The Role of Disease Severity and Demographics in the Clinical Course of COVID-19 Patients Treated with Convalescent Plasma

ABSTRACTTreatment of patients with COVID-19 using convalescent plasma from recently recovered patients has been shown to be safe, but the time course of change in clinical status following plasma transfusion in relation to baseline disease severity has not yet been described. We analyzed short, descriptive daily reports of patient status in 7,180 hospitalized recipients of COVID-19 convalescent plasma in the Mayo Clinic Expanded Access Program. We assessed, from the day following transfusion, whether the patient was categorized by his or her physician as better, worse or unchanged compared to the day before, and whether, on the reporting day, the patient received mechanical ventilation, was in the ICU, had died or had been discharged. Most patients improved following transfusion, but clinical improvement was most notable in mild to moderately ill patients. Patients classified as severely ill upon enrollment improved, but not as rapidly, while patients classified as critically ill/end-stage and patients on ventilators showed worsening of disease status even after treatment with convalescent plasma. Patients age 80 and over showed little or no clinical improvement following transfusion. Clinical status at enrollment and age appear to be the primary factors in determining the therapeutic effectiveness of COVID-19 convalescent plasma among hospitalized patients.

A longitudinal study of CMT1A using Rasch analysis based CMT neuropathy and examination scores

ObjectiveTo evaluate the sensitivity of Rasch analysis-based, weighted Charcot-Marie-Tooth Neuropathy and Examination Scores (CMTNS-R and CMTES-R) to clinical progression in patients with Charcot-Marie-Tooth disease type 1A (CMT1A).MethodsPatients with CMT1A from 18 sites of the Inherited Neuropathies Consortium were evaluated between 2009 and 2018. Weighted CMTNS and CMTES modified category responses were developed with Rasch analysis of the standard scores. Change from baseline for CMTNS-R and CMTES-R was estimated with longitudinal regression models.ResultsBaseline CMTNS-R and CMTES-R scores were available for 517 and 1,177 participants, respectively. Mean ± SD age of participants with available CMTES-R scores was 41 ± 18 (range 4–87) years, and 56% were female. Follow-up CMTES-R assessments at 1, 2, and 3 years were available for 377, 321, and 244 patients. A mixed regression model showed significant change in CMTES-R score at years 2 through 6 compared to baseline (mean change from baseline 0.59 points at 2 years, p = 0.0004, n = 321). Compared to the original CMTES, the CMTES-R revealed a 55% improvement in the standardized response mean (mean change/SD change) at 2 years (0.17 vs 0.11). Change in CMTES-R at 2 years was greatest in mildly to moderately affected patients (1.48-point mean change, 95% confidence interval 0.99–1.97, p < 0.0001, for baseline CMTES-R score 0–9).ConclusionThe CMTES-R demonstrates change over time in patients with CMT1A and is more sensitive than the original CMTES. The CMTES-R was most sensitive to change in patients with mild to moderate baseline disease severity and failed to capture progression in patients with severe CMT1A.ClinicalTrials.gov identifierNCT01193075.

P376 Real life health care utilisation in paediatric patients with inflammatory bowel disease in the era of biologics

Background The burden associated with the management of paediatric patients with inflammatory bowel disease (IBD) has been rising as the incidence of IBD is increasing in children. In addition, the widespread use of biologics and a treat-to-target approach also contributes to the increase of healthcare utilisation. Methods The purpose of this study was to assess the health care services utilisation and the associated factors in a prospective cohort of children diagnosed with IBD in Quebec, Canada. Patients diagnosed from 2013 to 2015 and followed up until the transfer to adult care were identified in our IBD database. Data on IBD related services and treatments: imaging procedures, hospitalisations and outpatient visits, medications from diagnosis to transition was extracted. We analyzed the healthcare utilisation according to the baseline disease severity (paediatric Crohn’s disease activity index or paediatric ulcerative colitis activity index) at diagnosis, and according to exposition to intravenous biologics. Results In total, 144 patients were included in the study [(77 males), CD (N = 98), UC (N = 31) and IBD-U (N = 15); median (interquartile(IQR)) age at diagnosis 15.2 (14.3–16.3) years]. The median (IQR) duration of paediatric follow-up was 2.9 (1.8–3.9) years. The median (min-max) number of imaging procedures varied largely: esophagogastroduodenoscopy 1(0–2), colonoscopy 1(1–6), abdominal ultrasound1(0–13), abdominal MRI 1(0–4), tomodensitometry 0(0–2), bone densitometry 1(0–5). Patients had various follow-up encounters (median(min–max)): outpatient visits 9(1–28), IBD nurses phone follow-ups 4(0–33). Sixty-four per cent of patients had at least one hospitalisation [median(min–max)1(0–10); median duration 4(0–150 days)] and 35.41% had at least one emergency visit. Baseline disease severity did not predict the disease burden: the mean number of encounters was 3.0/year in the moderate/severe group as compared with 2.5/year in the mild group; p = 0.61. Among the, 63.5% of patients exposed to an intravenous biologic (Infliximab or Vedolizumab), those exposed earlier (&lt;3 months after diagnosis) used more health care services (mean = 3.3/year) than those exposed later (mean = 2.23/year); p &lt;0.0001. In addition, the median (IQR) cumulative days of healthcare utilisation (missing school days) for patients treated with intravenous biologics was 48.5(32.4–67.9) days during paediatric care. Conclusion Adolescents with IBD have several healthcare encounters between the diagnosis and transfer to adult care. Disease severity at diagnosis was not related to a higher level of health services utilisation during follow-up. However, treatment with intravenous biologics was associated with a high health service utilisation and school missing during follow-up.

P100 REAL-WORLD COMPARISON OF ARTHRALGIAS WITH INFLIXIMAB VS. VEDOLIZUMAB IN THE TREATMENT OF BIO-NAIVE INFLAMMATORY BOWEL DISEASE

Background Both infliximab (IFX) and vedolizumab (VDZ) are approved for the treatment of inflammatory bowel disease (IBD) in adults. VDZ is gut-specific and thought to be less effective in controlling extraintestinal manifestations than IFX. The purpose of this study was to compare the incidence and timing of arthralgias between IFX and VDZ. Methods We performed a retrospective cohort study of bio-naïve adult patients treated with IFX or VDZ for ulcerative colitis (UC) or Crohn’s disease (CD) at a large multicenter gastroenterology private practice. Patients were case-matched 1:1 based on age, gender, diagnosis, and baseline disease severity using the partial Mayo (pMayo) for UC and the modified Harvey-Bradshaw Index (mHBI) for CD. Arthralgias were captured out to 12 months of therapy and classified as pre-existing or new-onset based on time to occurrence. Those with pre-existing arthralgias were excluded from new-onset arthralgias analyses. Rates of arthralgias and time to new-onset arthralgias were compared between IFX and VDZ patients. Results A total of 77 IFX (58 UC, 19 CD) and 77 VDZ (58 UC, 19 CD) case-matched pairs were generated. Baseline demographics were similar between IFX and VDZ groups: mean age 45±16.9 vs 46±16.2, male gender 60% vs 61%. Rates of pre-existing arthralgias were 13/77 (17%) and 12/77 (16%) in IFX and VDZ cohorts (p=0.83), respectively. Resolution of pre-existing arthralgias was also similar between groups (6/13 vs 7/12, p=0.70). Of the remaining 64 IFX and 65 VDZ patients without arthralgias at baseline, 16 (25%) IFX patients and 17 (26%) VDZ patients experienced new-onset arthralgias (p=1.0). Median time to new-onset arthralgias was 5.0 (IQR 3.4–7.0) months in IFX patients, compared to 3.3 (IQR 1.4–5.3) months in VDZ patients (p=0.15). While VDZ patients appeared to develop new-onset arthralgias earlier, this was not significant (p=0.20) [Figure 1]. Of note, two IFX patients discontinued therapy due to suspected drug-induced lupus with arthralgias; there were no VDZ discontinuations due to arthralgias. Conclusions Our data suggests that resolution of pre-existing arthralgias and new-onset arthralgias are similar, despite the gut selectivity of VDZ compared to IFX. Additionally, there was no difference in overall time to new-onset arthralgias. These data need to be verified in a larger cohort.

Efficacy of Caplacizumab in Patients with aTTP in the HERCULES Study According to Baseline Disease Severity

Background: Acquired thrombotic thrombocytopenic purpura (aTTP) is a rare, life-threatening autoimmune thrombotic microangiopathy that involves abnormal processing of von-Willebrand factor (vWF) and results in multiple organ dysfunction. Although aTTP remains a very unpredictable disease, risk factors for death include older age, lactate dehydrogenase (LDH) levels >10x the upper limit of normal (ULN), and cerebral involvement (i.e., the French severity score) (Benhamou et al. Haematologica 2012;97:1181-1186). In addition, raised cardiac troponin-I (cTnI) levels of >2.5 µg/L have also been linked with a higher risk of mortality or refractoriness (Benhamou et al. J Thromb Haemost 2015;13:293-302). In the randomized, double-blind, placebo-controlled phase 3 HERCULES study, patients with aTTP were randomized to placebo or caplacizumab, plus daily therapeutic plasma exchange and immunosuppression. This analysis aimed to determine the efficacy of caplacizumab in patients participating in HERCULES according to baseline disease severity. Methods: In the HERCULES study, very severe disease was defined as: a French severity score ≥3, orsevere neurological involvement (i.e. coma, seizures, focal deficit), orcardiac involvement (cTnI >2.5xULN) All of these factors have independently been associated with worse outcomes and higher mortality. The French severity score is a discrete score from 0 to 4, involving evaluation of 3 parameters: Cerebral involvement: yes=1; no=0LDH: >10xULN=1; ≤10xULN=0Age: >60 years=2; >40 and ≤60 years=1; ≤40 years=0 Scores ≥3 indicate very severe disease. Data from patients participating in HERCULES were extracted and analyzed according to less severe/very severe disease and are presented descriptively. Results: Overall efficacy outcomes according to baseline disease severity are presented in Table 1. Patients who presented with less severe disease at baseline had a similar risk of mortality compared with patients who presented with very severe disease. Similar trends were observed for other clinically relevant outcomes, such as exacerbations of aTTP and refractoriness. Treatment with caplacizumab improved outcomes in both patient subgroups. Irrespective of disease severity, caplacizumab treatment resulted in faster platelet count normalization and a lower proportion of patients experiencing the composite endpoint of TTP-related death, exacerbation of TTP, or treatment-emergent major thromboembolic event during the double-blind treatment period. No patients who received caplacizumab died, while deaths occurred in 1 (2.1%) and 2 patients (8.0%) in the less severe and very severe subgroups of patients who received placebo, respectively. No patients receiving caplacizumab developed refractory disease, whereas 1 (2.1%) and 2 placebo-treated patients (8.0%) with less severe and very severe disease, respectively, developed refractory disease. Conclusions: aTTP can be unpredictable, and, although this analysis included a small patient population, our results suggest that patients with less severe disease at baseline are equally at risk of death, refractoriness and exacerbations as patients with very severe disease. A clear treatment benefit was observed in all patients who received caplacizumab irrespective of disease severity at baseline, which highlights the importance of starting therapy early in all patients with aTTP. Table 1. Overall efficacy outcomes according to baseline disease severity in the HERCULES study, during the double-blind treatment period. Table 1 Disclosures Coppo: Shire: Consultancy; Alexion: Consultancy; Ablynx/Sanofi: Consultancy. Cataland:Ablynx/Sanofi: Consultancy, Research Funding; Alexion: Consultancy, Research Funding. Peyvandi:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Kedrion: Honoraria; Grifols: Honoraria; Alnylam: Honoraria; Bioverativ: Membership on an entity's Board of Directors or advisory committees; Octapharma: Research Funding. Knoebl:Ablynx/Sanofi: Consultancy; Novo-Nordisk: Consultancy, Research Funding; Shire/Takeda: Consultancy; CSL-Behring: Consultancy; Roche: Consultancy. Scully:Novartis: Consultancy; Shire: Research Funding; Alexion: Consultancy; Shire/Takeda: Consultancy; Ablynx/Sanofi: Consultancy. Kremer Hovinga:Ablynx/Sanofi: Consultancy, Honoraria, Other: Honoraria go to employer (Insel Gruppe AG, Department of Hematology); Roche: Honoraria, Other: Honoraria go to employer (Insel Gruppe AG, Department of Hematology); Shire: Consultancy, Other: Honoraria go to employer (Insel Gruppe AG, Department of Hematology), Research Funding; CSL-Behring: Honoraria, Other: Honoraria go to employer (Insel Gruppe AG, Department of Hematology); Siemens: Honoraria, Other: Honoraria go to employer (Insel Gruppe AG, Department of Hematology). Metjian:AblynxNV/Sanofi: Consultancy, Research Funding; Genentech: Consultancy, Research Funding. De La Rubia:Takeda: Consultancy; AMGEN: Consultancy; AbbVie: Consultancy; Janssen: Consultancy; Celgene Corporation: Consultancy. Pavenski:Shire: Honoraria; Alexion: Honoraria, Research Funding; Octapharma: Research Funding; Bioverativ: Research Funding; Ablynx: Honoraria, Research Funding. De Winter:Ablynx, a Sanofi company: Employment. de Passos Sousa:Sanofi: Employment. Callewaert:Sanofi (formerly employed by Ablynx, a Sanofi company): Employment.