatology (ACR) and European Alliance of Associations for Rheumatology (EULAR) websites were searched from January 1, 2017, to June 12, 2021, for clinical practice guidelines. RCTs referenced by each guideline were identified, and information regarding design and outcomes were extracted. Clinical practice recommendations from each guideline were also analyzed. RESULTS: Fifteen ACR- and nine EULAR-endorsed guidelines were included, which cited 609 RCTs and provided 481 recommendations. Referenced RCTs enrolled an average of 418 patients (SD 985), most commonly evaluated biologic/targeted synthetic disease-modifying antirheumatic drugs (70.1%), and infrequently used a head-to-head design (28%). A minority of recommendations received a high level of evidence (LOE) by the Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) methodology (2.9%) or an "A" grade by the Oxford Centre for Evidence based Medicine Standards (OCEBM) methodology (28.9%). LOE was higher for recommendations informed by RCTs (P < 0.001) or head-to-head RCTs (P = 0.008). Many recommendations received a strong recommendation despite low (8 [2.6%]) or very low (25 [8.3%]) LOE. CONCLUSION: Less than one in six rheumatology guideline recommendations are informed by head-to-head RCTs. Recommendations that were informed by head-to-head RCTs were more likely to have a high LOE by both GRADE and OCEBM. Efforts to introduce more comparative efficacy RCTs should be undertaken.

The role of calcineurin/NFAT in SFRP2 induced angiogenesis--a rationale for breast cancer treatment with the calcineurin inhibitor tacrolimus.

Tacrolimus (FK506) is an immunosuppressive drug that binds to the immunophilin FKBPB12. The FK506-FKBP12 complex associates with calcineurin and inhibits its phosphatase activity, resulting in inhibition of nuclear translocation of nuclear factor of activated T-cells (NFAT). There is increasing data supporting a critical role of NFAT in mediating angiogenic responses stimulated by both vascular endothelial growth factor (VEGF) and a novel angiogenesis factor, secreted frizzled-related protein 2 (SFRP2). Since both VEGF and SFRP2 are expressed in breast carcinomas, we hypothesized that tacrolimus would inhibit breast carcinoma growth. Using IHC (IHC) with antibodies to FKBP12 on breast carcinomas we found that FKBP12 localizes to breast tumor vasculature. Treatment of MMTV-neu transgenic mice with tacrolimus (3 mg/kg i.p. daily) (n = 19) resulted in a 73% reduction in the growth rate for tacrolimus treated mice compared to control (n = 15), p = 0.003; which was associated with an 82% reduction in tumor microvascular density (p<0.001) by IHC. Tacrolimus (1 µM) inhibited SFRP2 induced endothelial tube formation by 71% (p = 0.005) and inhibited VEGF induced endothelial tube formation by 67% (p = 0.004). To show that NFATc3 is required for SFRP2 stimulated angiogenesis, NFATc3 was silenced with shRNA in endothelial cells. Sham transfected cells responded to SFRP2 stimulation in a tube formation assay with an increase in the number of branch points (p<0.003), however, cells transfected with shRNA to NFATc3 showed no increase in tube formation in response to SFRP2. This demonstrates that NFATc3 is required for SFRP2 induced tube formation, and tacrolimus inhibits angiogenesis in vitro and breast carcinoma growth in vivo. This provides a rationale for examining the therapeutic potential of tacrolimus at inhibiting breast carcinoma growth in humans.

Efficient In Vivo Selection of a Novel Tumor-Associated Peptide from a Phage Display Library.

We developed a screening procedure to identify ligands from a phage display random peptide library that are selective for circulating bone marrow derived cells homing to angiogenic tumors. Panning the library on blood outgrowth endothelial cell suspension in vitro followed by in vivo selection based on homing of bone marrow-bound phage to angiogenic tumors, yielded the peptide QFPPKLTNNSML. Upon intravenous injection phage displaying this peptide homed to Lewis lung carcinoma (LLC) tumors in vivo whereas control phage did not localize to tumor tissue. Phage carrying the QFPPKLTNNSML peptide labeled with 64Cu radionuclide when administered intravenously into a tumor bearing mouse was detected noninvasively with positron emission tomography (PET) around the tumor. These proof-of-principle experiments demonstrate the ability of the QFPPKLTNNSML peptide to deliver payload (radiolabeled phage conjugates) in vivo to sites of ongoing angiogenesis and point to its potential clinical utility in a variety of physiologic and pathologic processes where neovascular growth is a critical component.

Secreted frizzle-related protein 2 stimulates angiogenesis via a calcineurin/NFAT signaling pathway.

Secreted frizzle-related protein 2 (SFRP2), a modulator of Wnt signaling, has recently been found to be overexpressed in the vasculature of 85% of human breast tumors; however, its role in angiogenesis is unknown. We found that SFRP2 induced angiogenesis in the mouse Matrigel plug assay and the chick chorioallantoic membrane assay. SFRP2 inhibited hypoxia induced endothelial cell apoptosis, increased endothelial cell migration, and induced endothelial tube formation. The canonical Wnt pathway was not affected by SFRP2 in endothelial cells; however, a component of the noncanonical Wnt/Ca2+ pathway was affected by SFRP2 as shown by an increase in NFATc3 in the nuclear fraction of SFRP2-treated endothelial cells. Tacrolimus, a calcineurin inhibitor that inhibits dephosphorylation of NFAT, inhibited SFRP2-induced endothelial tube formation. Tacrolimus 3 mg/kg/d inhibited the growth of SVR angiosarcoma xenografts in mice by 46% (P = 0.04). In conclusion, SFRP2 is a novel stimulator of angiogenesis that stimulates angiogenesis via a calcineurin/NFAT pathway and may be a favorable target for the inhibition of angiogenesis in solid tumors.

Sleep duration of an individual has adverse influence on auditory episodic memory.

The present study evaluated the influence of habitual sleep duration on episodic memory in a wakeful state. Episodic memory was assessed for auditory and visual processing pathways. A total of 96 medical students (53 male and 43 female, between the age group 18-23 years) accustomed to different sleep durations volunteered in the tests. The tests included auditory free recall of 10 common words, pictorial free recall of 10 pictures and recognition of 10 miniature animal replicas with 10 distracters. There was no gender-related difference in the visual and the auditory memory scores. The visual episodic memory scores were similar in persons sleeping longer or shorter duration. On the other hand auditory memory scores were significantly lower in persons accustomed to >10 h sleep. The results indicate the importance of sleep duration on episodic memory processing of learned material even during wakeful state specially which involves auditory system.