Predictors of pharmacotherapy outcomes for body dysmorphic disorder: a machine learning approach

Background Serotonin-reuptake inhibitors (SRIs) are first-line pharmacotherapy for the treatment of body dysmorphic disorder (BDD), a common and severe disorder. However, prior research has not focused on or identified definitive predictors of SRI treatment outcomes. Leveraging precision medicine techniques such as machine learning can facilitate the prediction of treatment outcomes. Methods The study used 10-fold cross-validation support vector machine (SVM) learning models to predict three treatment outcomes (i.e. response, partial remission, and full remission) for 97 patients with BDD receiving up to 14-weeks of open-label treatment with the SRI escitalopram. SVM models used baseline clinical and demographic variables as predictors. Feature importance analyses complemented traditional SVM modeling to identify which variables most successfully predicted treatment response. Results SVM models indicated acceptable classification performance for predicting treatment response with an area under the curve (AUC) of 0.77 (sensitivity = 0.77 and specificity = 0.63), partial remission with an AUC of 0.75 (sensitivity = 0.67 and specificity = 0.73), and full remission with an AUC of 0.79 (sensitivity = 0.70 and specificity = 0.79). Feature importance analyses supported constructs such as better quality of life and less severe depression, general psychopathology symptoms, and hopelessness as more predictive of better treatment outcome; demographic variables were least predictive. Conclusions The current study is the first to demonstrate that machine learning algorithms can successfully predict treatment outcomes for pharmacotherapy for BDD. Consistent with precision medicine initiatives in psychiatry, the current study provides a foundation for personalized pharmacotherapy strategies for patients with BDD.

Real-World Effects of Chinese Herbal Medicine for Idiopathic Membranous Nephropathy (REACH-MN): Protocol of a Registry-Based Cohort Study

Introduction: Some encouraging findings of Chinese herbal medicine (CHM) in management of idiopathic membranous nephropathy (IMN) obtained in the setting of clinical trials are hard to validate in the daily clinical practice due to a complicated treatment scenario of CHM in practice. The primary objective of this registry is to provide a description of treatment patterns used in management of IMN and assess clinical remission in daily practice in a Chinese population sample with IMN.Methods and analysis: This is a prospective, multicenter cohort which will comprise 2000 adults with IMN regardless of urinary protein levels that will be recruited from 11 nephrology centers across China. The participants will be followed for up to at least 2 years. Primary outcome is composite remission (either complete remission or partial remission) 24 months after enrolment. The secondary outcomes are complete remission, partial remission, time to remission, no response, relapse, proteinuria, annual change of glomerular filtration rate, antibodies against PLA2R, and composite endpoint of 40% reduction of glomerular filtration rate, doubling of serum creatinine, end-stage renal disease, and death. Propensity score analysis will be used for matching and adjustment.Ethics and dissemination: This study has been approved by the Ethics Committee of Guangdong Provincial Hospital of Chinese Medicine (BF2020-094-01). Results of the study will be published in both national and international peer-reviewed journals, and presented at scientific conferences. Investigators will inform the participants as well as other IMN patients of the findings via health education.Study registration: ChiCTR2000033680 (prospectively registered).

Analysis and Study on Epidemiological Features and Prognosis of Nephrotic Syndrome in Xinjiang and Heilongjiang

Backgrounds. The pathogenesis of nephrotic syndrome (NS) is complex, and there are differences between regions. This study attempted to collect clinicopathological data of patients diagnosed with NS in Xinjiang and Heilongjiang in the past 2 years, so as to explore the onset features of NS and treatment and prognosis of patients in the two regions. Methods. Clinical data of 375 patients diagnosed with NS using renal biopsy in Xinjiang and Heilongjiang from March 2019 to March 2021 were collected. Clinical data of patients before treatment were collected, and the chi-square test was utilized to compare the differences in the sex distribution of two groups. The U test was utilized to compare abnormal distribution continuous data between two groups, such as age, hemoglobin, plasma albumin, proteinuria, and triglycerides. Independent sample t -test was utilized to compare normal distribution continuous data between two groups, such as serum total protein, serum creatinine, blood urea nitrogen, glomerular filtration rate, and total cholesterol. The independent sample t -test was also used to compare the immunoglobulin levels and complement levels between the two groups after treatment, including IgA, IgG, IgM, C3, and C4. Kaplan-Meier method was used to analyze and plot the cumulative curves of complete remission rate and partial remission rate. Results. For 275 NS patients from Xinjiang, the male-to-female ratio was 0.81 : 1. For 84 patients from Heilongjiang, the male-to-female ratio was 1.05 : 1. The onset ages of patients in Xinjiang and Heilongjiang were 22-45 years old and 22-47 years old, respectively. Respectively, there were 221 cases (80.36%) and 66 cases (78.57%) of primary NS in Xinjiang and Heilongjiang. There were 54 cases (19.64%) and 18 cases (21.43%) of secondary NS in Xinjiang and Heilongjiang, respectively. There was no statistically significant difference in cause distribution between the two regions ( p = 0.756 ). After treatment, immunoglobulin levels (IgA ( p = 0.009 ), IgG ( p = 0.002 ), IgM ( p < 0.001 )) and complement C3 ( p < 0.001 ) and C4 ( p < 0.001 ) levels in Xinjiang and Heilongjiang were statistically significant. 129 cases in Xinjiang (46.91%) and 55 cases in Heilongjiang (65.48%) were treated with glucocorticoid (GC) combined with immunosuppressive therapy, respectively. After receiving treatment, 67 (24.36%) of 275 patients in Xinjiang achieved complete remission, 166 (60.36%) achieved partial remission, 22 (26.19%) of 84 patients in Heilongjiang achieved complete remission, and 56 (66.67%) achieved partial remission, and there was no statistically significant difference in remission rate between the two regions ( p = 0.159 ). Patients in Xinjiang and Heilongjiang achieved complete remission at an average of 10.34 weeks (9.98-10.70) and 9.95 weeks (9.26-10.65), respectively. There was no significant difference in complete remission rates between the two regions ( p = 0.663 ). Patients in Xinjiang and Heilongjiang achieved partial remission at an average of 8.76 weeks (8.38-9.14) and 7.99 weeks (7.33-8.65), respectively. There was no significant difference in the partial remission rate between the two regions ( p = 0.065 ). Conclusion. The causes of NS in Xinjiang and Heilongjiang were similar. After treatment, there were differences in immunoglobulin levels (IgA, IgG, IgM) and complement levels (C3, C4) in the two regions. The main treatment methods used in the two regions were GC combined with immunosuppressive therapy. The prognosis of patients in the two regions was similar. The complete remission rate and partial remission rate after treatment in the two regions were similar, and the average time required to achieve complete remission and partial remission was also similar.

Modern possibilities of therapy for primary cutaneous T-cell lymphomas: the first results of the use of brentuximab vedotin in the Russian Federation

Background. Primary cutaneous T-cell lymphomas are rare heterogeneous group of lymphoproliferative diseases characterized by primarily involving skin and subcutaneous adipose tissue. Half of these cases are mycosis fungoides (MF), for about 25% are cutaneous CD30+ lymphoproliferative diseases (CD30+ LPD): primary cutaneous anaplastic large cell lymphoma (pcALCL) and lymphomatoid papulosis (LyP). During the initiating treatment of patients with MF and Szary syndrome (SS), carried out on the territory of the Russian Federation, for about 30% of patients are resistant to various therapeutic effects, especially in the later stages. The problem of the treatment of CD30+ LPD is extracutaneous dissemination in case of pcALCL, steadily relapsing course of LyP without symptom-free intervals. These characteristics of the therapy of cutaneous lymphomas demand for the need to search for new treatment options. Brentuximab vedotin, according to the results of the international randomized ALCANZA trial, has shown high efficiency in the treatment of cutaneous T-cell lymphoproliferative diseases. Aim. To evaluate the efficacy of brentuximab vedotin application in patients with cutaneous T-cell lymphomas in adverse risk group received at least one line of systemic therapy. Materials and methods. The study included 21 patients: 16 men and 5 women. The diagnosis of MF was verified in 8 patients, SS in 5 patients, cutaneous CD30+ LPD in 6 patients (5 patients pcALCL, 1 patient LyP) and a primary cutaneous peripheral T-cell lymphoma, unspecified in 2 patients. The diagnosis of cutaneous T-cell lymphoma was verified on the basis of the anamnesis of the disease, on the character of cutaneous lesions, on histological, immunohistochemical and in some cases on molecular genetic testing of the biopted sample of the skin (the assessment of T-cell receptor gene rearrangement). Results. The late stages of the disease were diagnosed in 12 of 13 patients with MF/SS. Extracutaneous lesions were diagnosed in 57% of cases. The median of prior lines therapy was 3 (18 variants of treatment). The overall response to the treatment was achieved in 91% of cases (in 19 of 21 patients): the complete remission was obtained in 53% of cases, very good partial remission in 31% of cases and partial remission in 16% of cases. The progression of the disease was determined in 2 patients (after the first and fourth cycles). Some patients with partial remission as a result of therapy using brentuximab vedotin had the additional therapy (radiation therapy, interferon , the cycles of systemic therapy) and these acts gave an option of achieving deeper antitumor response. The early relapse was diagnosed in 2 of 19 patients who had responded to the treatment. The treatment tolerability was acceptable, and the toxicity did not exceed the already known one described in earlier studies. Thus, the stable overall antitumor response had been persisting in 89% of patients (the median of the observation was 10 months). Conclusion. The use of targeted therapy with brentuximab vedotin gave an option of achieving high treatment results in group of patients with advanced stages of the disease and inefficiency of several lines of therapy.

Effectiveness of a Short Term Induction Regimen of a Biosimilar Adalimumab in the Long Term Management of Symptomatic Ankylosing Spondylitis: A Community Based Proof of Concept Observational Study

Cost and drug toxicity often deter prolonged therapeutic use of anti TNF agents in ankylosing spondylitis (AS). A planned study was completed to endorse our clinic based observation of long term relief following short term administration of anti-TNF agent. Methods: 50 consenting patients with symptomatic active chronic AS under rheumatology care in a community clinic were enrolled. They had no past history of anti-TNF use. 40 mg standard biosimilar adalimumab (BS-ADA, Exemptia trade name)was injected subcutaneously every fortnight for six injections (10 weeks). Patients were monitored at several time points. Improvement was assessed at regular interval as per protocol which included standard indices (Bath and Assessment Spondyloarthritis International Society /ASAS). An intention to treat analysis with significant p<0.05 was carried out. Results: Patients showed early and substantial significant improvement in pain, NSAID requirement, function and in several indices (ASAS 20 & 40, ASAS partial remission, BASDAI, BASFI, ASDAS) which persisted after stopping injections. 84% and 52 % of patients respectively showed ASAS 20 improvement at week 12 and 48: corresponding ASAS partial remission 34% and 24%. Over 50% patients maintained prolonged improvement and provided proof of concept (defined a-priori). Serum Interleukin-6 assay showed a sharp reduction at 24 weeks. None developed TB or serious drug toxicity. 11 patients withdrew (mostly inadequate response). Absence of control was a limitation. Conclusion: A ten-week administration of biosimilar adalimumab in difficult to treat AS showed early substantial improvement which often persisted for 24 weeks. This unconventional strategy was socioeconomically appealing. It merits further validation and acceptance especially in resource strained settings.

Ixazomib Versus Lenalidomide or Ixazomib and Lenalidomide Combination As Maintenance Regimens for Patients with Multiple Myeloma: Interim Analysis of a Multi-Center Prospective Study in China

Background Maintenance therapy (MT) deepens response and prolongs progression free survival (PFS) in patients with newly diagnosed multiple myeloma (NDMM) after frontline regimens. Ixazomib, a 2 nd generation oral proteasome inhibitor (PI), has been approved for MT because of the convenience and tolerability. Aims We conducted this prospective multi-center study to compare the efficacy and safety of Ixazomib (I-MT) or Ixazomib plus Lenalidomide (IL-MT) to Lenalidomide (L-MT) as maintenance regimens in NDMM patients. Methods This study was approved by the Institutional Review Board of Peking Union Medical College Hospital and registered (NCT04217967). NDMM patients were enrolled from 10 centers of North China MM Registry since September 2019. After 4 cycles of front-line induction therapy, patients who reached partial response (PR) would receive autologous stem cell transplantation (ASCT) if eligible, or keep up to 5 cycles of front regimens if ineligible, then start maintenance therapy. Patients did not reach PR would switch to a 2nd-line induction for 2-5 cycles and start MT once PR was achieved. For MT, 4mg of Ixazomib was given on day 1,8,15, and 25mg of Lenalidomide every other day on days 1-21 of a 28-day cycle. Patients in dual drug group were administrated with both Ixazomib and Lenalidomide, dose as listed above. The primary endpoint was PFS from MT. Results A total of 149 patients were enrolled, including 54 in I-MT, 65 in L-MT and 30 in IL-MT. The demographic and clinical characteristics were comparable among three groups at baseline (Table 1), including gender ratio, age, paraprotein isotype, ISS, R-ISS, response status before MT, and ASCT rate. The proportions of patients with high-risk cytogenetic abnormalities (HRCAs), defined as amplification 1q21, deletion 17p, t(4,14) and t(14,16), were comparable. The median follow-up duration since MT was 6.1, 11.1, and 5.9 months in I-MT, L-MT and IL-MT group, respectively. Disease progression developed in 9.3%, 12.3% and 10% (N=5, 8, 3, respectively) patients. The median PFS was not reached (NR) in all groups. Only one death occurred in I-MT group. There were 84%, 72.3% and 83.3% of the patients reached very good partial response (VGPR) or better before MT, while the best response rates rose to 93%, 82.3% and 90% during maintenance. The prevalence of peripheral neuropathy was 18.5% on I-MT, 10.8% on L-MT and 30% on IL-MT. Grade 2 PN occurred in 3, 1, and 0 patients, respectively. The incidence of gastrointestinal events was 11.1%, 1.5% and 20%, respectively. Grade 3-4 hematologic toxicities was 3.7%, 4.6%, and 3.3%. Infection rates were 7.4%, 6.2% and 3.3%. Skin rashes were more common in lenalidomide containing regimens (3.7%, 7.3% and 6.7%). No drug withdrawal was related to adverse events. Conclusions Due to inadequate access to melphalan and low rate of ASCT in China, there is still a gap of PFS in NDMM patients with those in western countries. We herein design this multi-centered prospective study to evaluate if dual drug MT will further strengthen response and make up the gap. Though the primary endpoint--PFS has not been reached in all treatment groups, dual MT improves response most and is quite tolerable. Figure 1. Baseline Characteristics in three groups. Abbreviations: ISS: international staging system; R-ISS: revised-ISS; HRCAs: high risk cytogenetic abnormalities. sCR: stringent complete remission. CR: complete remission. VGPR: very good partial remission. PR: partial remission. * p ＜ 0.05. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

High-Dose Carfilzomib Recaptures Response in Relapsed/Refractory Multiple Myeloma Resistant to Low-Dose Carfilzomib By Co-Inhibiting β2 Subunit of Proteasome Complex: The First in Human Evidence

Background Proteasome, a complex involved in the intracellular protein degradation, consists of multiple subunits, but only three subunits have enzymatic activity to cleave and degrade proteins, namely β1, β2 and β5. Carfilzomib (CFZ), a second-generation proteasome inhibitor (PI), can induce cell death by selective and irreversible inhibition of β5 subunit of proteasome. Preclinical data suggested that high-dose CFZ could co-inhibit predominantly β2 proteasome activity, followed by β1 inhibition (Besse et al, Cell Chem Biol. 2019). Over the past few years, CFZ has become a corner stone for multiple myeloma (MM) therapy. Currently, CFZ is approved by the FDA in different dosing schedules in combination with lenalidomide or daratumumab and dexamethasone. However, the optimal CFZ dosing is still a matter of debate, with the approved dosage ranging from 20to 70mg/m 2 in different regimens. In addition, if response can be recaptured by escalating CFZ dose in patients progressing from low-dose CFZ has yet to be determined. The aim of our current study was to analyse the profile of proteasome inhibition in the respective dose cohorts and to elucidate if high-dose CFZ could recapture response in patients resistant to low-dose CFZ. Methods We prospectively collected clinical data and peripheral blood mononuclear cells (PBMC) of 32 patients with relapsed/refractory (RR) MM before and 1-8 hours after CFZ administration. PBMC were lysed and labelled for the activity of individual proteasome subunits using activity based proteasome probes and the proteasome subunits were separated using SDS-PAGE. The activity of constitutive and immunoproteasome β1, β2 and β5 subunits was evaluated by densitometry analysis and combination of the activity of constitutive and immunoproteasome individual subunit was used for further analysis. Results Overall, six, nine, twelve and five patients received CFZ at a dose of 20, 27, 36 and 56 mg/m 2, respectively. As expected, the total activity of proteasome decreased with higher doses of CFZ. Significant inhibition (median inhibition &gt; 50%) of β5 subunit was observed already at 20 mg/m 2 dose, while β2 subunit started to be co-inhibited only at a dose of ≥27 mg/m 2. Significant co-inhibition of β2 activity was seen at 36 mg/m 2 dose, at which also β1 subunit started to be co-inhibited. Finally, at 56 mg/m 2, the activity of all active subunits was inhibited with a median inhibition of &gt; 50%, with the strongest inhibition of the β5 subunit, followed by β2 and then β1. When we compared the patient groups low-dose CFZ (20 or 27 mg/m 2) versus high-dose CFZ (36 or 56 mg/m 2), we observed a significant difference in β2 (P=0.002) and β5 (P=0.02) subunit inhibition between the both groups. In terms of total proteasome activity, high-dose CFZ demonstrated a significantly higher proteasome inhibition in comparison with patients receiving low-dose CFZ (P=0.01). In brief, our results suggested that high-dose CFZ, in contrast to low-dose CFZ, could obtain superior proteasome inhibition by co-inhibiting β2 subunit of proteasome complex. In light of this finding, we successfully treated six RRMM patients who were resistant to low-dose CFZ with CFZ dose escalation. All six patients were heavily pretreated with 3-12 lines of therapy including daratumumab, two PIs, two immunomodulatory drugs and autologous stem cell transplant. Additionally, one and two patients received prior treatment with B-cell maturation antigen targeted bi-specific antibody and chimeric antigen receptor modified T-cell, respectively. In the last line of treatment, these six patients showed progression during CFZ based regimens with low-dose CFZ, namely 20 or 27 mg/m 2. We therefore increased the CFZ dose to 36 or 56 mg/m 2 and the doses of agents other than CFZ in the combination regimens remained the same. High-dose CFZ dose recaptured response in all six patients with four and two patients that achieved partial remission and very good partial remission, respectively, and the progression free survival ranged from 1-13 months. Conclusion In summary, high-dose CFZ, namely ≥ 36mg/m 2, showed more effective proteasome inhibition via blocking β5 and β2 subunits, while low-dose CFZ could not achieve a sufficient inhibition of β2 subunit. We provided the first in human evidence that high-dose CFZ could recapture response in RRMM patients resistant to low-dose CFZ by co-inhibiting the β2 subunit activity of proteasome complex. Figure 1 Figure 1. Disclosures Einsele: Janssen, Celgene/BMS, Amgen, GSK, Sanofi: Consultancy, Honoraria, Research Funding.