Faculty Bibliography

OBJECTIVE:Mycophenolate (MPA) and cyclosporin A (CsA) are two immunosuppressive agents currently used for the treatment of autoimmune diseases. However, reports regarding their effects on inflammation and lipid handling are controversial. Here, we compare the effect of these two drugs on the expression of proteins involved in cholesterol handling and lipid accumulation in a macrophage cell system utilizing M0, M1 and M2 human macrophages and in murine bone marrow-derived macrophages (BMDM). METHODS:. RESULTS:In M0 macrophages, MPA increased expression of ABCA1 and CXCL16 in a concentration-dependent manner. In M1 THP-1 macrophages, MPA caused a significant increase of 27-hydroxylase mRNA and CD36 and SR-A1 receptor mRNAs. Exposure of M2 macrophages to MPA also stimulated expression of 27-hydroxylase, while downregulating all evaluated scavenger receptors. In contrast, CsA had no impact on cholesterol efflux in M0 and M1 macrophages, but significantly augmented expression of ABCA1 and 27-hydroxylase in M2 macrophages. CsA significantly increased expression of the LOX1 receptor in naïve macrophages, downregulated expression of CD36 and SR-A1 in the M1 subpopulation and upregulated expression of all evaluated scavenger receptors. However, CsA enhanced foam cell transformation in M0 and M2 macrophages, while MPA had no effect on foam cell formation unless used at a high concentration in the M2 subtype. CONCLUSIONS:Our results clearly underline the importance of further evaluation of the effects of these drugs when used in atherosclerosis-prone patients with autoimmune or renal disease.

Background andObjectives: Atherosclerotic cardiovascular disease (CVD) remains a major cause of morbidity and mortality in persons with systemic lupus erythematosus (SLE, lupus). Atherosclerosis, which involves interplay between cholesterol metabolism and cellular inflammatory pathways, is primarily treated with statins since statins have lipid-lowering and anti-inflammatory properties. The Lupus Atherosclerosis Prevention Study (LAPS) was designed to investigate the efficacy of statins against CVD in SLE patients. LAPS demonstrated that 2 years of atorvastatin administration did not reduce atherosclerosis progression in lupus patients. In this LAPs substudy, we use cultured macrophages to explore the atherogenic properties of plasma from LAPS subjects to explain the mechanistic rationale for the inability of statins to reduce CVD in lupus. Materials and Methods: THP-1 differentiated macrophages were treated for 18 h with 10% SLE patient plasma obtained pre- and post-atorvastatin therapy or placebo. Gene expression of the following cholesterol transport genes was measured by qRT-PCR. For efflux-ATP binding cassette transporter (ABC)A1 and ABCG1, 27-hydroxylase, peroxisome proliferator-activated receptor (PPAR)γ, and liver X receptor (LXR)α; and for influx-cluster of differentiation 36 (CD36) and scavenger receptor (ScR)A1. Results: Macrophages exposed to plasma from both statin-treated and placebo-treated groups showed a significant decrease in cholesterol efflux proteins ATP binding cassette (ABC) transporters A1 and ABCG1, an increase in 27-hydroxylase, an increase in the LDL receptor and a decrease in intracellular free cholesterol. No change in influx receptors ScRA1 and CD36, nor nuclear proteins LXRα and PPARγ was observed. Conclusions: Statins do not normalize pro-atherogenic changes induced by lupus and these changes continue to worsen over time. This study provides mechanistic insight into LAPS findings by demonstrating that statins are overall ineffective in altering the balance of cholesterol transport gene expression in human macrophages. Furthermore, our study suggests that statins as a CVD treatment may not be useful in attenuating lipid overload in the SLE environment.

Background: Primary Sjogren's syndrome (pSS) is a systemic progressive autoimmune disease characterised by formation of lymphoid structures and germinal centres within glandular tissue. Iscalimab (CFZ533) is a novel monoclonal antibody that potently and selectively blocks CD40, a co-stimulatory pathway receptor important for germinal centre reactions and B cell activation. Iscalimab showed clinical efficacy in a Proof of Concept randomised controlled trial at a dose of 10 mg/kg intravenously (IV), whereas subcutaneous (SC) dosing at 3 mg/kg was associated with unexpectedly low plasma concentrations and reduced efficacy, likely due to efficient pre-systemic target-mediated clearance.
Objective(s): To test IV versus SC loading doses of iscalimab followed by SC maintenance dosing, as a means of achieving target drug exposure and clinical efficacy.
Method(s): Patients with clinically active pSS [EULAR Sjogren's Syndrome Disease Activity Index (ESSDAI) >=6] were randomised to receive either 600 mg SC iscalimab weekly on 4 occasions, followed by 300 mg SC weekly until week 12, or a single IV dose of 10 mg/kg iscalimab on study Day 1, followed by 300 mg SC weekly until week 12. Subjects and investigator staff remained blinded to study treatment allocation until first dosing.
Result(s): Twenty-five patients were randomised; 13 in the SC loading and 12 in the IV loading arms. Baseline characteristics were similar to the previous phase IIa cohorts with mean ESSDAI scores of 12.7 (SD 6.1) and 10.4 (5.9) in the SC and IV loading arms respectively. In Arm 1 (SC) and Arm 2 (IV), the mean trough plasma concentrations were 169mug/mL (SD 64.1, CV 38%) and 135mug/mL (SD 70.9, CV 53%) on Day 85, respectively. Both values were well above levels previously reported to be sufficient for suppression of germinal centre development and T dependent antigen responses in cynomolgus monkeys. Consistent with this finding, clinically important improvements were seen in both arms with a mean decrease in ESSDAI scores of -5.5 (+/- SD: 5.5) and -7.6 (+/- 7.1) points from baseline to Day 85 in the SC and IV dosing arms. Improvements were also seen in EULAR Sjogren's Syndrome Patient Reported Index (ESSPRI) scores: -1.67 (+/- 1.8) and -1.17 (+/- 2.3), respectively. Other secondary efficacy outcomes showed similar patterns of improvement. Treatment with iscalimab was associated with a reduction in the germinal centre-related serum biomarker CXCL13 in both groups. Overall, iscalimab was safe and well-tolerated with no new safety signal emerging. One subject experienced three SAEs (hemarthrosis, worsening of right knee pain and swelling requiring arthroscopy) in the safety followup period, all unrelated to study drug.
Conclusion(s): These results further support the safety and efficacy of iscalimab in pSS and the suitability of SC dosing for future development

BACKGROUND:Rheumatoid arthritis (RA) is a chronic systemic autoimmune inflammatory disorder that increases the risk of developing cardiovascular disease. There is accumulating evidence that the RA disease state accelerates the formation of atherosclerotic plaques. Treatments for RA improve joint symptomatology and may reduce inflammation, but consideration of their effects on the cardiovascular system is generally low priority. OBJECTIVE:Since cardiovascular disease is the leading cause of mortality in RA patients, the impact of RA therapies on atherosclerosis is an area in need of attention and the focus of this review. RESULTS:The drugs used to treat RA may be analgesics, conventional disease-modifying anti-rheumatic drugs, and/or biologics, including antibodies against the cytokine tumor necrosis factor-α. Pain relievers such as non-selective non-steroidal anti-inflammatory drugs and cyclooxygenase inhibitors may adversely affect lipid metabolism and cyclooxygenase inhibitors have been associated with increased adverse cardiovascular events, such as myocardial infarction and stroke. Methotrexate, the anchor disease-modifying anti-rheumatic drug in RA treatment, has multiple atheroprotective advantages and is often combined with other therapies. Biologic inhibitors of tumor necrosis factor-α may be beneficial in preventing cardiovascular disease because tumor necrosis factor-α promotes initiation and progression of atherosclerosis. However, some studies show a worsening of the lipid profile in RA with blockade of this cytokine, leading to higher total cholesterol and triglycerides. CONCLUSION/CONCLUSIONS:Greater understanding of the pharmacologic activity of RA treatments on the atherosclerotic process may lead to improved care, addressing both damage to the joints and damage to the heart.

Background. Oral complications in Sjogren's can lead to painful oral infection/ lesions/irritation, rampant caries and loss of teeth, in addition to difficulty eating and talking, which compromise the quality of life of patients with Sjogren's. There is a clear unmet need for managing the lack of saliva and its consequences in Sjogren's. The Sjogren's Syndrome Foundation (SSF) launched a major initiative to address this need in 2012, and clinical practice guidelines for caries prevention were published in 2016 in the Journal of the American Dental Association (JADA) and included in the Rheumatic Diseases Clinics of North America. Phase 2 oral guidelines are now well underway and include coverage of mucosal management and treatment and use of secretagogues in Sjogren's. Guidelines on caries restoration and management and parotid gland swelling also will be developed. Methods. Guidelines members developed a rigorous and transparent process based on standards set by the American Dental Association, American College of Rheumatology and American Society of Clinical Oncology. The methodology utilizes a Delphi-type consensus process and includes drafting clinical questions and defining literature search parameters and study criteria a priori to execution of the search. Eligible abstracts then are identified, and a minimum of 2 guidelines members extract the data on study characteristics, evidence and quality assessment. Recommendations will be drafted and finalized with input from at least 30 oral healthcare professionals who were not involved in the guidelines development. Results. The Mucosal Management and Treatment Topic Review Group (TRG) drafted clinical questions for its outline covering oral symptoms of mucosal pain and/or inflammation in Sjogren's, including prevalence and identification of oral cancer. Prevention and management of burning mouth; oral candidiasis; lichenoid reactions or hypersensitivity-induced mucositis; and oral trauma associated with oral dryness were discussed. The Secretagogues TRG's clinical questions explore whether studies have demonstrated that sialogogues improve salivary flow and composition; reduce the occurrence of candida, other oral infections and burning mouth; and translate to better outcomes for the incidence of caries, periodontal disease, taste disturbance; hoarseness, chronic cough, and subjective and objective dryness and discomfort. Conclusions. Initial clinically relevant questions for Clinical Practice Guidelines for oral mucosal management and use of secretagogues for dry mouth in Sjogren's were established by Sjogren's experts across the U.S. Literature searches, data extraction, and recommendation development is underway. Recommendations utilize evidence from Sjogren's studies when available and expert opinion when little to no evidence in Sjogren's literature is available. Areas for future research will be delineated with a focus on patient-perceived areas of unmet need

Background. Standardization of the diagnosis and treatment of neurologic manifestations of Sjogren's remains an unmet clinical need. A multi-disciplinary task force of rheumatologists, neurologists and other specialists has been formed to develop consensus recommendations concerning the neurological features of the disease. Methods. Guidelines members in rheumatology and neurology were organized into central (CNS) and peripheral nervous system (PNS) Topic Review Groups (TRGs). Additional specialists include neuro-ophthalmology, vasculitis, psychiatry, neuro-psychology, and sleep medicine. The initial guidelines development process is based on American College of Rheumatology and American Society of Clinical Oncology procedures, including drafting and ranking of clinical questions, defining literature search parameters and determining outcome measures to be addressed prior to the literature review. Members then will identify eligible abstracts and a minimum of 2 TRG members extract data on evidence and study quality. Recommendations will be drafted and finalized via the Delphi method. The American Academy of Neurology appointed representatives to both TRGs. Results. PNS coverage areas were based upon both the neuro-anatomic localization to the motor, sensory and autonomic nerves and the etiology involving demyelinating, axonal and antibody-based pathologies. These include cranial neuropathies; axonal or sensory motor or sensory neuropathies; small fiber neuropathies (length-dependent or non-length dependent); ataxic sensory neuropathies/large fiber ganglionopathies; mononeuritis multiplex/multiple mononeuropathies; and autonomic neuropathies. CNS coverage areas were based upon the clinical syndromes involving encephalopathies, seizures, strokes, and myelopathies and etiologies including demyelinating and vasculopathic pathology. Included are vasculitis; optic neuritis; vestibular/auditory, olfactory, taste; autoimmune encephalitis; myelitis or other demyelinating syndromes; psychiatric (anxiety, depression, psychosis); cognitive dysfunction; and impaired sleep. Conclusions. The initial clinically relevant questions for Clinical Practice Guidelines for neurological manifestations in Sjogren's were developed by multi-specialty teams of Sjogren's experts across the U.S. Literature searches, data extraction, and recommendations for the diagnosis and treatment of neurological manifestations of Sjogren's are based on published studies related to Sjogren's or related diseases. When results of clinical investigation are not available, consensus expert opinion will be used as an initial step to standardize management and treatment

Background. Management guidelines for Sjogren's patients remain a major unmet need, particularly for potentially severe extraglandular (systemic) manifestations. To meet this patient and clinician need, the Sjogren's Syndrome Foundation (SSF) launched a major initiative to develop Clinical Practice Guidelines for Sjogren's in 2012. Goals include: improving quality and consistency of care, creating guidance documents for US clinicians, obtaining broad acceptance of guidelines by key professional and government organizations, educating payers and identifying gaps in evidence to spur much needed research. Following 4 recent publications by the SSF on initial Clinical Practice Guidelines under the rheumatology/systemic, oral, and ocular topics, Phase 2 is now well underway. This phase aims to comprehensively collate scientific evidence and expert opinion on the management of pulmonary manifestations of Sjogren's. Methods. Guideline members developed a rigorous and transparent process based on American College of Rheumatology quality of care standards and protocols developed by other professional organizations such as the American Society of Clinical Oncology. A unique aspect of these guidelines is the inclusion of multiple specialists. The Pulmonary Topic Review Group (TRG) includes an equal number of rheumatologists and pulmonologists as well as an oncologist with expertise in Sjogren's. The process involved drafting and ranking clinical questions, defining the literature search and study criteria, and outcome measures to be addressed a priori to execution of the search. Members then identified eligible abstracts, and a minimum of 2 TRG members extracted data into tables, which included study characteristics and evidence and quality assessment. Recommendations will be drafted and finalized via a Delphi-type consensus process involving more than 30 medical specialists. Results. Areas of pulmonary coverage were outlined and include screening and diagnosis; upper airway disease (xerostomia, dysphagia, laryngopharyngeal reflux, vocal cord, obstructive sleep apnea); lower airway disease (xerotrachea, bronchiectasis, bronchiolitis, obstructive lung diseases including COPD and asthma); interstitial lung disease; lymphoproliferative disease (including bronchus- associated lymphoid tissue lymphoma/ non- Hodgkin lymphoma, amyloid, and nodular lymphoid hyperplasia); vascular lung disease; lung transplant; and peri-operative and other non-medication management. Almost 200 informational and clinical questions were drafted. Conclusions. Clinically relevant questions for the development of Clinical Practice Guidelines for pulmonary manifestations in Sjogren's were developed by multi-specialty teams of Sjogren's experts across the U.S. Literature searches, data extraction, and recommendation development are underway. Recommendations will utilize evidence in Sjogren's when available and evidence from closely related diseases and expert opinion when little to no evidence in Sjogren's is available. Areas for future research will be delineated with a focus on patient-perceived areas of unmet need