Long-term treatment with rilzabrutinib in patients with immune thrombocytopenia.

ABSTRACT: Immune thrombocytopenia (ITP) is an autoimmune disease associated with autoantibody-mediated platelet destruction and impaired platelet production, resulting in thrombocytopenia and a predisposition to bleeding. The ongoing, global phase 1/2 study showed that rilzabrutinib, a Bruton tyrosine kinase inhibitor specifically developed to treat autoimmune disorders, could be an efficacious and well-tolerated treatment for ITP. Clinical activity, durability of response, and safety were evaluated in 16 responding patients who continued rilzabrutinib 400 mg twice daily in the long-term extension (LTE) study. At LTE entry, the median platelet count was 87 × 109/L in all patients, 68 × 109/L in those who had rilzabrutinib monotherapy (n = 5), and 156 × 109/L in patients who received concomitant ITP medication (thrombopoietin-receptor agonists and/or corticosteroids, n = 11). At a median duration of treatment of 478 days (range, 303-764), 11 of 16 patients (69%) continued to receive rilzabrutinib. A platelet count of ≥50 × 109/L was reported in 93% of patients for more than half of their monthly visits. The median percentage of LTE weeks with platelet counts ≥30 × 109/L and ≥50 × 109/L was 100% and 88%, respectively. Five patients discontinued concomitant ITP therapy and maintained median platelet counts of 106 × 109/L at 3 to 6 months after stopping concomitant ITP therapy. Adverse events related to treatment were grade 1 or 2 and transient, with no bleeding, thrombotic, or serious adverse events. With continued rilzabrutinib treatment in the LTE, platelet responses were durable and stable over time with no new safety signals. This trial is registered at www.clinicaltrials.gov as #NCT03395210 and www.clinicaltrialsregister.eu as EudraCT 2017-004012-19.

Safety and efficacy of SARS-CoV-2 vaccination in patients with immune thrombocytopenia: A two-centre review.

Multiple studies have reported immune thrombocytopenia (ITP) relapse following SARS-CoV-2 vaccination, however baseline ITP relapse rate and antibody response to vaccination are not known. Patients with ITP who received at least one of the first three SARS-CoV-2 vaccination doses were included in the study. One hundred and twenty-four patients met the inclusion criteria. Relapse rate was 4.2% following a first vaccine dose, 9.1% after a second and 2.9% after a third; baseline relapse rate was 7.6%. Ninety-four per cent of patients who received three vaccine doses developed a clinical antibody response. SARS-CoV-2 vaccination appears to be safe and effective in patients with ITP.

Patient preferences and experiences regarding thrombopoietin-receptor agonists for immune thrombocytopenia in The Netherlands (TRAPeze Netherlands study).

OBJECTIVE: Identify patient experience and preference towards thrombopoietin-receptor agonists (TPO-RAs) in treatment of immune thrombocytopenia (ITP) in the Netherlands. METHODS: The Thrombopoietin-Receptor Agonist Patient experience (TRAPeze) survey used a discrete choice experiment (DCE) to elicit patient preferences and a patient burden survey (PBS) to evaluate the clinical and social impact of ITP. TRAPeze collected responses from 6th October to 19th November 2021. RESULTS: Seventy-six respondents completed the DCE: treatment preference appeared to be driven by method of administration (odds ratio [OR] 4.33; 95% confidence interval [CI] 2.88-6.52), frequency of dosing (OR 2.33; 95% CI 1.86-2.92) and drug-food interactions (OR 1.91; 95% CI 1.54-2.37). Respondents preferred therapies delivered orally over subcutaneous injection (OR 4.22; 95% CI 2.76-6.46), dosed once weekly over once daily (OR 2.37; 95% CI 1.58-3.54) and without food restrictions over with restrictions (OR 1.90; 95% CI 1.52-2.38). Sixty-nine respondents completed the DCE and PBS (mean [range] age 53 [19-83] years, 65% female). Seven incomplete PBS responses were excluded from analysis. Respondents were currently, or most recently, receiving eltrombopag (n = 43) or romiplostim (n = 26), of which 30% (n = 21/69) had previously received another TPO-RA. Loss (29%, n = 6/21) and lack (29%, n = 6/21) of response were the most common reasons for switching TPO-RA. Only 28% (n = 18/65) of respondents felt their TPO-RA increased energy levels. CONCLUSION: Patients preferred therapies delivered orally, dosed less frequently and without food restrictions. QoL of ITP patients on TPO-RAs can be improved; the burden analyses presented can inform future efforts towards this.

Coagulation biomarkers for ischemic stroke.

A State of the Art lecture titled "coagulation biomarkers for ischemic stroke" was presented at the International Society on Thrombosis and Haemostasis (ISTH) Congress in 2022. Ischemic stroke (IS) is a common disease with major morbidity and mortality. It is a challenge to determine which patients are at risk for IS or have poor clinical outcome after IS. An imbalance of coagulation markers may contribute to the progression and prognosis of IS. Therefore, we now discuss studies on the association of selected coagulation biomarkers from the hemostasis, inflammation, and immunothrombosis systems with the risk of IS, stroke severity at the acute phase, and clinical outcome after treatment. We report on coagulation biomarker-induced risk of IS, stroke severity, and outcomes following IS derived from prospective population studies, case-control studies, and acute-phase IS studies. We found indications that many coagulation and inflammation biomarkers are associated with IS, but it is early to conclude that any of these biomarkers can be applied in a therapeutic setting to predict patients at risk of IS, stroke severity at the acute phase, and clinical outcome after treatment. The strongest evidence for a role in IS was found for beta-thromboglobulin, von Willebrand factor, factor VIII, fibrinogen, thrombin-activatable fibrinolysis inhibitor, D-dimer, and neutrophil extracellular traps, and therefore, they are promising candidates. Further research and validation in large-size populations using well-defined study designs are warranted. Finally, we provide a selection of recent data relevant to this subject that was presented at the 2022 ISTH Congress.

Platelet Transfusion before CVC Placement in Patients with Thrombocytopenia.

BACKGROUND: Transfusion guidelines regarding platelet-count thresholds before the placement of a central venous catheter (CVC) offer conflicting recommendations because of a lack of good-quality evidence. The routine use of ultrasound guidance has decreased CVC-related bleeding complications. METHODS: In a multicenter, randomized, controlled, noninferiority trial, we randomly assigned patients with severe thrombocytopenia (platelet count, 10,000 to 50,000 per cubic millimeter) who were being treated on the hematology ward or in the intensive care unit to receive either one unit of prophylactic platelet transfusion or no platelet transfusion before ultrasound-guided CVC placement. The primary outcome was catheter-related bleeding of grade 2 to 4; a key secondary outcome was grade 3 or 4 bleeding. The noninferiority margin was an upper boundary of the 90% confidence interval of 3.5 for the relative risk. RESULTS: We included 373 episodes of CVC placement involving 338 patients in the per-protocol primary analysis. Catheter-related bleeding of grade 2 to 4 occurred in 9 of 188 patients (4.8%) in the transfusion group and in 22 of 185 patients (11.9%) in the no-transfusion group (relative risk, 2.45; 90% confidence interval [CI], 1.27 to 4.70). Catheter-related bleeding of grade 3 or 4 occurred in 4 of 188 patients (2.1%) in the transfusion group and in 9 of 185 patients (4.9%) in the no-transfusion group (relative risk, 2.43; 95% CI, 0.75 to 7.93). A total of 15 adverse events were observed; of these events, 13 (all grade 3 catheter-related bleeding [4 in the transfusion group and 9 in the no-transfusion group]) were categorized as serious. The net savings of withholding prophylactic platelet transfusion before CVC placement was $410 per catheter placement. CONCLUSIONS: The withholding of prophylactic platelet transfusion before CVC placement in patients with a platelet count of 10,000 to 50,000 per cubic millimeter did not meet the predefined margin for noninferiority and resulted in more CVC-related bleeding events than prophylactic platelet transfusion. (Funded by ZonMw; PACER Dutch Trial Register number, NL5534.).

Quantitative super-resolution imaging of platelet degranulation reveals differential release of von Willebrand factor and von Willebrand factor propeptide from alpha-granules.

BACKGROUND: Von Willebrand factor (VWF) and VWF propeptide (VWFpp) are stored in eccentric nanodomains within platelet alpha-granules. VWF and VWFpp can undergo differential secretion following Weibel-Palade body exocytosis in endothelial cells; however, it is unclear if the same process occurs during platelet alpha-granule exocytosis. Using a high-throughput 3-dimensional super-resolution imaging workflow for quantification of individual platelet alpha-granule cargo, we studied alpha-granule cargo release in response to different physiological stimuli. OBJECTIVES: To investigate how VWF and VWFpp are released from alpha-granules in response to physiological stimuli. METHODS: Platelets were activated with protease-activated receptor 1 (PAR-1) activating peptide (PAR-1 ap) or collagen-related peptide (CRP-XL). Alpha-tubulin, VWF, VWFpp, secreted protein acidic and cysteine rich (SPARC), and fibrinogen were imaged using 3-dimensional structured illumination microscopy, followed by semiautomated analysis in FIJI. Uptake of anti-VWF nanobody during degranulation was used to identify alpha-granules that partially released content. RESULTS: VWFpp overlapped with VWF in eccentric alpha-granule subdomains in resting platelets and showed a higher degree of overlap with VWF than SPARC or fibrinogen. Activation of PAR-1 (0.6-20 µM PAR-1 ap) or glycoprotein VI (GPVI) (0.25-1 µg/mL CRP-XL) signaling pathways caused a dose-dependent increase in alpha-granule exocytosis. More than 80% of alpha-granules remained positive for VWF, even at the highest agonist concentrations. In contrast, the residual fraction of alpha-granules containing VWFpp decreased in a dose-dependent manner to 23%, whereas SPARC and fibrinogen were detected in 60% to 70% of alpha-granules when stimulated with 20 µM PAR-1 ap. Similar results were obtained using CRP-XL. Using an extracellular anti-VWF nanobody, we identified VWF in postexocytotic alpha-granules. CONCLUSION: We provide evidence for differential secretion of VWF and VWFpp from individual alpha-granules.

Oculocerebrorenal syndrome of Lowe protein controls cytoskeletal reorganisation during human platelet spreading.

Lowe syndrome (LS) is a rare, X-linked disorder characterised by numerous symptoms affecting the brain, the eyes, and the kidneys. It is caused by mutations in the oculocerebrorenal syndrome of Lowe (OCRL) protein, a 5-phosphatase localised in different cellular compartments that dephosphorylates phosphatidylinositol-4,5-bisphosphate into phosphatidylinositol-4-monophosphate. Some patients with LS also have bleeding disorders, with normal to low platelet (PLT) count and impaired PLT function. However, the mechanism of PLT dysfunction in patients with LS is not completely understood. The main function of PLTs is to activate upon vessel wall injury and stop the bleeding by clot formation. PLT activation is accompanied by a shape change that is a result of massive cytoskeletal rearrangements. Here, we show that OCRL-inhibited human PLTs do not fully spread, form mostly filopodia, and accumulate actin nodules. These nodules co-localise with ARP2/3 subunit p34, vinculin, and sorting nexin 9. Furthermore, OCRL-inhibited PLTs have a retained microtubular coil with high levels of acetylated tubulin. Also, myosin light chain phosphorylation is decreased upon OCRL inhibition, without impaired degranulation or integrin activation. Taken together, these results suggest that OCRL contributes to cytoskeletal rearrangements during PLT activation that could explain mild bleeding problems in patients with LS.

Lupus anticoagulant associates with thrombosis in patients with COVID-19 admitted to intensive care units: A retrospective cohort study.

Background: Thrombosis is a frequent and severe complication in patients with coronavirus disease 2019 (COVID-19) admitted to the intensive care unit (ICU). Lupus anticoagulant (LA) is a strong acquired risk factor for thrombosis in various diseases and is frequently observed in patients with COVID-19. Whether LA is associated with thrombosis in patients with severe COVID-19 is currently unclear. Objective: To investigate if LA is associated with thrombosis in critically ill patients with COVID-19. Patients/Methods: The presence of LA and other antiphospholipid antibodies was assessed in patients with COVID-19 admitted to the ICU. LA was determined with dilute Russell's viper venom time (dRVVT) and LA-sensitive activated partial thromboplastin time (aPTT) reagents. Results: Of 169 patients with COVID-19, 116 (69%) tested positive for at least one antiphospholipid antibody upon admission to the ICU. Forty (24%) patients tested positive for LA; of whom 29 (17%) tested positive with a dRVVT, 19 (11%) tested positive with an LA-sensitive aPTT, and 8 (5%) tested positive on both tests. Fifty-eight (34%) patients developed thrombosis after ICU admission. The odds ratio (OR) for thrombosis in patients with LA based on a dRVVT was 2.5 (95% confidence interval [CI], 1.1-5.7), which increased to 4.5 (95% CI, 1.4-14.3) in patients at or below the median age in this study (64 years). LA positivity based on a dRVVT or LA-sensitive aPTT was only associated with thrombosis in patients aged less than 65 years (OR, 3.8; 95% CI, 1.3-11.4) and disappeared after adjustment for C-reactive protein. Conclusion: Lupus anticoagulant on admission is strongly associated with thrombosis in critically ill patients with COVID-19, especially in patients aged less than 65 years.

Platelet degranulation and bleeding phenotype in a large cohort of Von Willebrand disease patients.

Von Willebrand disease (VWD) is a bleeding disorder caused by quantitative (type 1 or 3) or qualitative (type 2A/2B/2M/2N) defects of circulating von Willebrand factor (VWF). Circulating VWF levels not always fully explain bleeding phenotypes, suggesting a role for alternative factors, like platelets. Here, we investigated platelet factor 4 (PF4) in a large cohort of patients with VWD. PF4 levels were lower in type 2B and current bleeding phenotype was significantly associated with higher PF4 levels, particularly in type 1 VWD. Based on our findings we speculate that platelet degranulation and cargo release may play a role across VWD subtypes.

Rilzabrutinib, an Oral BTK Inhibitor, in Immune Thrombocytopenia.

BACKGROUND: Rilzabrutinib, an oral, reversible covalent inhibitor of Bruton's tyrosine kinase, may increase platelet counts in patients with immune thrombocytopenia by means of dual mechanisms of action: decreased macrophage (Fcγ receptor)-mediated platelet destruction and reduced production of pathogenic autoantibodies. METHODS: In an international, adaptive, open-label, dose-finding, phase 1-2 clinical trial, we evaluated rilzabrutinib therapy in previously treated patients with immune thrombocytopenia. We used intrapatient dose escalation of oral rilzabrutinib over a period of 24 weeks; the lowest starting dose was 200 mg once daily, with higher starting doses of 400 mg once daily, 300 mg twice daily, and 400 mg twice daily. The primary end points were safety and platelet response (defined as at least two consecutive platelet counts of ≥50×103 per cubic millimeter and an increase from baseline of ≥20×103 per cubic millimeter without the use of rescue medication). RESULTS: Sixty patients were enrolled. At baseline, the median platelet count was 15×103 per cubic millimeter, the median duration of disease was 6.3 years, and patients had received a median of four different immune thrombocytopenia therapies previously. All the treatment-related adverse events were of grade 1 or 2 and transient. There were no treatment-related bleeding or thrombotic events of grade 2 or higher. At a median of 167.5 days (range, 4 to 293) of treatment, 24 of 60 patients (40%) overall and 18 of the 45 patients (40%) who had started rilzabrutinib treatment at the highest dose met the primary end point of platelet response. The median time to the first platelet count of at least 50×103 per cubic millimeter was 11.5 days. Among patients with a primary platelet response, the mean percentage of weeks with a platelet count of at least 50×103 per cubic millimeter was 65%. CONCLUSIONS: Rilzabrutinib was active and associated with only low-level toxic effects at all dose levels. The dose of 400 mg twice daily was identified as the dose for further testing. Overall, rilzabrutinib showed a rapid and durable clinical activity that improved with length of treatment. (Funded by Sanofi; ClinicalTrials.gov number, NCT03395210; EudraCT number, 2017-004012-19.).

COVID-19 vaccination in patients with immune thrombocytopenia.

Immune thrombocytopenia (ITP) is an acquired autoimmune disorder that is characterized by low platelet count and increased bleeding risk. COVID-19 vaccination has been described as a risk factor for de novo ITP, but the effects of COVID-19 vaccination in patients with ITP are unknown. We aimed to investigate the effects of COVID-19 vaccination in patients with ITP on platelet count, bleeding complications, and ITP exacerbation (≥50% decline in platelet count, or nadir platelet count < 30 × 109/L with a >20% decrease from baseline, or use of rescue therapy). Platelet counts in patients with ITP and healthy controls were collected immediately before and 1 and 4 weeks after the first and second vaccinations. Linear mixed-effects modeling was applied to analyze platelet counts over time. We included 218 patients with ITP (50.9% female; mean age, 55 years; and median platelet count, 106 × 109/L) and 200 healthy controls (60.0% female; mean age, 58 years; median platelet count, 256 × 109/L). Platelet counts decreased by 6.3% after vaccination. We did not observe any difference in decrease between the groups. Thirty patients with ITP (13.8%; 95% confidence interval [CI], 9.5-19.1) had an exacerbation and 5 (2.2%; 95% CI, 0.7-5.3) suffered from a bleeding event. Risk factors for ITP exacerbation were platelet count < 50 × 109/L (odds ratio [OR], 5.3; 95% CI, 2.1-13.7), ITP treatment at time of vaccination (OR, 3.4; 95% CI, 1.5-8.0), and age (OR, 0.96 per year; 95% CI, 0.94-0.99). Our study highlights the safety of COVID-19 vaccination in patients with ITP and the importance of the close monitoring of platelet counts in a subgroup of patients with ITP. Patients with ITP with exacerbation responded well on therapy.

Indication and outcome of lupus anticoagulant and antiphospholipid antibodies testing in routine clinical practice.

OBJECTIVES: Lupus anticoagulans (LACs) and aPLs, both further summarized as aPL, are frequently assessed in routine daily clinical practice in diagnostic workups for suspected autoimmune diseases or to test for underlying risk factors in patients with thrombosis or obstetric complications. The aim of this study was to determine the prevalence of aPL positivity in patients with an indication for aPL testing in routine clinical practice. METHODS: In this retrospective single-centre study, indication for aPL testing, aPL test results and clinical data were collected for patients tested between June 2015 and April 2018. RESULTS: During the study period, 16 847 single aPL tests were performed in 2139 patients. In 212 patients one or more positive aPL test was found, confirmed in 43.9% with a second positive test. Indications for aPL testing were diagnostic workup/follow-up of autoimmune diseases (33.6%), thrombosis (21.4%) and obstetric complications (28%). Seventy-four patients (3.5% of all patients) fulfilled the criteria of APS, of whom 51% were newly diagnosed. Second positive aPL titres and titres of APS patients were significantly higher compared with positive aPL titres at the first measurement (P < 0.05). Patients with indications of arterial thrombosis and diagnostic workup/follow-up of autoimmune diseases had significantly higher levels of aCL IgG and anti-ß2 glycoprotein I (ß2GPI) IgG compared with patients with other indications. CONCLUSION: The prevalence of one or more positive aPL test was 9.9% and APS was diagnosed in 3.5% of the patients. Patients with arterial thrombosis had significantly higher anti-ß2GPI IgG and aCL IgG, which should be confirmed in future studies.

Therapeutic plasma exchange for anticoagulant-refractory antiphospholipid syndrome with severe ischemic and necrotic skin lesions: A case series.

Antiphospholipid syndrome (APS) is a systemic autoimmune disease characterized by clinical findings including thrombosis and/or obstetric complication and laboratory findings, e.g. ≥1 positive antiphospholipid antibodies (aPL) (lupus anticoagulant, anticardiolipin IgG/IgM and/or anti-ß2-glycoprotein IgG/IgM). A rare APS clinical entity is severe necrosis which is difficult to treat and often does not respond to anticoagulant therapy. Three consecutive patients with primary or secondary APS who presented with necrotic skin lesions secondary to APS were treated with therapeutic plasma exchange (TPE), glucocorticoids and low-molecular-weight heparin. All patients had a rapid-onset, either full or significant recovery of their APS-related necrotic lesions. Upon treatment, one patients showed resolution of lupus anticoagulant. Two patients had a decrease of at least 88 % in aPL titers after the initial treatment, and were kept on TPE maintenance every 5-6 weeks. None of the patients experienced significant side effects of the TPE. This is the first case series showing the clinical benefits of TPE in patients with ischemic and necrotic skin lesions due to severe anticoagulant-refractory vascular APS.

Erratum to: Diagnosis and treatment of patients with antiphospholipid syndrome: a mixed-method evaluation of care in The Netherlands.

[This corrects the article DOI: 10.1093/rap/rkaa021.].

Diagnosis and treatment of patients with antiphospholipid syndrome: a mixed-method evaluation of care in The Netherlands.

OBJECTIVES: The aims were to gain insight into the care provided to patients with APS in The Netherlands and to identify areas for improvement from the perspective of both patients and medical specialists. METHODS: APS care was evaluated using qualitative and quantitative methods. Perspectives on APS care were explored using semi-structured interviews with medical specialists, patient focus groups and a cross-sectional, online patient survey. In order to assess current practice, medical records were reviewed retrospectively to collect data on clinical and laboratory manifestations and pharmacological treatment in six Dutch hospitals. RESULTS: Fourteen medical specialists were interviewed, 14 patients participated in the focus groups and 79 patients completed the survey. Medical records of 237 patients were reviewed. Medical record review showed that only one-third of patients were diagnosed with APS within 3 months after entering specialist care. The diagnostic approach and management varied between centres and specialists. Almost 10% of all patients and 7% of triple-positive patients with thrombotic APS were not receiving any anticoagulant treatment at the time of medical record review. Correspondingly, poor recognition and fragmentation of care were reported as the main problems by medical specialists. Additionally, patients reported the lack of accessible, reliable patient education, psychosocial support and trust in physicians as important points for improvement. CONCLUSION: Delayed diagnosis, variability in management strategies and fragmentation of care were important limitations of APS care identified in this study. A remarkable 10% of patients did not receive any anticoagulant treatment.

Influenza-induced thrombocytopenia is dependent on the subtype and sialoglycan receptor and increases with virus pathogenicity.

Thrombocytopenia is a common complication of influenza virus infection, and its severity predicts the clinical outcome of critically ill patients. The underlying cause(s) remain incompletely understood. In this study, in patients with an influenza A/H1N1 virus infection, viral load and platelet count correlated inversely during the acute infection phase. We confirmed this finding in a ferret model of influenza virus infection. In these animals, platelet count decreased with the degree of virus pathogenicity varying from 0% in animals infected with the influenza A/H3N2 virus, to 22% in those with the pandemic influenza A/H1N1 virus, up to 62% in animals with a highly pathogenic A/H5N1 virus infection. This thrombocytopenia is associated with virus-containing platelets that circulate in the blood. Uptake of influenza virus particles by platelets requires binding to sialoglycans and results in the removal of sialic acids by the virus neuraminidase, a trigger for hepatic clearance of platelets. We propose the clearance of influenza virus by platelets as a paradigm. These insights clarify the pathophysiology of influenza virus infection and show how severe respiratory infections, including COVID-19, may propagate thrombocytopenia and/or thromboembolic complications.

First line treatment of adult patients with primary immune thrombocytopenia: a real-world study.

Immune thrombocytopenia (ITP) is an autoimmune disease with a mild to severe risk of bleeding complications. First line treatment includes corticosteroids, immunoglobulins, or other. In this large cohort study, first-line strategies for treatment-naive adult primary ITP was studied in a real-world setting. Records from all adult ITP patients who received first-line treatment between January 2010 and December 2017 at Qilu Hospital were reviewed retrospectively (n = 699). During the study period, 271 patients were treated with high-dose dexamethasone (HDD) and 289 patients were treated with conventional prednisone (alone or in combination with other drugs). Initial responses were similar for the two groups (88.56% vs. 86.51%, P = 0.462), but patients in the HDD group responded earlier than the prednisone group (3 days vs. 5 days, P < 0.001). The sustained response (SR) at 6 months was lower in the HDD group than in the prednisone group (35.4% vs. 47.1%, P = 0.040). However, the SR at 12 months and at the end of our follow-up were not significantly different between the groups. Overall duration of response (DOR) in the prednisone group was longer than in the HDD group throughout the follow-up period (P = 0.007). However, the incidence of SR and overall DOR were not significantly different between the HDD group and the prednisone 3 months group (prednisone terminated within 3 months). The presence of anti-GPIb-IX autoantibodies was a predictive factor for a poor initial response to corticosteroids therapy (P < 0.05). However, neither of the two antiplatelet autoantibodies were correlated with the opportunity to achieve SR and overall DOR in both groups throughout the follow-up period (P > 0.05). Adverse events were more frequent and long-lasting in the prednisone group. Our study showed that HDD provided an effective and more rapid response as initial treatment of ITP, with comparable long-term prognosis and better tolerance when compared with conventional PDN (less than 3 months) in the real-world setting.