SciCombinator

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Journal: Lupus

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Lupus patients are in need of modern drugs to treat specific manifestations of their disease effectively and safely. In the past half century, only one new treatment has been approved by the US Food and Drug Administration (FDA) for systemic lupus erythematosus (SLE). In 2014-2015, the FDA approved 71 new drugs, only one of which targeted a rheumatic disease and none of which was approved for use in SLE. Repositioning/repurposing drugs approved for other diseases using multiple approaches is one possible means to find new treatment options for lupus patients. “Big Data” analysis approaches this challenge from an unbiased standpoint whereas literature mining and crowd sourcing for candidates assessed by the CoLTs (Combined Lupus Treatment Scoring) system provide a hypothesis-based approach to rank potential therapeutic candidates for possible clinical application. Both approaches mitigate risk since the candidates assessed have largely been extensively tested in clinical trials for other indications. The usefulness of a multi-pronged approach to drug repositioning in lupus is highlighted by orthogonal confirmation of hypothesis-based drug repositioning predictions by “Big Data” analysis of differentially expressed genes from lupus patient samples. The goal is to identify novel therapies that have the potential to affect disease processes specifically. Involvement of SLE patients and the scientists that study this disease in thinking about new drugs that may be effective in lupus though crowd-sourcing sites such as LRxL-STAT (www.linkedin.com/in/lrxlstat) is important in stimulating the momentum needed to test these novel drug targets for efficacy in lupus rapidly in small, proof-of-concept trials conducted by LuCIN, the Lupus Clinical Investigators Network (www.linkedin.com/in/lucinstat).

Concepts: Rheumatoid arthritis, Rheumatology, Systemic lupus erythematosus, Lupus erythematosus

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One challenge in caring for patients with systemic lupus erythematosus (SLE) is a paucity of approved therapeutics for treatment of the diverse disease manifestations. In the last 60 years, only one drug, belimumab, has been approved for SLE treatment. Critical evaluation of investigator initiated and pharma-sponsored randomized controlled trials (RCTs) highlights barriers to successful drug development in SLE, including disease heterogeneity, inadequate trial size or duration, insufficient dose finding before initiation of large trials, handling of background medications, and choice of primary endpoint. Herein we examine lessons learned from landmark SLE RCTs and subsequent advances in trial design, as well as discuss efforts to address limitations in current SLE outcome measures that will improve detection of true therapeutic responses in future RCTs.

Concepts: Pharmacology, Corticosteroid, Systemic lupus erythematosus, Lupus erythematosus

3

Significant differences have been reported in disease phenotype and severity of systemic lupus erythematosus (SLE) presenting in different age groups. Most indicate a more severe phenotype in juvenile-onset SLE (JSLE). There have been limited studies in older patients and no large studies looking at SLE across all age groups.

Concepts: Systemic lupus erythematosus, Lupus erythematosus

2

In recent years, there have been a number of studies suggesting that POTS may have an autoimmune etiology. This study examined whether the prevalence of antinuclear antibodies (ANA), other markers of autoimmunity and co-morbid autoimmune disorders is higher in patients with POTS than in the general population.

Concepts: Immune system, Immunology, Rheumatoid arthritis, Graves' disease, Postural orthostatic tachycardia syndrome

2

The current mainstay of the treatment of thrombotic antiphospholipid syndrome (APS) is long-term anticoagulation with vitamin K antagonists (VKAs) such as warfarin. Non-VKA oral anticoagulants (NOACs), which include rivaroxaban, have been shown to be effective and safe compared with warfarin for the treatment of venous thromboembolism (VTE) in major phase III prospective, randomized controlled trials (RCTs), but the results may not be directly generalizable to patients with APS.

Concepts: Clinical trial, Stroke, Thrombosis, Warfarin, Anticoagulant, Heparin, Anticoagulants, Vitamin K

1

Background Twenty-five years ago attorneys representing ailing women in class action litigation against silicone breast implant manufacturers made the procedural error of defining silicone-induced toxicity in the courtroom before it was properly studied in the exam room. This aberrant methodology perverted the proper research process, rendered verification of any real disease elusive, and cemented the groundwork for a repeat public health crisis potentially affecting two million women in the USA who possess new silicone gel devices inserted over the past 10 years. Patients and methods Six women, previously well, aged 27 to 53 (mean 42), were recipients of the new generations of cohesive silicone gel-filled breast implants approved for general use by the Food and Drug Administration (FDA) since December of 2006. They averaged seven years of total implantation time, and none experienced implant rupture. Results All six became ill on average 3.5 years from the time of implantation. By seven years the women manifested multiple types of skin rashes, polyarthritis, fatigue, protracted AM stiffness, myalgias, headaches, photosensitivity, hair loss, paresthesias, tinnitus, lymphadenopathy, chest pain, cognitive dysfunction, dry eyes, skin pigment changes, itching, muscle twitching, dizziness, nausea, easy bruising, and odor and smell sensitivity. Three of the four who were explanted noted improvement and/or resolution of at least 50% of their total disease manifestations. Conclusions These six women are representative of over 70,000 other breast implant recipients who, over the past three years, have had their new silicone devices permanently removed because of alleged gel-induced toxicity. The recurrence of this public health crisis has been fueled by manufacturers' research fraud, FDA ineptness, faulty informed consent, patient abandonment, proprietary manufacturing secrecy, misleading advertising, physician indifference, aberrant research methodology, and lax Congressional oversight.

Concepts: Informed consent, Implants, Implantation, Pigment, Human skin color, Breast reconstruction, Silicone, Breast implant

1

To examine long-term organ damage and safety following treatment with belimumab plus standard of care (SoC) in patients with systemic lupus erythematosus (SLE).

Concepts: Systemic lupus erythematosus, Lupus erythematosus

1

The current mode of therapy for many patients with musculoskeletal pain is unsatisfactory.

Concepts: Vitamin D, Vitamin, Pain, The Current

1

ObjectivesWhile patients with systemic lupus erythematosus (SLE) have poorer health-related quality of life (HRQoL) and are more depressed than healthy people, the impact of proinflammatory cytokines, particularly tumour necrosis factor-alpha (TNFα), on these unfavourable psychosocial parameters is unclear. We aim to explore potential relationships between lupus-related proinflammatory cytokines, HRQoL and depressive symptoms in patients with SLE.MethodsPatients with SLE and age-matched healthy subjects were assessed for HRQoL and depressive and anxiety symptoms by the Short Form Health Survey-36 (SF-36) and Hospital Anxiety and Depression Scale (HADS) respectively. Using multiplex immunoassay, a panel of serum proinflammatory cytokines including TNFα, interleukin (IL)-1β, IL-6, IL-17, IL-23 and IL-33 were determined and compared between both groups. Independent associations between SF-36, serum proinflammatory cytokine levels and HADS scores were studied by regression models.ResultsIn total, 54 patients and 54 healthy controls were studied. Lupus patients had significantly poorer HRQoL (p < 0.001) and were significantly more depressed (p = 0.006) and anxious (p = 0.022) than their healthy counterparts. Amongst the proinflammatory cytokines studied, serum TNFα was significantly higher in lupus patients (p < 0.001). After multivariate adjustment, higher serum TNFα (β = -0.224, p = 0.047) remained significantly associated with lower SF-36, along with smoking (β = -0.253, p = 0.014) and more severe depressive symptoms (β = -0.433, p = 0.002). In healthy subjects, serum TNFα was associated with depressive symptoms but not with SF-36.ConclusionsHigher serum TNFα level is independently associated with poorer HRQoL and more severe depressive symptoms in SLE patients. These associations suggest a potential impact of inflammatory response on depressive symptoms and the quality of life in patients with SLE.

Concepts: Inflammation, Rheumatoid arthritis, Systemic lupus erythematosus, Lupus erythematosus, Glomerulonephritis

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Presentation of a combination of branch retinal artery occlusion (BRAO)/central retinal artery occlusion (CRAO) and central retinal vein occlusion (CRVO) in systemic lupus erythematosus (SLE) is extremely rare. Herein, we have presented the case of a 29-year-old female with SLE, who simultaneously developed bilateral CRVO and BRAO/CRAO in the absence of antiphospholipid syndrome (APS) as a catastrophic form of clinical flare. A combinatorial diagnosis of CRVO and BRAO/CRAO should be considered during clinical flare-up in a patient with SLE who presents with rapidly progressive visual loss.