Long-term Maintenance Therapy Research Articles

Clinical Manifestations and Prognosis of Giant Cell Arteritis: A Retrospective Cohort Study.

. A retrospective study included 166 patients with newly diagnosed GCA. Clinical, laboratory, and instrumental data and three sets of classification criteria were used to confirm the diagnosis: the American College of Rheumatology (ACR) 1990, the revised ACR criteria of 2016 and/or the new ACR and European Alliance of Rheumatologic Associations (EULAR) 2022 criteria. Some of the patients underwent instrumental investigations: temporal artery ultrasound Doppler (n = 61), contrast-enhanced computed tomography (n = 5), CT angiography (n = 6), magnetic resonance imaging (n = 4), MR angiography (n = 3), and 18F-FDG PET/CT (n = 47). Overall and recurrence-free survival rates were analyzed using survival tables and Kaplan-Meier method. . The most frequent first manifestations of GCA were headache (81.8%), weakness (64%), fever (63.8%), and symptoms of rheumatic polymyalgia (56.6%). Changes in temporal arteries in color duplex scanning were detected in 44 out of 61 patients. GCs therapy was performed in all patients who agreed to be treated (n = 158), methotrexate was used in 49 out of 158 patients, leflunomide in 9 patients. In 45 (28.5%) out of 158 patients, a stable remission was achieved as a result of GC monotherapy; in 120 (75.9%) patients, long-term maintenance therapy with GCs was required to prevent exacerbations, including 71 (44.9%) patients in combination with methotrexate or other immunosuppressive drugs. The follow-up period of patients with a history of relapses was 21.0 (8.0-54.0) months. Relapses developed in 73 (46.2%) patients. The overall one-year survival rate was 97.1% [95% CI 94.3; 99.9], and the five-year survival rate of patients was 94.6% [95% CI 90.2; 99.0]. The one-year relapse-free survival rate was 86.4% [95% CI 80.5; 92.3], and the five-year relapse-free survival rate was 52.4% [95% CI 42.0; 62.8]. Twelve (7.2%) of 166 patients died. The cause of death was myocardial infarction in two patients, stroke in two patients, and breast cancer in one patient; in the remaining seven cases, the cause of death was not determined. : Given the high frequency of disease exacerbation, patients with GCA require long-term follow-up, especially during the first year after diagnosis.

A real-world, patient-reported outcomes study in patients with platinum-sensitive recurrent ovarian cancer receiving long-term maintenance therapy with niraparib.

e23164 Background: Niraparib has been approved for the maintenance treatment of newly diagnosed advanced and platinum-sensitive recurrent ovarian cancer (PSR OC). The phase 3 PRIMA and NOVA studies showed that maintenance niraparib did not worsen quality of life (QoL) compared with placebo. However, no QoL data have been reported for Asian OC patients treated with niraparib. Here, we report patient-reported outcomes (PROs) for PSR OC patients who received niraparib as maintenance therapy for more than two years in a real-world setting. Methods: This prospective, real-world study included OC patients participating in the Niraparib Patient Assistance Program (PAP) in China (NCT06037213). Eligible patients had histologically confirmed PSR epithelial OC, fallopian tube, or primary peritoneal cancer, had been maintained on niraparib for more than two years without disease progression and were still receiving niraparib within 28 days. PROs were assessed every 4-6 weeks for three times using the EQ-5D-5L questionnaire and the FOSI. In addition, a 6-question niraparib medication questionnaire including starting dose, adaptive dose, dose adjustments and reasons, missed doses, concomitant medications was administered at baseline. Results: The PAP enrolled 3154 PSR OC patients, 1151 had been on niraparib for more than two years and could be followed up. From August 2023 to January 2024, 604 eligible patients were recruited and completed at least one assessment. The median age was 58 years (range, 27-82 years). The median duration of treatment with niraparib was 34.8 months (range, 30.5-46.7 months). Among 445 patients with BRCAm status, 104 were BRCAm (23.4%) and 341 were BRCAwt (76.6%). A total of 491 patients (81.3%) received niraparib 200 mg as a starting dose, while 107 (17.7%) required dose adjustments in clinical practice. Presently, 503 (83.3%) were on 200mg. 523 (86.6%) were compliant with the daily oral dose of niraparib, without missing any doses in the previous 6 months. 193 patients (32.0%) had common chronic disease, and 176 (29.1%) were taking concomitant medications during maintenance. The EQ-5D-5L HUI and VAS scores remained stable across the three assessments. The baseline mean EQ-5D-5L HUI and VAS scores were 0.98 (SD 0.05) and 84.31 (SD 10.50), respectively, and the least squares (LS) mean changes from baseline to the third assessment were -0.004 (SE 0.001) and -0.609 (SE 0.248), respectively. A similar situation was observed for the FOSI score. The baseline mean FOSI score was 31.13 (SD 1.37), and the LS mean change from baseline to the third assessment was -0.359 (SE 0.033). Conclusions: In the real world, patients with PSR OC who underwent long-term maintenance treatment with niraparib exhibited a consistently stable QoL. This finding highlights the significant clinical value of niraparib in maintaining QoL in these populations.

What are the Optimal Systemic Treatment Options for Rhabdomyosarcoma?

Rhabdomyosarcoma, a soft tissue sarcoma commonly observed in childhood, requires multidisciplinary treatment, including surgical tumor resection, chemotherapy, and radiation therapy. Although long-term survival can be expected in patients with localized rhabdomyosarcoma, the clinical outcomes in patients with metastatic or unresectable rhabdomyosarcoma remain unsatisfactory. To improve the outcomes of rhabdomyosarcoma, it is important to explore effective systemic treatments for metastatic rhabdomyosarcoma. Currently, multiagent chemotherapy comprising vincristine, actinomycin D, and ifosfamide/cyclophosphamide remains standard systemic treatment for rhabdomyosarcoma. On the other hand, new treatment, such as immune checkpoint inhibitors and molecular targeted drugs, have demonstrated superior clinical outcomes compared to those of standard treatments in various type of malignancies. Therefore, it is necessary to assess the efficacies of these treatments in patients with rhabdomyosarcoma. Recent clinical studies have shown efficacies and safeties of temozolomide combined with vincristine/irinotecan, olaratumab combined with doxorubicin or vincristine/irinotecan, and long-term maintenance therapy. Furthermore, basic researches demonstrated new therapeutic targets. Future studies using these approaches are required to assess their clinical significances.

Functional and multi-omics signatures of mitapivat efficacy upon activation of pyruvate kinase in red blood cells from patients with sickle cell disease.

Mitapivat, a pyruvate kinase (PK) activator, shows great potential as a sickle cell disease (SCD)- modifying therapy. Safety and efficacy of mitapivat as a long-term maintenance therapy is currently being evaluated in two open-label studies. Here we apply a comprehensive multi-omics approach to investigate the impact of activating PK on red blood cells (RBCs) from 15 SCD patients. HbSS patients were enrolled in one of the open label, extended studies (NCT04610866). Leuko-depleted RBCs obtained from fresh whole blood at baseline (visit 1, V1), prior to drug initiation and longitudinal time points over the course of the study were processed for multiomics through a stepwise extraction of metabolites, lipids and proteins. Mitapivat therapy had significant effects on the metabolome, lipidome and proteome of SCD RBCs. Mitapivat decreased 2,3-diphosphoglycerate (DPG) levels, increased adenosine triphosphate (ATP) levels, and improved hematologic and sickling parameters in patients with SCD. Agreement between omics measurements and clinical measurements confirmed the specificity of mitapivat on targeting late glycolysis, with glycolytic metabolites ranking as the top correlates to parameters of hemoglobin S (HbS) oxygen affinity (p50) and sickling kinetics (t50) during treatment. Mitapivat markedly reduced levels of proteins of mitochondrial origin within 2 weeks of initiation of drug treatment, with minimal changes in the reticulocyte counts. The first six months of treatment also witnessed transient elevation of lysophosphatidylcholines and oxylipins with depletion in free fatty acids, suggestive of an effect on membrane lipid remodeling. Multi-omics analysis of RBCs identified benefits for glycolysis, as well as activation of the Lands cycle.

Abstract A001: Financial toxicity and social needs in patients with ovarian cancer: a multi-practice survey

Abstract Background: Treatment of ovarian cancer often involves expensive, sequential treatments, such as chemotherapy and surgery followed by long-term maintenance therapy. The direct and indirect costs of these treatments may create a significant financial burden and new care needs for patients. Our objective was to characterize financial toxicity and social needs in patients with ovarian cancer seen in a multi-practice health system. Methods: Patients in the University of Pennsylvania gynecologic oncology practices from January 2020 to February 2022 who had a patient portal account (n=6,925) were surveyed twice between March and April 2022, on financial toxicity. Those with ovarian cancer were included in this study. The survey included the 11-item Comprehensive Score for Financial Toxicity (COST) tool and a social needs question, “What service would be of most benefit to you in reducing financial toxicity of your treatment?” Responses were categorized as: very important; important; slightly important; and not at all important. We defined responses of “very important” and “important” as meeting high social need. Chi-squared and z-tests were used to compare differences between patients reporting high (COST< 26) and low (COST ≥26) financial toxicity. Results: 111 of 498 survey respondents identified as having ovarian cancer. The median COST score was 29 (range 6-44). 39% (n=37) had high financial toxicity, and 7% (7) had severe financial toxicity (COST<14). 19%(18) described their ovarian cancer as causing financial hardship to them and their family. 48% (26) of patients with private insurance and 48% (25) of patients under age 65 experienced high financial toxicity. Patients with private insurance were more likely to experience high financial toxicity (p=0.03) compared to patients with Medicare. Younger patients were more likely to experience high financial toxicity (p<0.001). Patients who were unemployed were more likely to experience high financial toxicity than those who were employed (p<0.001). Patients reported assistance with indirect costs of care (e.g., lost work) would be the most helpful in reducing financial toxicity (36%, 38) followed by assistance with out-of-pocket costs (29%, 31); housing and heating costs (27%, 28); and transportation (22%, 23). Conclusions: In a multi-practice survey, 39% of patients with ovarian cancer experienced financial toxicity, and 19% experienced financial hardship due to their cancer. Half of patients under age 65 and half of privately insured patients experienced financial toxicity. Patients identified assistance with direct and indirect costs of care (e.g., lost work, out-of-pocket costs) as the most helpful interventions. Interventions to address social needs and reduce financial toxicity are needed for patients with ovarian cancer. Citation Format: Anna Jo B. Smith, Maya H. Sharma, Kristina Powell, Meredith Doherty, Stefanie N. Hinkle, Emily M. Ko. Financial toxicity and social needs in patients with ovarian cancer: a multi-practice survey [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr A001.

The survival of periodontally treated molars in long-term maintenance: A systematic review and meta-analysis.

This systematic review and meta-analysis aimed to determine the survival of periodontally treated molars during maintenance care and identify the risk factors associated with molar loss among patients with periodontitis who received professional periodontal therapy and maintenance. Longitudinal studies with a minimum follow-up duration of 5 years published until 28 August 2023 were retrieved from the following databases: the Cochrane Library, Embase, MEDLINE and Web of Science. All included studies reported data on molar retention. Meta-analysis was performed using Review Manager 5.4. A modified version of the Newcastle-Ottawa Scale was used to evaluate the study quality. Statistical results of analyses of the overall survival rate and molar loss are presented as estimated standardized mean differences, whereas the results of the analyses of risk factors are presented as risk ratios with 95% confidence intervals (95% CIs). From among the 1323 potentially eligible reports, 41 studies (5584 patients, 29,908 molars retained at the beginning of maintenance therapy, mean follow-up duration of 14.7 years) were included. The pooled survival rate of the molars during maintenance therapy was 82% (95% CI: 80%-84%). The average loss of molars was 0.05 per patient per year (95% CI: 0.04-0.06) among the patients receiving long-term periodontal maintenance (PM) therapy. Fifteen factors were examined in this meta-analysis. Six patient-related factors (older age, lack of compliance, smoking, bruxism, diabetes and lack of private insurance) and five tooth-related factors (maxillary location, high probing pocket depth, furcation involvement, higher mobility and lack of pulpal vitality) were identified as risk factors for molar loss during maintenance therapy. The findings of the present study suggest that the long-term retention of periodontally compromised molars can be achieved. The average number of molars lost per decade was <1 among the patients receiving long-term PM therapy. Older age, noncompliance, smoking, bruxism, diabetes, lack of private insurance coverage, maxillary location, furcation involvement, higher mobility, increase in the probing pocket depth and loss of pulpal vitality are strong risk factors for the long-term prognosis of molars.

Comparative Inhibitory Effects of Tacrolimus, Cyclosporine, and Rapamycin on Human Anti-Pig Xenogeneic Mixed Lymphocyte Reactions.

Long-term immunosuppressive maintenance therapy is necessary to prevent the rejection of xenografts. However, it is still unclear which oral immunosuppressant is most suitable for pig-to-human xenotransplantation . A xenogeneic mixed lymphocyte reaction (MLR) system was established using peripheral blood mononuclear cells (PBMCs) isolated from wildtype (WT) or GTKO/CMAHKO/β4GalNT2KO (TKO) pigs as stimulator cells and human PBMCs as responder cells. Various concentrations of tacrolimus (Tac), cyclosporine (CsA), or rapamycin (Rapa) were added to the MLR system as interventions. The inhibitory effects of the three immunosuppressants on the proliferation and cytokine production of human T cells were studied and compared. The inhibitory effect of anti-CD154 mAb alone or in combination with Tac/CsA/Rapa on xenoreactive MLR was also investigated. PBMCs from both WT and TKO pigs stimulated significant proliferation of human T cells. Tac had a strong inhibitory effect on human T-cell proliferation stimulated by pig PBMCs. CsA inhibited human T-cell proliferation in a typical dose-dependent manner. When Tac and CsA concentrations reached 5 and 200ng/mL, respectively, the proliferation rates of CD3+/CD4+/CD8+ T cells were reduced almost to a negative level. Even at high concentrations, Rapa had only a moderate inhibitory effect on xenogeneic MLR. The inhibitory effects of these three immunosuppressants on xenogeneic T-cell responses were further confirmed by the detection of CD25 expression and supernatant cytokines (IL-2, IL-6, IFN-γ, TNF-α, IL-4, IL-10, and IL-17). Although anti-CD154 mAb monotherapy showed only moderate inhibitory effects on xenoreactive T-cell proliferation, low-dose anti-CD154 mAb combined with low-dose Tac, CSA, or Rapa could produce significant synergistic inhibitory effects. Tac is more efficient than CsA or Rapa in inhibiting xenogeneic T-cell responses in vitro. If used in combination with anti-CD154 mAb, all the three immunosuppressants can achieve satisfactory synergistic inhibitory effects.

Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS): contemporary advances and current controversies.

Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) is an inflammatory syndrome with characteristic clinical, radiological, and pathological features, and can be effectively treated with corticosteroid-based immunotherapies. The exact pathogenesis of CLIPPERS remains unclear, and specific diagnostic biomarkers are not available. According to the 2017 diagnostic criteria, probable CLIPPERS should be considered in middle-aged patients with subacute onset of pontocerebellar symptoms and typical punctuate and curvilinear gadolinium enhancement lesions ("salt-and-pepper" appearance) located in the hindbrain (especially pons) on magnetic resonance imaging. In addition, CLIPPERS-mimics, such as central nervous system (CNS) lymphoma, and several antibody-associated autoimmune CNS diseases (e.g., myelin oligodendrocyte glycoprotein antibody-associated disease, autoimmune glial fibrillary acidic protein astrocytopathy, and anti-N-methyl-D-aspartatereceptor encephalitis), should be extensively excluded. The prerequisite for definite CLIPPERS is the perivascular T-cell-predominant inflammatory infiltration observed on pathological analysis. A biopsy is strongly suggested when clinical/radiological red flags are present. Most patients with CLIPPERS respond well to corticosteroids and have a good prognosis. Long-term low-dose corticosteroid maintenance therapy or corticosteroids coupled with immunosuppressants are recommended to prevent the recurrence of the syndrome. The potential progression of CLIPPERS to lymphoma has been suggested in some cases; therefore, at least 2-year clinical and radiological follow-up is essential. Here, we critically review the recent developments and provided an update on the clinical characteristics, diagnostic criteria, differential diagnoses, and therapeutic management of CLIPPERS. We also discuss the current controversies in this context that can be resolved in future research studies.

DOP53 Long-term Efficacy and Safety of Risankizumab in Patients With Moderate to Severe Crohn's Disease up to 3 Years of Treatment: Results From the FORTIFY Open-Label Long-term Extension

Abstract Background The ongoing FORTIFY maintenance open-label extension (OLE) substudy evaluates the long-term efficacy and safety of risankizumab (RZB), a p19 interleukin-23 inhibitor, for treatment of moderate to severe Crohn’s disease (CD). Here, we report 2-year results of FORTIFY OLE. Methods The FORTIFY (NCT03105102) OLE enrolled patients (pts) who completed 52-wks maintenance dosing in the FORTIFY substudies or RZB phase 2 OLE.1,2 All pts received 180 mg subcutaneous (SC) RZB every 8 wks (Q8w), starting at wk56, except for pts who had prior rescue therapy (single 1200mg intravenous [IV] RZB dose then 360mg SC Q8w) who continued 360mg SC Q8w in the OLE. Pts with inadequate response (increased symptoms plus objective marker of inflammation) during the OLE could receive rescue therapy as described above. Pooled data from both treatment groups (RZB 180 mg &amp; 360 mg SC) were assessed. Clinical outcomes were evaluated every 24 wks (endpoint definitions in Figure footnote). Endoscopy was performed every 96 wks. Results are reported as observed. Efficacy data for pts receiving rescue therapy in the OLE were included up to rescue initiation. Safety was assessed through the cutoff date of 05MAR2023. As this trial is ongoing, most patients have not reached the wk152 study visit. Any treatment-emergent adverse events (TEAEs) reported on or after the first dose in the OLE were analysed. Results As of the cutoff date, 1147 pts entered the OLE, of which 203 (17.6%) pts received rescue therapy during the OLE. Clinical response and remission rates were generally maintained with RZB from wks 56 to 152 (CD activity index [CDAI] clinical response, 85.8% to 86.5%, respectively; enhanced clinical response, 88.6% to 89.2%; CDAI clinical remission, 68.5% to 77.6%; stool frequency/abdominal pain score clinical remission, 64.4% to 71.0%) (Figure). At wks 56 and 152, respectively, rates of endoscopic response were 53.4% and 74.2%, endoscopic remission were 37.5%, and 58.9%, and ulcer-free endoscopy were 31.0% and 50.0%. There were no new trends for exposure-adjusted rates of TEAEs, and rates of adjudicated major cardiovascular adverse events, malignancies, serious infections and hepatic events remained stable with no new safety risks identified. There were no events of active tuberculosis, serious hypersensitivity, or adjudicated anaphylactic reaction. Three deaths occurred during the OLE (see Table footnote), all assessed by investigators as unrelated to study drug. Conclusion Pts receiving long-term RZB maintenance therapy in FORTIFY demonstrated sustained clinical and endoscopic efficacy with at least 3 years of treatment. The safety profile is consistent and supports long-term RZB treatment. 1doi: 10.1093/ecco-jcc/jjab093 2doi: 10.1016/S0140-6736(22)00466-4.

Rare, late onset of immune checkpoint inhibitor-induced type 1 diabetes mellitus in a patient with small-cell lung cancer treated with serplulimab: a case report and review of the literature

BackgroundAs a newly approved immune checkpoint inhibitor in China, serplulimab has been widely used in the immunotherapy of tumors. However, the immune-related adverse events of immune checkpoint inhibitors should not be ignored. Although immune checkpoint inhibitor-induced type 1 diabetes mellitus is a rare complication, it may cause diabetic ketoacidosis and endanger the lives of patients.Case presentationThis case report describes a 55-year-old male of Han nationality from China diagnosed with small-cell lung cancer with multiple metastases who experienced an adverse event of type 1 diabetes mellitus 68 weeks after receiving serplulimab therapy. The patient presented with typical symptoms of diabetic ketoacidosis, including severe thirst, nausea, vomiting, deep respirations, and stupor. Despite the absence of diabetes-related autoantibodies, the patient had extremely low levels of insulin and C-peptide release. Other potential causes of diabetes were ruled out, confirming the condition as serplulimab-induced immune checkpoint inhibitor-induced type 1 diabetes mellitus. After aggressive treatment to correct diabetic ketoacidosis, the patient’s blood glucose levels stabilized and symptoms of diabetes improved significantly, although long-term insulin maintenance therapy was necessary.ConclusionThis case highlights a rare, late-onset adverse event of immune checkpoint inhibitor-induced type 1 diabetes mellitus that may be overlooked during treatment with serplulimab. The monitoring of blood glucose levels and early signs and symptoms of diabetes cannot be relaxed at the late stage of treatment, even if patients do not have elevated blood glucose levels before and during the middle stage of treatment.

HLA-DRB1 Is Associated with Therapeutic Responsiveness in IgG4-related Disease.

Objective Glucocorticoids are key drugs used in remission induction therapy for IgG4-related disease (IgG4-RD). However, the therapeutic outcomes vary widely, with some patients requiring long-term maintenance therapy and others relapsing repeatedly, whereas still others can tolerate withdrawal. These variations underscore the need for personalized treatment strategies for IgG4-RD. We examined the relationship between human leukocyte antigen (HLA) genotypes and the response to glucocorticoid treatment in patients with IgG4-RD. Methods Eighteen IgG4-RD patients visiting our hospital were included in the study. Peripheral blood samples were collected, HLA genotypes were determined, and the response to glucocorticoid treatment (maintenance dose at the time of last observation, glucocorticoid dose when the serum IgG4 level was the lowest after remission induction therapy, and occurrence of relapse) was examined retrospectively. Results The DQB1*12:01 genotypes were associated with a prednisolone maintenance dose of <7 mg/day. A prednisolone dose ≥10 mg with a minimum serum IgG4 level was significantly more common in B*40:01 and DRB1-GB-7-Val (DRB1*04:01, *04:03, *04:05, *04:06, and *04:10) patients than other alleles. Relapse also tended to be more common in DRB1-GB-7-Val carriers than other alleles. Conclusion These data suggest that HLA-DRB1 is associated with glucocorticoid treatment responsiveness and is important for follow-up monitoring of serum IgG4 levels during glucocorticoid tapering. We believe that these data will contribute to the future development of personalized medicine for IgG4-RD.

Clinical manifestations and prognosis of giant cell arteritis: A retrospective cohort study

The aim of the study was to evaluate the clinical manifestations and survival of patients with giant cell arteritis (GCA).Methods. A retrospective study included 166 patients with newly diagnosed GCA. Clinical, laboratory and instrumental data, three sets of classification criteria were used to confirm the diagnosis: the American College of Rheumatology (ACR) 1990, the revised ACR criteria of 2016 and/or the new ACR and European Alliance of Associations for Rheumatology (EULAR) 2022 criteria. Some of the patients underwent instrumental investigations: temporal artery ultrasound Doppler (n=61), contrast-enhanced computed tomography (CT) (n=5), CT angiography (n=6), magnetic resonance imaging (n=4), magnetic resonance angiography (n=3) and 18F-FDG positron emission tomography/CT (n=47). Overall and recurrence-free survival were analyzed using survival tables, Kaplan – Meier method.Results. The most frequent first manifestations of GCA were headache (81.8%), weakness (64%), fever (63.8%) and symptoms of rheumatic polymyalgia (56.6%). Changes of temporal arteries in color duplex scanning were detected in 44 out of 61 patients. GCs therapy was performed in all patients who agreed to be treated (n=158), methotrexate was used in 49 out of 158 patients, leflunomide – in 9 patients. In 45 (28.5%) out of 158 patients a stable remission was achieved as a result of GCs monotherapy, in 120 (75.9%) patients long-term maintenance therapy with GCs was required to prevent exacerbations, including 71 (44.9%) patients – in combination with methotrexate or other immunosuppressive drugs. The follow-up period of patients with a history of relapses was 21.0 (8.0–54.0) months. Relapses developed in 73 (46.2%) patients. The overall one-year survival rate was 97.1% [95% confidence interval (CI): 94.3; 99.9], and the five-year survival rate of patients was 94.6% [95% CI: 90.2; 99.0]. The one-year relapse-free survival rate was 86.4% [95% CI: 80.5; 92.3], and the five-year relapse-free survival rate was 52.4% [95% CI: 42.0; 62.8]. 12 (7.2%) of 166 patients died. The cause of death was myocardial infarction in two patients, stroke in two patients, and breast cancer in one patient; in the remaining seven cases, the cause of death was not determined.Conclusion. Given the high frequency of disease exacerbation, patients with GCA require long-term follow-up, especially during the first year after diagnosis.

Case report: pomalidomide as maintenance after salvage autologous stem cell transplantation in a patient with relapsed multiple myeloma

Currently, lenalidomide is the only immunomodulatory drug (IMiD) approved for maintenance therapy in patients with newly diagnosed multiple myeloma who have received high-dose chemotherapy and autologous stem cell transplantation (ASCT). The maintenance with lenalidomide showed an advantage over placebo or observation for both progression-free and overall survival in a series of phase 3 randomized trials. Salvage ASCT can be performed after disease relapse in case of a long-term response after the first transplantation or if this option has not been performed before. Pomalidomide is a third-generation IMiD approved for the treatment of relapsed and refractory multiple myeloma, which is efficient in patients with resistance to lenalidomide and proteasome inhibitors. Structurally, lenalidomide and pomalidomide are similar, and therefore the latter can also be considered as a drug for maintenance, however, there are no relevant phase 3 randomized trials. In this article, we present a clinical case of a 60-year-old patient with newly diagnosed multiple myeloma who progressed after 2 lines of induction therapy, which included lenalidomide and two proteasome inhibitors (bortezomib, ixazomib). The use of Pd combination (pomalidomide, dexamethasone) made it possible to achieve a repeated response and implement of salvage ASCT. The second ASCT was carried out only 12 months later after the first due to the COVID-19 pandemic. Subsequent long-term maintenance therapy with pomalidomide resulted in a complete response and minimal residual disease negativity. The resulting response has persisted at the time of this writing for over 2 years. To discuss the presented clinical case, the data of the French phase 2 IFM 2013-01 study were used, in which patients with failed first-line transplantation in case of relapse received PCd (pomalidomide, cyclophosphamide, dexamethasone) induction, salvage ASCT, and maintenance by Pd until disease progression. Pomalidomide may be an acceptable substitute for lenalidomide in patients with prior intolerance or refractory to this IMiD.

Preparation, Characterization and in vitro/vivo Evaluation of Long-Acting Rivaroxaban-Loaded Microspheres.

Rivaroxaban is widely used for long-term prevention and maintenance therapy of thromboembolic disorders. The existing oral dosage forms of rivaroxaban lead to poor patient adherence because of repeated daily administration. The aim of this study is to design long-acting rivaroxaban- loaded microspheres to reduce dosing frequency and improve patient compliance. Rivaroxaban-loaded microspheres were prepared using the emulsion-solvent evaporation method. The microspheres were evaluated in terms of morphology, particle size, drug loading and encapsulation efficiency, the physical state of the drug in the matrix, in vitro release/release mechanism, and in vivo pharmacokinetics in Sprague Dawley rats. Rivaroxaban-loaded microspheres presented spherical-shaped particles displaying a mean particle size of 89.3 μm, drug loading of 16.5% and encapsulation efficiency of 97.8%. The X-ray diffraction indicated that rivaroxaban existed in crystal form in the microspheres. in vitro release lasting approximately 50 days was characterized as a tri-phasic pattern: (1) an initial burst release, mainly due to the dissolution of drug particles with direct access to the microparticles' surface, (2) a "plateau" phase with a slow-release rate controlled by the diffusion and (3) a final, rapid drug release phase controlled by polymer erosion. Pharmacokinetic studies showed that rivaroxaban microspheres maintained a sustained release for more than 42 days. Rivaroxaban-loaded microspheres have great potential clinical advantages in reducing dosing frequency and improving patient compliance. The data obtained from this study could be used as scientific evidence for decision-making in future formulation development.

No Benefits from Glucocorticoid Maintenance Therapy in Patients with PNH

Introduction Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, complement-mediated hemolytic anemia resulting from a somatic phosphatidylinositol glycan class A ( PIGA) mutation which bugs the biosynthesis of glycosylphosphatidylinositol (GPI). The lack of GPI-anchored proteins, especially CD55 and CD59 molecules, prompts blood cells to be prone to complement attack and lysis. Targeted on the terminal complement inhibitor has been recommended as a first-line treatment, such as eculizumab (C5 inhibitors), which not only controls hemolytic anemia, reduces thrombosis and blood transfusion, but also improves the staging status of chronic kidney disease in PNH patients. Complement inhibitors are not yet widely administrated by Chinese PNH patients, so glucocorticoids are still mostly used for the first-line treatment. However, the efficacy of glucocorticoid maintenance therapy in PNH is uncertain. Methods We conducted a prospective self-controlled comparison of 40 PNH patients with high disease activity (HDA), collecting anemia, hemolysis, thrombosis and renal function indicators at baseline and 1st, 3rd and 6th month after treatment in the Chinese Eastern Collaboration Group of Anemia (CECGA). All enrolled patients were administrated with prednisone 1.0 mg/kg/d at first and then adjusted the dosage according to the situation. The clinical trial registration number is ChiCTR2100050945. Results A total of 40 patients with PNH were enrolled in this study, 21 (52.5%, 21/40) were male, 19 (47.5%, 19/40) were female and the median age was 33.5 years (range 18-69 years). 29 of 40 (72.5%) presented classical PNH and 11 patients (27.5%) were diagnosed as PNH associated with bone marrow disease (BMD)-10 were aplastic anemia and 1 was myelodysplastic syndrome. Four cases detected single-site thrombosis and one had multi-site thrombosis. The most common locations were portal vein thrombus (2/6, 33.33%) and lower extremity intermuscular thrombus (2/6, 33.33%), others included mesentery vein, hepatic vein, splenic vein and intracranial microthrombus. The laboratory indexes at baseline were presented in Table 1. Compared to the baseline (Table 2), at 1 st, 3 rd, and 6 th month after treatment, both hemoglobin and red blood cell (RBC) have improved, but hemoglobin and RBC didn't keep rising, and showed no difference when comparing 3 rd month with 1 st month and 6 th month with 3 rd month. 19 patients (19/40, 47.5%) required blood transfusion before treatment, and 11 patients (11/40, 27.5%) needed transfusion at 1 st month ( P=0.021). Then 13 patients (13/40, 32.5%) at 3 rd month, 15 patients (15/40, 37.5%) at 6 th month were transfusion dependent ( P=0.109; P=0.388). After 6-month treatment, 3 cases of severe anemia (Hb &amp;lt; 30 g/L) at baseline were still severe anemia (3/7, 42.86%), and 4 cases (4/7, 57.14%) were upgraded to moderate anemia (60 g/L ≤ Hb ≤ 90 g/L). Among the original moderate anemia, 20 (20/31, 64.52%) cases were still moderate anemia, 6 (6/31, 19.35%) cases decreased to severe anemia and 5 (5/31, 16.13%) cases were improved to mild anemia (Hb &amp;gt; 90 g/L). 1 (1/2, 50%) patient of mild anemia originally maintained mid anemia and one (1/2, 50%) patient decreased to moderate anemia. The levels of LDH, indirect bilirubin (IBIL) and reticulocyte (Ret) were not changed significantly at 1 st, 3 rd, 6 th month after treatment. At 1 st, 3 rd, 6 th month, only 1, 2 and 2 patients achieved hemolytic control (LDH &amp;lt; 1.5 ULN). The d-dimer and glomerular filtration rate (GFR) also were indicated no difference. At 1 st, 3 rd, 6 th month, 3 (3/11, 27.27%), 4 (4/11, 36.36%), 6 (6/11, 54.54%) patients were back to normal range, 1 (1/11, 9.09%), 2 (2/11, 18.18%), 4 (4/11, 36.36%) patient was newly elevated (D-dimer &amp;gt; 0.55 mg/L) separately. At baseline 2 patients' renal function was severely reduced (GFR＜60ml/min/1.73m 2), and at 1 st, 3 rd, 6 th month, 1, 1, 2 patients had declined respectively. Discussions and Conclusions The use of prednisone in PNH patients with HDA may initially improve anemia, but the improvement in anemia may also be due to self-remission after paroxysmal episodes of PNH itself, or transfusion. The maintenance therapy with prednisone cannot control hemolysis, improve thrombosis and renal function damage. Long-term glucocorticoid maintenance therapy for PNH is not recommended.

Long-Term Safety and Efficacy of Mitapivat, an Oral Pyruvate Kinase Activator, in Adults with Sickle Cell Disease: Extension of a Phase 1 Dose Escalation Study

BACKGROUND In a Phase I study (NCT04000165, Xu et al, 2022), we showed that mitapivat, an investigational oral allosteric activator of pyruvate kinase (PK), demonstrated an acceptable safety and tolerability profile at multiple ascending dose levels in patients (pts) with sickle cell disease (SCD). We also established proof-of-concept for activating PK as a viable therapeutic approach; mitapivat decreased 2,3- diphosphoglycerate (2,3-DPG) and increased adenosine triphosphate (ATP) levels, improved hematologic parameters, and reduced sickling in pts with SCD (HbSS). In this extension study (NCT04610866), we evaluated the safety, tolerability and efficacy of mitapivat as a long-term maintenance therapy for pts with SCD. METHODS We enrolled 15 adult pts (age &amp;gt;18 years) with confirmed SCD (HbSS) and baseline hemoglobin (Hb) 7.1 - 10.5 g/dL, with no recent blood transfusions, erythropoietin therapy, or changes in SCD-specific therapies including hydroxyurea (HU) and L-glutamine. Thirteen pts had participated in the Phase 1 study and 2 pts were mitapivat naïve. All pts started mitapivat at 50 mg twice daily (BID), escalating after 4 weeks (wks) to 100 mg BID, unless a rapid Hb rise was observed (increase of ≥2 g/dL), the maximum Hb level of 12.5 g/dL had been reached, or per PI discretion. Patients continued on this maintenance dose of mitapivat through the end of the study. Dose reductions were performed at any time during the extension phase for safety and tolerability. After completion of the 24-wk core period, pts had an option to continue on mitapivat treatment in the extension period for up to 6 years. Study visits were conducted every 2 wks (x2), 4 wks (x2), and then every 12 wks for first 2 years (yrs) and will continue every 6 months for the remaining 4 yrs. The extension period of the study is ongoing; here we report data for up to 2 years (data cutoff March 23, 2023). Any and all vaso-occlusive crises (VOCs) that occurred while on study, regardless of attribution, were considered adverse events. RESULTS Of the 15 pts who completed the core period, 14 entered the extension study with 1 pt on 5 mg BID, 1 pt on 50 mg BID, 3 alternating between 50 and 100 mg BID, and the rest on 100 mg BID. Mean age of the 15 pts was 39 yrs (range: 25-57 yrs); 10 were male, and 11 were on HU. As of the cut-off date, median duration of mitapivat treatment for pts who entered the extension period was 84 wks (range: 48-108 wks), 1 pt discontinued after 2 yrs (pt decision) and 10 pts received 72 wks or more of treatment (Table 1) with a total of 1080 pt-wks of drug exposure thus far. Mitapivat was generally well tolerated; no treatment emergent adverse events (TEAEs) resulted in discontinuation of study drug or death during the extension period. The most common TEAEs (reported in 5 or more pts) were VOCs (n=8), estrone decrease (n=7), testosterone increase (n=6) and cough (n = 5); changes in laboratory values were not clinically significant. The most common serious TEAEs (reported in 2 or more pts) were VOCs (n=8) and lung infection (n = 2). Two pts experienced VOCs that were assessed as possibly drug-related (1 during drug escalation, and 1 during drug taper). All VOCs occurred in the setting of known VOC triggers. Three pts required dose reduction, 1 each secondary to pruritis, bloating and insomnia, respectively. In the latter 2 cases, the doses were subsequently increased to 100 mg BID, as TEAEs resolved. Other serious TEAEs were not considered related to study drug. The mean Hb at 24 wks increased significantly from baseline (mean: 1.38 g/dL, SD: 0.88 g/dL; p&amp;lt;0.0001), a result generally upheld at other follow-up periods (Fig. 1). 14/15 (93%) of the pts achieved a Hb response, defined as a ≥ 1 g/dL increase in Hb at any timepoint within the core period, compared to baseline. Improvements in Hb achieved in the core period were accompanied by improvements in markers of hemolysis, oxygen affinity (p50), sickling kinetics (t50), decreases in 2,3-DPG and increases in ATP levels, and were sustained in the extension study (Fig. 1 and 2). Concurrently, there were also improvements in red cell deformability (LORRCA) (Lundt et al, 2022) and trends in improvements in cardiopulmonary status (not shown). CONCLUSION Long-term use of mitapivat is safe and well tolerated in pts with SCD with evidence of sustained long-term improvements in Hb, hemolytic and sickling kinetics. Mitapivat offers a novel disease-modifying approach.

Nationwide consensus on the clinical management of treatment-resistant depression in Italy: a Delphi panel

BackgroundTreatment-resistant depression (TRD) is defined by the European Medicines Agency as a lack of clinically meaningful improvement after treatment, with at least two different antidepressants. Individual, familiar, and socio-economic burden of TRD is huge. Given the lack of clear guidelines, the large variability of TRD approaches across different countries and the availability of new medications to meet the need of effective and rapid acting therapeutic strategies, it is important to understand the consensus regarding the clinical characteristics and treatment pathways of patients with TRD in Italian routine clinical practice, particularly in view of the recent availability of esketamine nasal spray.MethodsA Delphi questionnaire with 17 statements (with a 7 points Likert scale for agreement) was administered via a customized web-based platform to Italian psychiatrists with at least 5 years of experience and specific expertise in the field of depression. In the second-round physicians were asked to answer the same statements considering the interquartile range of each question as an index of their colleagues’ responses. Stata 16.1 software was used for the analyses.ResultsSixty panellists, representative of the Italian territory, answered the questionnaire at the first round. For 8/17 statements more than 75% of panellists reached agreement and a high consensus as they assigned similar scores; for 4 statements the panellists assigned similar scores but in the middle of the Likert scale showing a moderate agreement with the statement, while for 5 statements there was indecision in the agreement and low consensus with the statement.ConclusionsThis Delphi Panel showed that there is a wide heterogeneity in Italy in the management of TRD patients, and a compelling need of standardised strategies and treatments specifically approved for TRD. A high level of consensus and agreement was obtained about the importance of adding lithium and/or antipsychotics as augmentation therapies and in the meantime about the need for long-term maintenance therapy. A high level of consensus and agreement was equally reached for the identification of esketamine nasal spray as the best option for TRD patients and for the possibility to administrate without difficulties esketamine in a community outpatient setting, highlighting the benefit of an appropriate educational support for patients.

Symposium 6

The ultimate goal of treatment of systemic lupus erythematosus (SLE) is to prolong survival without compromising the quality of life. The survival rates of SLE have plateaued since the 2000s’ and morbidities related to disease activity and treatment are still problematic. A big unmet need for SLE therapy is to develop strategies that can enhance efficacy, reduce disease flares and drug related complications. Cocktail immunosuppressive therapies for the synergistic effect of individual drugs may enhance efficacy and enable dosage reduction. However, risk of infective complications, adoption of a step-up or step-down approach and the choice of agents are still controversial, partly because of the issue of cost-effectiveness. Belimumab is the first biological agent licensed for pediatric and adult patients with renal and non-renal SLE, based on several pivotal randomized controlled trials (BLISS-52, BLISS-76, BLISS-NEA, BLISS-SC, BLISS-LN). The continuous use of belimumab enables reduction of disease flares, glucocorticoid doses and organ damage. Anifrolumab, a monoclonal antibody against type I interferon receptors, has shown efficacy for non-renal SLE in the TULIP studies. It is recently licensed for moderate to severe SLE patients who are receiving standard therapies. Although rituximab did not show benefit in renal and non-renal SLE, it is commonly used off-label to treat refractory lupus manifestations. The newer generation anti-CD20 biologic, obinutuzumab, shows promising preliminary results in a phase 2 lupus nephritis (LN) trial. Combination of anti-CD20 and anti-BAFF is being studied in LN but the results are conflicting hitherto. Ianalumab, a monoclonal antibody against BAFF receptor that exhibits dual mechanisms of action (BAFF inhibition and B cell depletion), is being studied in LN. The updated 2023 EULAR recommendations for SLE have included the role of biological agents in the treatment algorithm. Belimumab and anifrolumab may be considered in non-major organ SLE, including skin disease, that is refractory to hydroxychloroquine with or without other immunosuppressive agents. Initial combination therapy of glucocorticoids, mycophenolate mofetil or low dose cyclophosphamide, with belimumab is an option for the treatment of severe LN, and belimumab may be used as long-term maintenance therapy of SLE/LN. In this talk, the evidence and the role of the older and newer biologic and targeted agents in SLE/LN will be reviewed.

Real-world Prescription Patterns and Patient Satisfaction Regarding Maintenance Therapy of Gastroesophageal Reflux Disease: An Observational, Cross-sectional, Multicenter Study.

Gastroesophageal reflux disease (GERD) is a common chronic gastrointestinal disorder that typically requires long-term maintenance therapy. However, little is known about patient preferences and satisfaction and real-world prescription patterns regarding maintenance therapy for GERD. This observational, cross-sectional, multicenter study involved patients from 18 referral hospitals in Korea. We surveyed patients who had been prescribed proton pump inhibitors (PPIs) for GERD for at least 90 days with a minimum follow-up duration of 1 year. The main outcome was overall patient satisfaction with different maintenance therapy modalities. A total of 197 patients were enrolled. Overall patient satisfaction, patient preferences, and GERD health-related quality of life scores did not significantly differ among the maintenance therapy modality groups. However, the on-demand therapy group experienced a significantly longer disease duration than the continuous therapy group. The continuous therapy group demonstrated a lower level of awareness of potential adverse effects associated with PPIs than the on-demand therapy group but received higher doses of PPIs than the on-demand therapy group. The prescribed doses of PPIs also varied based on the phenotype of GERD, with higher doses prescribed for non-erosive reflux disease than erosive reflux disease. Although overall patient satisfaction did not significantly differ among the different PPI maintenance therapy modality groups, awareness of potential adverse effects was significantly different between the on-demand and continuous therapy groups.

Should complete B cell depletion be maintained in patients treated long-term with rituximab for rheumatoid arthritis?

To determine whether persistent complete B cell (BC) depletion was associated with a better clinical response in rheumatoid arthritis (RA) patients long-term treated with rituximab (RTX). We conducted a retrospective study including RA patients admitted for a new infusion between 2019 and 2021. The primary endpoint was the comparison of the mean disease activity score based on 28 joints (DAS28)-CRP at each of the four last infusion visits between patients with persistent complete BC depletion (mean CD19 counts <18/µl at each of the last four visits) or without persistent complete BC depletion (mean CD19 counts of the last four visits ≥18/µl). Secondary endpoints included DAS28, pain/fatigue visual analogue scale, CRP, gammaglobulins and the frequency of self-reported RA flares. Of the 126 patients in maintenance therapy with RTX [exposure period: 76 (5) months, 14 (7) infusions received], 43 (34%) had persistent complete BC depletion at each of the four last infusions. The mean DAS28-CRP calculated at each of the four last infusion visits did not significantly differ according to persistence or not of complete BC depletion. This result remained unchanged after adjusting for antibody status, number of previous therapies, number of RTX infusion and cumulative RTX dose. All secondary outcomes were also not significantly different between the two groups. Maintaining complete BC depletion does not appear to be a therapeutic target to achieve in RA patients in long-term maintenance therapy with RTX. There is a limited benefit of monitoring CD19 in RA patients long-term treated with RTX and having achieved low disease activity/remission.