233 Background: In oligometastatic prostate cancer (OMPC), delaying time to initiation of androgen deprivation therapy (ADT) may have oncologic and quality of life benefits. Additionally, there is an emerging role for metastatic/primary tumor site-directed therapy for patients with OMPC. Prostate apoptosis response-4 (PAR-4) is a potent tumor suppressor, facilitating apoptosis in prostate cancer cells. Hydroxychloroquine (HCQ) has been identified to be a potent inducer of PAR-4 secretion and downstream tumor inhibition in preclinical models and Phase I trials. We present a single institution Phase II trial assessing induction of PAR-4 levels in the plasma of patients in response to HCQ administration in combination with radiation therapy (RT) for OMPC. Methods: Men with OMPC (≤5 synchronous metastatic lesions) following primary tumor treatment were eligible. Patients received 400 mg HCQ daily for 2 weeks prior to metastatic site-directed RT and 400 mg HCQ daily for 90 days post-radiation. Plasma samples were collected on Day 0, 14, 30, 60, and 90. The primary endpoint was induction of ≥50% serum PAR-4 expression above baseline level within 90 days of treatment initiation. We hypothesized that over half of patients would exhibit ≥50% induction of serum PAR-4 expression. Results: Nineteen participants met inclusion criteria and were treated with 90 days of HCQ and RT to oligometastatic lesions. Median age was 68 years (range 55-77), the majority of patients were Caucasian (94%) and the median baseline PSA was 6.30 ng/ml (range 0.99 to 27.80). Prior primary tumor treatment included radiation therapy in 26%, radical prostatectomy in 32%, and radical prostatectomy with radiation in 42%. Eleven patients (58%) showed ≥50% increase in plasma PAR-4 above baseline levels (p=0.0006). This was associated with a concomitant PSA decline at 6-months (mean -0.98 ng/ml, 95% CI -6.61 to 4.65) and 12-months (mean -7.21 ng/ml, 95% CI -12.45 to -1.97). At 12-month follow-up, seven patients (37%) were free from ADT and median progression-free survival was 9.3 months (95% CI 6.4 to N/A). Twelve patients (63%) reported at least one adverse event, with 2 patients (11%) experiencing grade 3 toxicity. Conclusions: Oral administration of HCQ is well tolerated and effectively induces plasma expression of the potent tumor suppressor PAR-4 in patients with OMPC. Given the promising findings, further investigation into possible radiosensitizing and anti-tumor benefits of HQC in a larger cohort of OMPC is necessary. Clinical trial information: NCT04011410 .

Sjögren's disease (SjD) is a chronic, systemic autoimmune disease with no approved disease-modifying therapies. Dazodalibep (DAZ), a novel nonantibody fusion protein, is a CD40 ligand antagonist that blocks costimulatory signals between T and B cells and antigen-presenting cells, and therefore may suppress the wide spectrum of cellular and humoral responses that drive autoimmunity in SjD. This study was a phase 2, randomized, double-blinded, placebo (PBO)-controlled trial of DAZ with a crossover stage in two distinct populations of participants with SjD. Population 1 had moderate-to-severe systemic disease activity and population 2 had an unacceptable symptom burden and limited systemic organ involvement. All participants had a diagnosis of SjD, with 21.6% and 10.1% having an associated connective tissue disease (rheumatoid arthritis or systemic lupus erythematosus) in populations 1 and 2, respectively. The remaining participants would be considered as having primary Sjögren's syndrome. The primary endpoint for population 1 (n = 74) was the change from baseline in the European League Against Rheumatism Sjögren's Syndrome Disease Activity Index at day 169. The primary endpoint for population 2 (n = 109) was the change from baseline in the European League Against Rheumatism Sjögren's Syndrome Patient Reported Index at day 169. The primary endpoints (least squares mean ± standard error) were achieved with statistical significance for both population 1 (DAZ, -6.3 ± 0.6; PBO, -4.1 ± 0.6; P = 0.0167) and population 2 (DAZ, -1.8 ± 0.2; PBO, -0.5 ± 0.2; P = 0.0002). DAZ was generally safe and well tolerated. Among the most frequently reported adverse events were COVID-19, diarrhea, headache, nasopharyngitis, upper respiratory tract infection, arthralgia, constipation and urinary tract infection. In summary, DAZ appears to be a potential new therapy for SjD and its efficacy implies an important role for the CD40/CD40 ligand pathway in its pathogenesis. ClinicalTrials.gov identifier: NCT04129164 .

Brain metastatic carcinoma is a rare occurrence among prostate cancer metastases. 68Gallium prostatespecific membrane antigen PET-CT ([Ga-68]PSMA PET/CT) is commonly used for prostate cancer staging and detection of biochemical recurrences. However, various CNS tumors exhibit activity on [Ga-68]PSMA PET/CT and may often be included in the differential diagnosis. Herein, we present a case of brain metastatic prostate cancer successfully treated with surgical resection and adjuvant stereotactic Gamma Knife radiosurgery (GKRS) followed by androgen deprivation therapy (ADT) to emphasize the need for histologic confirmation. A 70-year-old male with a history of very high-risk prostatic adenocarcinoma presented with biochemical recurrence following radical prostatectomy and irradiation of the prostatic fossa. [Ga-68]PSMA PET/CT and MRI identified a solitary lesion in the left occipital lobe; differential diagnosis included prostate metastasis, meningioma, or a new metastatic primary lesion. The patient underwent surgical resection, and immunohistochemical staining confirmed the lesion as brain metastatic prostate adenocarcinoma. One month after resection, the patient underwent GKRS to the tumor bed and two additional metastases, followed by ADT. Repeated imaging 15 months after GKRS revealed stable posttreatment changes with no evidence of new metastases, thus demonstrating durable, effective local and systemic control. Brain metastatic prostate adenocarcinoma without nodal or osseous metastases is a rare phenomenon. The affinity of [Ga-68]PSMA PET/CT for non-prostate histologies such as meningioma introduces uncertainty into the diagnostic process. This case demonstrates the durable local control conferred by GKRS toward these lesions and emphasizes the need for clinical, radiographic, and histopathologic data to identify disease presentations and facilitate appropriate treatment regimens.

PurposeTo demonstrate the ease and feasibility that hippocampal sparing whole brain (WB) simultaneous integrated boost (HSWB-SIB) plans can be generated using knowledge-based planning and Eclipse Scripting Application Programming Interface (ESAPI) for three different modalities, HyperArc on TrueBeam (TB-HA), a coplanar beam arrangement on TrueBeam (TB-Co), and the ring-mounted Halcyon LINAC (Hal).MethodsTwelve patients with 2-14 brain metastases were retrospectively replanned for HSWB-SIB using a published HSWB RapidPlan model with modifications for the automated addition of SIB to metastases. Prescribed dose was 30 Gy to the WB planning target volume (PTV) and 50 Gy to the metastases in 10 fractions. Eclipse treatment planning system (v16.1) was used with a 6 MV-FFF beam and Acuros XB dose algorithm.ResultsThe methodology was successfully used for all modalities, generating plans in under 30 min. The plan doses were normalized to the WB PTV D95% receiving 30 Gy. Reporting values in the order of Hal, TB-Co, and TB-HA: The WB PTV received a V48 Gy of 4.58, 3.98, and 4.45 cc with statistically insignificant differences (p = 0.806). The boost PTVs received a D95% of 50.60, 50.43, and 51.13 Gy with statistically significant comparisons between TB-HA and the other two modalities (p = 0.005). The hippocampus maximum dose was 11.81, 11.51, and 11.13 Gy with no statistically significant comparisons (p = 0.105). All other oragns-at-risk (OAR) doses were clinically acceptable. The modalities were evaluated using a dosimetric scorecard, achieving average scores of 84.85%, 86.45%, and 87.39%. End-to-end testing ensured the deliverability of the HSWB-SIB plans for all modalities.ConclusionThe novel modification of the preexisting HSWB RapidPlan model with the automated inclusion of SIB objectives allows for easy, intuitive planning of complex HSWB-SIB treatments. All modalities demonstrated can be used with clinically comparable results. Other institutions are recommended to pursue and validate this HSWB-SIB technique to increase the accessibility of a single-course of high-quality treatment for patients with multiple brain lesions.

PurposeTo evaluate the dosimetric impact on spatially fractionated radiation therapy (SFRT) plan quality due to intrafraction patient motion via multi-field MLC-based method for treating large and bulky (>= 8 cm) unresectable tumors. MethodsFor large tumors, a cone beam CT-guided 3D conformal MLC-based SFRT method was utilized with 15 Gy prescription. An MLC GTV-fitting algorithm provided 1 cm diameter apertures with a 2 cm center-to-center distance at the isocenter. This generated a highly heterogeneous sieve-like dose distribution within an hour, enabling same-day SFRT treatment. Fifteen previously treated SFRT patients were analyzed (5 head & neck [H&N], 5 chest and lungs, and 5 abdominal and pelvis masses). For each plan, intrafraction motion errors were simulated by incrementally shifting original isocenters of each field in different x-, y-, and z-directions from 1 to 5 mm. The dosimetric metrics analyzed were: peak-to-valley-dose-ratio (PVDR), percentage of GTV receiving 7.5 Gy, GTV mean dose, and maximum dose to organs-at-risk (OARs). ResultsFor +/- 1, +/- 2, +/- 3, +/- 4, and +/- 5 mm isocenter shifts: PVDR dropped by 3.9%, 3.8%, 4.0%, 4.1%, and 5.5% on average respectively. The GTV(V7.5) remained within 0.2%, and the GTV mean dose remained within 3.3% on average, compared to the original plans. The average PVDR drop for 5 mm shifts was 4.2% for H&N cases, 10% for chest and lung, and 2.2% for abdominal and pelvis cases. OAR doses also increased. The maximum dose to the spinal cord increased by up to 17 cGy in H&N plans, mean lung dose (MLD) changed was small for chest/lung, but the bowel dose varied up to 100 cGy for abdominal and pelvis cases. ConclusionDue to tumor size, location, and characteristics of MLC-based SFRT, isocenter shifts of up to +/- 5 mm in different directions had moderate effects on PVDR for H&N and pelvic tumors and a larger effect on chest tumors. The dosimetric impact on OAR doses depended on the treatment site. Site-specific patient masks, Vac-Lok bags, and proper immobilization devices similar to SBRT/SRT setups should be used to minimize these effects.

Background: Dazodalibep (DAZ) is a non-antibody fusion protein which targets CD40L and inhibits costimulatory signals between immune cells, including T cells, B cells, and antigen-presenting cells. CD40L blockade disrupts the formation of germinal centers (GCs), pathogenic B cells, and plasma cells, and the production of autoantibodies in rheumatoid arthritis. CXCL13 is a critical chemokine that enables T- and B-cell migration to the GC and their serum levels may reflect GC formation and activity. Objectives: To assess the impact of DAZ on T- and B-cells in using data from the MIDORA phase 2 clinical trial of patients with rheumatoid arthritis (RA, NCT04163991). Methods: This biomarker study focused on a total of 47 adult patients with moderate-to-severe active RA that responded inadequately to methotrexate, other conventional disease-modifying anti-rheumatic drugs, or tumor necrosis factor-α inhibitors. Eligible participants in this biomarker study were randomized to receive 1500 mg or 3000 mg intravenously of DAZ or placebo. Disease activity was assessed using the Disease Activity Score-28 with C-Reactive Protein (DAS28-CRP), Patient Global Assessment (PGA), Simplified Disease Activity Index (SDAI), Clinical Disease Activity Index (CDAI), Physician Global Assessment of Disease Activity (MDGA), Tender Joint Count (TJC), and Swollen Joint Count (SJC). Flow cytometry of whole blood was performed to examine for any changes in B and T cell subsets such as plasmablasts (CD27br/CD38br/IgD- subsets of CD19+ cells), precursor memory B cells (CD11cbr subsets of CD19+ cells), T follicular helper cells (CXCR5+/ICOS+ subsets of CD3+/CD4+ cells), proliferation of post-switch memory B cells (Ki67+ subsets of CD27br/IgD-/CD19+ cells), and proliferation of total T-cells (Ki67+ subsets of CD3+ cells). Serum levels of CXCL13 and rheumatoid factor (RF) autoantibodies were assessed by immunoassay and nephelometry, respectively. Results: DAZ improved DAS28-CRP, PGA, SDAI, CDAI, and MDGA scores, as well as tender and swollen joint total counts in RA participants.1 Compared to placebo, DAZ treatment also was associated with a reduction in the number of plasmablasts (CD27br/CD38br/IgD- subsets of CD19+ cells) and T follicular helper cells (CXCR5+/ICOS+ subsets of CD3+/CD4+ cells); the proliferation of post-switch memory B cells (Ki67+ subsets of CD27br/IgD-/CD19+ cells) and proliferation of total T-cells (Ki67+ subsets of CD3+ cells); and decreases in serum levels of CXCL13 and RF. No changes were found in the numbers of precursor memory B cells (CD11cbr subsets of CD19+ cells). Conclusion: DAZ-mediated CD40L blockade in patients with moderate-to-severe active RA demonstrated significant improvements in disease activity scores such as DAS28-CRP, Patient Global Assessment, SDAI, CDAI, and Physician Global Assessment including tender and swollen joint counts. Additionally, DAZ reduced biomarkers of T- and B-cell costimulatory blockade, and inhibition of GC formation activity, and autoantibody production. Together, these data demonstrate the biological impact of CD40-CD40L pathway blockade on selected blood biomarkers in RA. REFERENCES: [1] Kivitz, A., et al.. RMD Open 2023. 9 (3). Acknowledgements: Medical writing support provided by B Lujan, PhD, CMPP, an employee of Amgen Inc. (formerly Horizon Therapeutics plc). Disclosure of Interests: Tuyet-Hang Pham owns stock, is an employee of Amgen, Michael A. Smith owns stock, is an employee of Amgen, Nanette Mittereder owns stock, is an employee of Amgen, Ilias Alevizos owns stock, is an employee of Amgen, E. William St. Clair has consulted for Amgen, Bristol Myers Squibb, CSL Behring, Resolve Therapeutics, Sonoma Biotherapeutics, and receives royalties from UpToDate, Claire Emson owns stock, is an employee of Amgen.

The 2 Gy per fraction equivalent dose (EQD2) is an important quantity used in determining equivalent prescription doses for different fractionation regimens and evaluating different fractionation regimens, but it does not match its definition when it is used for normal tissues. We propose to use the fractionation-specific biological equivalent dose to determine normal tissue dose constraints for different fractionation regimens. The concept of the biological equivalent dose is defined based on the linear-quadratic equation. The EQD2 is derived based on the biological effective dose (BED), mimicking the prescription dose of a standard fractionation regimen with a fractional dose of 2 Gy and a fixed number of fractions. The FEQD(n) is also defined based on the BED as a function of the number of fractions, n, which is determined by the dose prescription. The FEQD(n) mimics any fractionation regimens with any fractional doses and numbers of fractionations. A given dose constraint can have different BED values and EQD2 values for different fractionation regimens. The number of fractions for a given 2 Gy per fraction regimen derived from the EQD2 for the target dose is different from that for the normal tissues. The value of the EQD2 derived for the target represents the total dose for the target for the 2 Gy fractional dose regimen, but the EQD2 value derived for the normal tissues does not represent the total dose for the normal tissue for the same fractionation regimen. The fractionation-specific biological equivalent dose (FEQD(n)) for both target and normal tissues has the same number of fractions for any fractionation regimen, and represents the total dose for either the target or the normal tissue. Based on the clinical outcomes, the FEQD(n) curves for the brainstem, spinal cord, rectum, and lung were derived and can be directly used as dose constraints for various fractionation regimens in clinical practice. The EQD2 does not match its definition and is not realistic when describing the biological equivalent dose for normal tissues. It is also not practical when used in determining tolerance doses or dose constraints. Instead, the FEQD(n) can be used to determine or convert the normal tissue dose constraints for any fractionation regimens in a realistic and practical manner. Using the FEQD(n), the dose constraints as a function of the number of fractions for the brainstem, spinal cord, rectum, and lung, which correspond to the given toxicity rates, were derived and can be directly used in clinical practice.

Background: Dazodalibep (DAZ) is a non-antibody fusion protein that acts as a CD40L antagonist and blocks costimulatory signals between immune cells, including T cells, B cells, and antigen-presenting cells. CD40L inhibition disrupts costimulatory signals that lead to activation of germinal centers (GC) and the formation of pathogenic B cells, plasma cells, and autoantibodies, mechanistic hallmarks of Sjögren’s Disease. Objectives: To evaluate the effects of DAZ on the serum proteome in the ALISS phase 2 clinical trial of subjects with Sjogren’s disease (NCT04129164). Methods: This study enrolled two distinct populations with Sjögren’s disease. Population 1 (Pop1) included 74 subjects with moderate-to-severe systemic disease activity as defined by the EULAR Sjögren’s Syndrome Disease Activity Index (ESSDAI) ≥ 5. Population 2 (Pop2) consisted of 109 subjects with unacceptable symptom burden and limited extraglandular systemic involvement as defined by the EULAR Sjögren’s Syndrome Patient Reported Index (ESSPRI) ≥ 5 and ESSDAI < 5. Eligible subjects were randomized 1:1 to receive intravenous DAZ 1500 mg or placebo. The Olink Explore 3072 panel was used to comprehensively profile the serum proteome at baseline, Day 15, and Day 169. Protein profiles were analyzed using AUC-ROC analysis to identify proteins which differentiated subjects with Sjogren’s disease at baseline from age-matched healthy individuals (n=50) with AUC-ROC > 0.7. A mixed linear model was applied to identify proteins impacted by DAZ treatment with Benjamini Hochberg FDR < 10%. Matrix decomposition techniques and pathways analysis were applied to identify protein networks within the dataset. Factor Analysis followed by a Varimax rotation was further used to identify proteins that shared correlation with high loadings (> 0.45) across a common vector. Results: A combination of unsupervised machine learning and statistical analysis identified a core set of 29 correlated proteins elevated in subjects with Sjogren’s disease at baseline compared to healthy individuals that were impacted by DAZ treatment. We found no significant differences at baseline in these biomarkers between Pop 1 and Pop 2 despite the difference in clinical disease manifestation. Pathway assessments revealed these 29 biomarkers were enriched for activation of B-, T-, and dendritic cells (e.g., LAMP3) and were significantly reduced (FDR < 10%) in Pop1 and Pop2 subjects with Sjögren’s disease by DAZ treatment. Conclusion: Compared to a healthy cohort, serum proteomics profiling revealed a core set of 29 biomarkers elevated in subjects with Sjogren’s disease at baseline and were associated with inflammatory and adaptive immune responses, particularly activation of B-, T-, and dendritic cells. Importantly, these biomarkers were shown to be significantly reduced by DAZ. These proteomics findings corroborate previous immunophenotyping flow cytometry data from the ALISS phase 2 study that demonstrated significant reductions of B and T cell activation and proliferation by DAZ in subjects with Sjogren’s disease across populations with either moderate-to-severe disease activity or high symptomatic burden. REFERENCES: NIL. Acknowledgements: Medical writing support provided by B Lujan, PhD, CMPP, an employee of Amgen Inc. (formerly Horizon Therapeutics plc). Disclosure of Interests: Tuyet-Hang Pham is an employee of Amgen, and owns stock, Michael A. Smith is an employee of Amgen, and owns stock, Ilias Alevizos is an employee of Amgen, and owns stock, E. William St. Clair has consulted for Amgen, Bristol Myers Squibb, CSL Behring, Resolve Therapeutics, Sonoma Biotherapeutics, and receive royalties from UpToDate, Claire Emson is an employee of Amgen, and owns stock.

Purpose: This study sought to evaluate the feasibility and efficacy of the Halcyon Ring Delivery System (RDS) for delivering stereotactic radiotherapy (SRT) treatments for intracranial tumors beds. Methods: Ten previously treated brain SRT patients for 30 Gy in five fractions with non-coplanar HyperArc plans on TrueBeam (6MV-FFF) were replanned on Halcyon (6MV-FFF) using the same number of arcs and Eclipse's AcurosXB dose engine. Plan quality evaluation metrics per SRT protocol included: PTV coverage, GTV dose (minimum and mean), target conformity indices (CI), heterogeneity index (HI), gradient index (GI), maximum dose 2 cm away from the PTV (D-2cm), and doses to organs-at-risk (OAR). Additionally, patient-specific quality assurance (QA) results and beam-on-time (BOT) were analyzed. Results:The Halcyon RDS provided highly conformal SRT plans for intracranial tumor beds with similar dose to target. When benchmarked against clinically delivered HyperArc plans, target coverage, CI(s) and HI were statistically similar. The Halcyon plans saw no statistical difference in maximum OAR doses to the brainstem, spinal cord, and cochlea. Due to the machine's coplanar geometry, the Halcyon plans showed a decrease in optic pathway dose (0.75 Gy vs. 2.08 Gy, p = 0.029). Overall, Halcyon's coplanar geometry resulted in a larger GI (3.33 vs. 2.72, p = 0.008) and a larger D-2cm (39.59% vs. 29.07%, p < 0.001). In this cohort, multiple cases had the PTV and the optic pathway in the same axial plane. In one such instance, the PTV was <2 cm away from the optic pathway but even at this close proximity OAR, Halcyon still adequately spared the optic pathway. Additionally, the Halcyon's geometry provided slightly larger amount of normal brain dose receiving 24.4 Gy (8.99 cc vs. 7.36 cc) and 28.8 Gy (2.9 cc vs. 2.5 cc), although statistically insignificant. The Halcyon plans achieved similar delivery accuracy, quantified by patient-specific QA results evaluated with a 2%/2 mm gamma criteria (99.42% vs. 99.70%). For both plans, independent Monte Carlo second checks calculation agreed within 1%. Average Halcyon BOT was slightly higher by 0.35 min (p = 0.045), however, due to the one-step patient set-up and verification overall estimated treatment times on Halcyon were lower compared to HyperArc treatments (7.61 min vs. 10.26 min, p < 0.001). Conclusions: When benchmarked against clinically delivered HyperArc treatments, the Halcyon brain SRT plans provided similar plan quality and delivery accuracy but achieved faster overall treatment times. We have started treating select brain SRT patients on the Halcyon RDS for patients having tumor beds greater than 1 cm in diameter with the closest OAR distance of greater than 2 cm away from the target. We recommend other clinics to consider commissioning SRT treatments on their Halcyon systems-allowing including remote Halcyon-only clinics to provide exceptionally high-quality therapeutic brain SRT treatments to an otherwise underserved patient cohort.

Background Sjögren's is a systemic autoimmune disease associated with marked morbidity and poor health-related quality of life, generally driven by the cardinal symptoms of the disease: dryness, pain, and fatigue (assessed via EULAR Sjögren's Syndrome Patient Reported Index [ESSPRI]). The population of Sjögren's patients with unacceptable symptomatic burden independent of systemic involvement represents a substantial proportion of Sjögren's patients who have largely been excluded from recent trials despite significant disease burden and overall unacceptable health status. Objectives The objective of this study (NCT04129164) was to evaluate the efficacy and safety of dazodalibep (DAZ), a non-antibody biologic antagonist of CD40L, in adult Sjögren's subjects with an unacceptable symptom burden but limited systemic organ involvement. Methods This was a randomized, double-blind, placebo-controlled, crossover study of DAZ in adult Sjögren's subjects with an unacceptable symptom burden but limited systemic organ involvement, as defined by having an ESSPRI score ≥ 5 and EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI) score <5. Eligible subjects were randomized 1:1 to receive intravenous DAZ 1500 mg or placebo (PBO) Q2W x 3 doses, then Q4W x 4 additional doses. Starting on Day 169, subjects initially randomized to DAZ received PBO Q4W x 5 doses and subjects randomized to PBO received DAZ Q4W x 5 doses and were then followed for 12 weeks. The primary endpoint was the change from baseline in ESSPRI at Day 169. Safety was also evaluated. Results A total of 109 subjects were randomized and received ≥1 dose of study medication (DAZ, N=54; PBO, N=55). The mean (standard deviation) age of subjects was 49.9 (12.1) years and most were female (94.5%). The change from baseline to Day 169 in ESSPRI (LS mean ± SE) was −1.80 ± 0.23 in the DAZ group compared to −0.53 ± 0.23 in the PBO group, a difference of −1.27 ± 0.33 (p = 0.0002). The change from baseline to Day 169 in each of the three domains of ESSPRI was significantly greater in the DAZ group compared to PBO (dryness: p = 0.0066; fatigue: p = 0.0022; pain: p = 0.0010). At Day 169, a significantly larger proportion of DAZ-treated subjects achieved a ≥1 point or ≥15% reduction in ESSPRI relative to PBO (66.7% vs 32.7%; p =0.008). The improvement from baseline to day 169 in the Functional Assessment of Chronic Illness Therapy-Fatigue score (LS mean ± SE) was significantly greater in the DAZ group (8.1 ± 1.4) relative to PBO (2.8 ± 1.4; p = 0.0095). Greater numerical improvement in DAZ-treated subjects was observed for the Ocular Surface Disease Index (−14.0 ± 3.0 vs −8.5 ± 2.9; p = 0.1936) and Patient's Global Impression of Severity (−0.6 ± 0.1 vs −0.4 ± 0.1; p = 0.1781) at Day 169 relative to PBO.Through Day 169, a total of 75 subjects reported an adverse event (AE; DAZ: 37 [68.5%]; PBO: 38 [69.1%]) and the majority were mild/moderate in severity. The most frequently reported AEs occurring in ≥5% of DAZ-treated subjects were COVID-19, nasopharyngitis, anemia, and diarrhea. There were three serious AEs in the DAZ group (pneumonia influenza, post-acute COVID-19 syndrome, and gammopathy) and one in the PBO group (neutropenia). All serious AEs were deemed by investigators to be unrelated to study medication. One subject in the DAZ group discontinued the study due to an AE compared to two subjects in the PBO group. Conclusion In this study of Sjögren's subjects with an unacceptable symptom burden but limited systemic organ involvement, the primary endpoint was achieved. DAZ-treated subjects experienced a statistically significant and clinically meaningful improvement in the key subjective symptoms of Sjögren's relative to PBO as measured by the improvement in ESSPRI and associated responder analysis. DAZ therapy was generally safe and well tolerated. Larger trials of DAZ therapy for Sjögren's are warranted to further explore its safety profile and confirm its clinical efficacy. REFERENCES NIL. Acknowledgments Medical writing support provided by Brendan Lujan, PhD, of Horizon Therapeutics. Disclosure of Interests E. William St. Clair Consultant of: Horizon Therapeutics, Bristol Myers Squibb, CSL Behring, Resolve Therapeutics, Sonoma Biotherapeutics and receives royalties from UpToDate, Ilias Alevizos Shareholder of: Horizon Therapeutics, Employee of: Horizon Therapeutics, William Rees Shareholder of: Horizon Therapeutics, Employee of: Horizon Therapeutics, Liangwei Wang Shareholder of: Horizon Therapeutics, Employee of: Horizon Therapeutics, Alan Baer Consultant of: Bristol-Myers Squibb, Wan Fai Ng Consultant of: Novartis, GlaxoSmithKline, Abbvie, BMS, Sanofi, MedImmune, Janssen, Resolve Therapeutics and UCB, Ghaith Noaiseh Consultant of: Novartis, Chiara Baldini Consultant of: GSK, and Sanofi.Figure 1Adjusted Mean Change from Baseline in ESSPRI Score. Dashed line represents the MCID. Data analyzed using MMRM. ESSPRI, EULAR Sjögren's Syndrome Patient Reported Index; LS, least squares; MCID, minimal clinically important difference; SE, standard error.

Objectives We investigated whether soluble immune checkpoints (sICPs) predict treatment resistance, relapse and infections in patients with antineutrophil cytoplasm antibody (ANCA)-associated vasculitis (AAV). Methods Plasma sICP concentrations from available samples obtained during conduct of the RAVE trial were measured by immunoabsorbent assays from patients with either proteinase 3 (PR3) or myeloperoxidase (MPO)-ANCA vasculitis and were correlated with clinical outcomes, a set of biomarkers and available flow cytometry analyses focusing on T cell subsets. Log-rank test was used to evaluate survival benefits, and optimal cut-off values of the marker molecules were calculated using Yeldons J. Results Analysis of 189 plasma samples at baseline revealed higher concentrations of sTim-3, sCD27, sLag-3, sPD-1 and sPD-L2 in patients with MPO-ANCA vasculitis (n=62) as compared with PR3-ANCA vasculitis (n=127). Among patients receiving rituximab induction therapy (n=95), the combination of lower soluble (s)Lag-3 (<90 pg/mL) and higher sCD27 (>3000 pg/mL) predicted therapy failure. Twenty-four out of 73 patients (32.9%) in the rituximab arm reaching remission at 6 months relapsed during follow-up. In this subgroup, high baseline values of sTim-3 (>1200 pg/mL), sCD27 (>1250 pg/mL) and sBTLA (>1000 pg/mL) were associated with both sustained remission and infectious complications. These findings could not be replicated in 94 patients randomised to receive cyclophosphamide/azathioprine. Conclusions Patients with AAV treated with rituximab achieved remission less frequently when concentrations of sLag-3 were low and concentrations of sCD27 were high. Higher concentrations of sTim-3, sCD27 and sBTLA at baseline predicted relapse in patients treated with rituximab. These results require confirmation but may contribute to a personalised treatment approach of AAV.

Objective Proteinase 3 (PR3) is the major antigen for anti-neutrophil cytoplasmic antibodies (ANCAs) in the systemic autoimmune vasculitis, granulomatosis with polyangiitis (GPA). PR3 anti-neutrophil cytoplasmic antibodies (PR3-ANCAs) recognize different epitopes on PR3. We aimed to study the effect of mutations on PR3 antigenicity. Methods The recombinant PR3 variants, iPR3 which is clinically used to detect PR3-ANCAs and iHm5 which contains three point mutations in Epitope 1 and 5 generated for epitope mapping studies, immunoassays and serum samples from patients enrolled in ANCA-associated vasculitis (AAV) clinical trials were used to screen the differential PR3-ANCA binding. Selective binding was determined by inhibition experiments. Results Rather than a reduced binding of PR3-ANCAs to iHm5, we found substantially increased binding of the majority of PR3-ANCAs to iHm5 compared with iPR3. A monoclonal ANCA (moANCA518) from a patient with GPA was found to selectively bind to iHm5 within the mutation-free Epitope 3 and distant from the point mutations of iHm5 contained in Epitope 1 and 5. Binding of iPR3 to monoclonal antibody MCPR3-2 also induced recognition by moANCA518. Conclusion The preferential binding of PR3-ANCAs from patients like the selective binding of moANCA518 to iHm5 is conferred by increased antigenicity of Epitope 3 on iHm5. This can also be induced on iPR3 when it is captured by monoclonal antibody MCPR-2. This previously unrecognized characteristic of PR3-ANCA interactions with its target antigen has implications for studying antibody-mediated autoimmune diseases, understanding of variable performance characteristics of immunoassays and design of potential novel treatment approaches.