Faculty Bibliography

BACKGROUND/UNASSIGNED:Preclinical and early human evidence indicate that splenic neuromodulation modulates immune activity either independently or in conjunction with biologic or targeted synthetic (b/ts) disease modifying antirheumatic drugs (DMARDs). This study evaluated the safety, tolerability, and preliminary effectiveness of splenic nerve stimulation (SpNS) as monotherapy and in combination with b/tsDMARDs in adult patients with difficult-to-treat rheumatoid arthritis. METHODS/UNASSIGNED:ConsideRAte was an early-feasibility, multicentre, randomised sham-controlled trial of an implantable device (Galvani System) delivering SpNS conducted across six centres in the USA and Netherlands. Adults with difficult-to-treat rheumatoid arthritis, defined by inadequate response to at least two b/tsDMARDs, were implanted and randomised 1:1 to active (STIM ON) or sham (STIM OFF) stimulation following five sentinel patients. Participants received 12 weeks of stimulation in the monotherapy phase, defined as stimulation added to stable conventional synthetic DMARDS (csDMARDs) and/or low dose corticosteroids. Participants with Disease Activity Score using Erythrocyte Sedimentation Rate (DAS28-ESR) improvement of ≥1.2 continued stimulation for an additional 12 weeks; non-responders discontinued stimulation and received baricitinib for 12 weeks. Thereafter, participants who were not in remission could receive adjunct tsDMARDs (baricitinib) together with SpNS in an open-label phase for six months, after which the participants moved to long-term-follow-up. The primary objective was to assess safety and tolerability of the Galvani System, its implantation and subsequent stimulation; key secondary outcomes included assessment of disease activity Disease Activity Score using C-Reactive Protein (DAS28-CRP) and patient-reported outcomes. This study is registered with ClinicalTrials.gov (NCT05003310). FINDINGS/UNASSIGNED:Between January 2022 and November 2024, eleven participants (Five Open Label STIM ON, six randomised to STIM ON (n = 3) and STIM OFF (n = 3)) were successfully implanted with the Galvani System. No device-related serious adverse events, or unanticipated adverse device effects occurred. During the 12-week monotherapy phase, mean DAS28-CRP decreased by 1.02 ± 0.45 (mean ± Standard Error, [SE]) in the STIM ON group compared with -0.34 ± 0.14 in the STIM OFF group. Five of eight (62.5%) STIM ON participants achieved a clinically meaningful improvement (≥1.0-point reduction). Nine participants entered the adjunct phase, with mean (±SE) DAS28-CRP decreasing with -2.95 ± 0.56 points at week 12 and -2.28 ± 0.69 points at week 24; 55.6% (5/9) achieved low disease activity (LDA) and 33.3% (3/9) remission. Two participants remained on monotherapy. In exploratory analysis, biomarkers were assessed in the monotherapy phase at the end of 12 weeks and trends for systemic proinflammatory cytokine reductions and in TH17 (T-helper 17) cell populations were observed in responders as defined by DAS28-CRP changes. INTERPRETATION/UNASSIGNED:SpNS demonstrated a favourable safety profile and was well tolerated in this small cohort. Clinical improvements were observed for monotherapy, and enhanced outcomes were observed for adjunct treatment resulting in multiple participants reaching LDA or remission. By engaging neuro-immune pathways rather than targeting single cytokines, this approach represents a novel therapeutic option that warrants further evaluation as stand-alone therapy or to complement existing pharmacological treatments for difficult-to-treat rheumatoid arthritis patients. FUNDING/UNASSIGNED:Galvani Bioelectronics.

Chimeric antigen receptor (CAR) T-cell therapy, long transformative in oncology, is now rapidly emerging as a frontier in autoimmune rheumatic diseases, particularly systemic lupus erythematosus (SLE), driven by accumulating evidence of deep B-cell depletion, immune "resetting," and durable drug-free remission in early studies, yet its translation into rheumatology demands mastery of formidable logistical, regulatory, clinical, and ethical complexities that span institutional readiness, multidisciplinary team formation, stringent regulatory compliance, sophisticated operational workflows, comprehensive patient selection and education, meticulous clinical management of both classical toxicities (CRS, ICANS, ICAHT) and autoimmune-specific reactions such as LICATS, robust financial and resource planning, and long-term follow-up extending 15 years or more; successful implementation requires coordinated expertise among rheumatologists, hematologist-oncologists, cellular therapy units, pharmacists, research coordinators, and ICU-capable teams, all embedded within disciplined communication structures, harmonized SOPs, validated PROs, biorepository governance frameworks, and adherence to national and international cellular therapy standards; in parallel, investigators must anticipate bottlenecks such as apheresis access, manufacturing slot scarcity, competing trial enrollment, fluctuating SLE phenotypes, and heterogeneity-driven signal variability, while sustaining patient engagement over years through education, navigation support, and transparent risk/benefit communication; finally, collaboration with industry partners, clinical trial networks, and patient-advocacy organizations is essential for overcoming operational barriers, securing financial sustainability, and ensuring ethical stewardship, so that CAR T-cell clinical trials in autoimmunity can be executed safely, rigorously, and with maximal therapeutic promise for patients.

Bone mineral density (BMD) reference data of non-Caucasian women is scarce but greatly needed for African-American women. The objective of this study was to establish a metacarpal normative reference database for African-American women using digital X-ray radiogrammetry (DXR) and hand radiographs and compare these values to existing Caucasian data. Two hundred and fifty healthy African-American women between the ages of 20 and 79 years old, 14 of whom were excluded, were recruited to participate from four different clinical sites. The study population was recruited in approximately equal number into the following groups: 20-29, 30-39, 40-49, 50-59, 60-69 and 70-79 years of age. A radiograph was acquired of each subject's non-dominant hand. The radiographs were scanned and analyzed using radiogrammetric techniques, and the BMD, MCI (Metacarpal Index), bone width and cortical thickness were calculated. The regression curve that best fit the data was a second order polynomial. The BMD and MCI of young adult women (20-40 years of age) were used to calculate T-score parameters. The young reference BMD and MCI with their associated standard deviations were found to be 0.6045 g/cm2+/-0.0529 g/cm2 and 0.5096 and 0.0792, respectively. However, the MCI was found to be approximately 2.5% lower (-0.0118) compared to Caucasian women. The African-American metacarpal BMD was found to be 3.5% (0.0207 g/cm2) higher across all ages when compared to existing Caucasian reference data acquired in a similar way. The differences were found to be entirely due to larger bone size, cortical diameter and bone width in the African-American women

There has been increasing interest in attempts to harness the body's normal inflammatory response mediated through the eicosanoid pathway to treat tumors. Accumulating data indicate that the growth of several different cancers is modulated by a group of pro-inflammatory bioactive lipids, the best known of which are the eicosanoids. Eicosanoid pathway constituents modulate cell function in several important ways, and an agent that activates PLA(2) and up-regulates LTB(4) levels could be expected to be an effective cytotoxic tumor agent, especially if it stimulated NK cells. PLAP is a 28-kDa polypeptide that is a member of the WD-repeat protein, G-protein-transducin superfamily. The pro-inflammatory properties of PLAP have been elucidated using a number of different approaches. PLAP has been found in inflamed tissues and synovial fluid from patients with rheumatoid arthritis. Based on knowledge of PLAP as a pro-inflammatory agent, its capacity to modulate the immune response and the role of the inflammatory and immune responses in immune surveillance, the role of PLAP in cancer therapy was explored. Significant tumor regression was observed 72 hours following a single treatment with PLAP in an animal air pouch model of glioma. PEG-PLAP treatment increased the life expectancy of animals with Lewis lung cancer, and in preliminary studies in MTVL breast tumors in mice, PLAP treatment resulted in a similar increase in life expectancy. These findings suggest that PLAP holds promise as a potential therapy for cancer, and warrants further study

An ideal form of cancer therapy is the harnessing of innate immunity to eradicate spontaneously arising clones of malignant cells. To date, attempts to develop effective immunotherapies have met with limited success. Prostaglandins and leukotrienes, collectively known as eicosanoids, are important mediators of immune and inflammatory responses. Harnessing these compounds could be a method to treat cancers. Eicosanoids are formed after cleavage of fatty acids from phospholipids by phospholipase enzymes. We have previously described, characterized and cloned a naturally occurring mammalian activator of phospholipase A2. Injection of a 24 amino acid peptide from this phospholipase A2 activating protein (PLAP), resulted in induction of an acute inflammatory response, and a concomitant regression of gliomas in rats. Administration of 500 micrograms of this protein resulted in a 50% decrease of the tumor mass within 72 h. Tumor regression coincided with a greater than twenty-fold increase in levels of prostaglandin E2(PGE2) and leukotriene B4(LTB4), and a marked infiltration of natural killer(NK) cells. These data suggest that activation of phospholipase A2 and modulation of the eicosanoid biosynthetic pathway may provide a novel therapeutic strategy for the successful treatment of malignant tumors of the nervous system

In vitro, rheumatoid arthritis (RA) synovial cells display several of the characteristics of neoplastic and virally transformed cells. The recent observation that synovial cell cultures, derived from collagenase digests of synovial membranes from RA patients, proliferate in serum-free medium suggests that these cells have the capacity to synthesize those factors essential for their growth. Direct immunocytochemical staining and Western analysis have identified transforming growth factor-beta (TGF-beta) band and basic fibroblast growth factor (FGF) in the cytoplasm of RA and normal synovial cells in long-term culture. Greater amounts of each growth factor were found in RA, as compared with normal synovial cell lysates. Western analysis identified a single TGF-beta band in RA and normal synovial cell lysates. Four bands were identified by Western analysis on RA synovial cell lysates probed with monoclonal antibodies recognizing bFGF, whereas only two bands (which co-migrated with human native recombinant bFGF) were identified in normal cell lysates probed with these antibodies. Gene expression analysis using PCR identified mRNA transcripts encoding TGF-beta 1 and FGF-2 (bFGF), but not TGF-beta 2 in all cell cultures studied. Taken together, these data indicate that cultured synovial cells co-express TGF-beta 1 and multiple isoforms of hFGF. These data further strengthen the concept that both polypeptide growth factors are involved in the regulation of synovial cell growth

OBJECTIVE: To demonstrate expression of transforming growth factor beta (TGF beta) and basic fibroblast growth factor (bFGF) by cultured rheumatoid arthritis (RA) synovial cells and to investigate their role as synovial cell mitogens. METHODS: Polypeptide growth factors were detected and identified by immunocytochemical staining and Western blot analysis. Messenger RNA (mRNA) transcripts encoding TGF beta and bFGF were identified by polymerase chain reaction analysis. The influence of neutralizing growth factor monoclonal antibodies (MAb) on RA synovial cell growth was investigated. TGF beta bioactivity was determined by Mv1Lu assay. RESULTS: Lysates of RA, as compared with normal, synovial cells contained greater amounts of TGF beta and bFGF. Western blot analysis identified a single TGF beta band (MW approximately 25 kd) in each of the cell lysates examined. Western blot analysis using MAb DE6 identified a doublet of bFGF bands (MW approximately 18.0 kd) in normal synovial cell lysates and 4 bFGF bands (MW approximately 18.0, 22.0, 22.6, and 25.2 kd) in RA synovial cell lysates. RA and normal synovial cells expressed mRNA transcripts encoding TGF beta 1 but not TGF beta 2, and FGF-2 (basic FGF). Additional mRNA transcripts encoding FGF-5 and FGF-7 were expressed by RA, but not normal, synovial cells in culture. In contrast to MAb 1D11.16, which caused a dose-dependent decrease in RA synovial cell growth, MAb DG2 (up to 100 micrograms/ml) had no effect on cell growth. CONCLUSION: RA and normal synovial cells cultured in serum-free medium express TGF beta 1 and native bFGF. However, only RA synovial cells in culture express higher molecular weight isoforms of bFGF. TGF beta 1 appears to regulate synovial cell growth in vitro through an external autocrine loop. Despite expression of high-affinity bFGF receptors on cultured synovial cells, the mechanisms by which bFGF modulates synovial cell growth are unknown

Cytokines have been implicated in the regulation of eicosanoid synthesis and synovial cell proliferation. To further define these mechanisms, we have compared the effects of basic fibroblast growth factor and platelet-derived growth factor on cell growth, prostaglandin E2 (PGE2) production and phospholipase A2 enzyme activity in long-term cultures of synovial cells from rheumatoid arthritis (RA) patients capable of proliferating in serum-free medium. Compared with serum-free medium alone, RA synovial cell growth was significantly enhanced by adding either basic fibroblast growth factor (bFGF) or platelet-derived growth factor (PDGF) to the culture medium. Growing RA synovial cells for 14 days in serum-free medium plus bFGF caused them to spontaneously release significant amounts of PGE2, an effect not seen if cells were grown in serum-free medium alone, or serum-free medium plus PDGF. Enhanced release of PGE2 occurred when arachidonic acid was added to bFGF but not PDGF-treated RA synovial cells, suggesting that bFGF increased cyclooxygenase enzyme activity in these cells. Moreover, phospholipase A2 (PLA2) enzyme activity was found to be significantly greater in RA synovial cells grown for 14 days in serum-free medium containing bFGF alone, or bFGF plus interleukin 1 beta (IL-1 beta) compared with cells grown in either serum-free medium alone, or serum-free medium plus PDGF. Similarly, bFGF plus IL-1 beta-stimulated release of PLA2 activating protein, a novel mammalian phospholipase stimulator found in high concentrations in RA synovial fluid.(ABSTRACT TRUNCATED AT 250 WORDS)

Rheumatoid arthritis (RA), and not osteoarthritis (OA) synovial cells proliferate in serum-free medium, a finding that suggests that, in vitro, RA synovial cells may be stimulated to grow by the continuous autocrine production of at least one polypeptide growth factor. Adding monoclonal antibody 1D11.16, or rabbit polyclonal anti-tumor growth factor beta (anti-TGF-beta) antibodies (both neutralizing antibodies to TGF-beta 1 and TGF-beta 2) to RA synovial cells, in culture, caused a significant reduction in cell growth, an effect not seen when other growth factor antibodies (platelet-derived growth factor [PDGF], epidermal growth factor [EGF], or EGF receptor) were added to the culture medium. Taken together, these data are consistent with the concept that RA synovial cell growth in vitro is driven endogenous TGF-beta. Moreover, when EGF was added to the culture medium, this caused the numbers of RA, and not OA, synovial cells to increase significantly. This finding suggests that RA synovial cells are in G1 phase of the cell cycle; an effect that could be mediated by endogenous TGF-beta