Treatment-refractory Group Research Articles

Lifetime cost-effectiveness analysis osseointegrated transfemoral versus socket prosthesis using Markov modelling.

Prior cost-effectiveness analyses on osseointegrated prosthesis for transfemoral unilateral amputees have analyzed outcomes in non-USA countries using generic quality of life instruments, which may not be appropriate when evaluating disease-specific quality of life. These prior analyses have also focused only on patients who had failed a socket-based prosthesis. The aim of the current study is to use a disease-specific quality of life instrument, which can more accurately reflect a patient's quality of life with this condition in order to evaluate cost-effectiveness, examining both treatment-naïve and socket refractory patients. Lifetime Markov models were developed evaluating active healthy middle-aged male amputees. Costs of the prostheses, associated complications, use/non-use, and annual costs of arthroplasty parts and service for both a socket and osseointegrated (OPRA) prosthesis were included. Effectiveness was evaluated using the questionnaire for persons with a transfemoral amputation (Q-TFA) until death. All costs and Q-TFA were discounted at 3% annually. Sensitivity analyses on those cost variables which affected a change in treatment (OPRA to socket, or socket to OPRA) were evaluated to determine threshold values. Incremental cost-effectiveness ratios (ICERs) were calculated. For treatment-naïve patients, the lifetime ICER for OPRA was $279/quality-adjusted life-year (QALY). For treatment-refractory patients the ICER was $273/QALY. In sensitivity analysis, the variable thresholds that would affect a change in the course of treatment based on cost (from socket to OPRA), included the following for the treatment-naïve group: yearly replacement components for socket > $8,511; cost yearly replacement parts OPRA < $1,758; and for treatment-refractory group: yearly replacement component for socket of > $12,467. The use of the OPRA prosthesis in physically active transfemoral amputees should be considered as a cost-effective alternative in both treatment-naïve and treatment-refractory socket prosthesis patients. Disease-specific quality of life assessments such as Q-TFA are more sensitive when evaluating cost-effectiveness.

Abstract A158: Rational development of synergistic therapies alongside BMI1 Inhibition for group 3 medulloblastoma

Abstract Medulloblastoma (MB) is the most common malignant pediatric brain tumor. Of its four distinct molecular subgroups, Group 3 MBs are associated with increased risk of recurrence, metastasis and overall poor patient outcome. In recent years, small molecule inhibitors that decrease BMI1 expression have shown to be efficacious against several types of malignant tumors including pediatric MB. Although in vivo studies provide a promising proof-of-concept for the therapeutic targeting of BMI1 in Group 3 MB, mice that receive treatment eventually succumb to their disease. These results suggest that additional mechanisms may underlie the maintenance of MB and underscore the main obstacle in treating a constantly evolving tumor. After initial preclinical validation of BMI1 inhibitor PTC-596, DNA barcoding clonal tracking technology was leveraged to profile in vivo clonal dynamics of Group 3 MB in response to the established chemoradiotherapy regimen alone and in combination with PTC-596. Comparison of clonal composition of tumors extracted from brains and spines post-treatment revealed the persistence of a small number of clones with the ability to escape therapy and drive subsequent tumor expansion. In order to better understand molecular susceptibilities of MB cells post-BMI1 inhibition, we undertook an in vitro genome-wide CRISPR/Cas9 screening to identify context-specific MB regulatory pathways that could be synergistically targeted along with BMI1. By comparing the results of the in vitro genome wide CRISPR/Cas9 screen to the essential genes in human neural stem cells (hNSCs), we identified several context specific regulators of mTOR, AKT and PLK1 pathways. Combination treatment alongside PTC-596 has demonstrated synergistic efficacy against MB cells with minimal toxicity to hNSCs in vitro and in preclinical in vivo studies. This study provides the foundation for clinical validation of small-molecule inhibitors synergistic with PTC-596 to improve the durability of remissions and extend survival of patients with treatment-refractory Group 3 MB. Citation Format: David Bakhshinyan, Stefan Custers, Ashley Adile, Kevin Brown, Maleeha Qazi, Chirayu Chokshi, Laura Escudero, Yujin Suk, Chitra Venugopal, Jason Moffat, Sheila Singh. Rational development of synergistic therapies alongside BMI1 Inhibition for group 3 medulloblastoma [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A158.

Vestibular and audiometric results after endolymphatic mastoid shunt surgery in patients with Menière’s disease

PurposeTreatment of Menière’s Disease (MD) comprises an array of both non-destructive and destructive treatment options. In patients who are therapy–refractory to non-destructive medical treatment, endolymphatic mastoid shunt surgery (EMSS) is both recommended and debated controversially. The aim of this study was to investigate safety in terms of hearing, vestibular function, complication rate, and efficacy with regards to vertigo control of EMSS in patients with MD according to the current diagnostic criteria of 2015.MethodsRetrospective analysis of 47 consecutive patients with definite or probable MD with description of demographic parameters, pre- and postoperative MD treatment, pre- and postoperative audiometric (pure tone audiometry) and vestibular (caloric testing) results. The parameters were compared between patients with and without postoperative vertigo control.Results31/47 patients (66.0%) had improved vertigo control postoperatively. Postoperative hearing and vestibular preservation were predominantly stable. No significant differences between patients with improved vertigo control and patients with no change or worse vertigo episodes were found. In the treatment refractory group, 4 patients required a revision EMSS and 6 a destructive MD treatment (5 gentamicin intratympanically, 1 labyrinthectomy). No peri- or postsurgical complications were reported.ConclusionsEMSS was found to be beneficial in two thirds of the patients with definite or probable Morbus Menière and a safe procedure regarding hearing and vestibular preservation with no postoperative complications. Therefore, EMSS should be considered before inducing destructive treatment options, such as intratympanic gentamicin application or labyrinthectomy.

Immunologic Basis of Type 2 Biologics for Severe Asthma.

Asthma is a chronic airway inflammatory disease characterized by reversible airway obstruction and airway hyperreactivity to various environmental stimuli, leading to recurrent cough, dyspnea, and wheezing episodes. Regarding inflammatory mechanisms, type 2/eosinophilic inflammation along with activated mast cells is the major one; however, diverse mechanisms, including structural cells-derived and non-type 2/neutrophilic inflammations are involved, presenting heterogenous phenotypes. Although most asthmatic patients could be properly controlled by the guided treatment, patients with severe asthma (SA; classified as a treatment-refractory group) suffer from uncontrolled symptoms with frequent asthma exacerbations even on regular anti-inflammatory medications, raising needs for additional controllers, including biologics that target specific molecules found in asthmatic airway, and achieving the precision medicine for asthma. This review summarizes the immunologic basis of airway inflammatory mechanisms and current biologics for SA in order to address unmet needs for future targets.

EMBR-22. RATIONAL DEVELOPMENT OF SYNERGISTIC THERAPIES ALONGSIDE BMI1 INHIBITION FOR GROUP 3 MEDULLOBLASTOMA

Medulloblastoma (MB) is the most common pediatric brain tumor. Of its four distinct molecular subgroups, Group 3 MBs are associated with increased risk of recurrence, metastasis and overall poor patient outcome. In recent years, small molecule inhibitors targeting BMI1 have shown to be efficacious against several types of malignant tumors including pediatric MB. Although in vivo studies provide a promising proof-of-concept for the therapeutic targeting of BMI1 in Group 3 MB, mice that receive treatment eventually succumb to their disease. These results suggest that additional mechanisms may underlie the maintenance of MB and underscores the main obstacle in treating a constantly evolving tumor. After initial preclinical validation of BMI1 inhibitor PTC-596, DNA barcoding clonal tracking technology was leveraged to profile in vivo clonal dynamics of Group 3 MB in response to the established chemoradiotherapy regimen alone and in combination with PTC-596. Comparison of clonal composition of the tumors extracted from the brains and spines post-treatment revealed the persistence of a small number of clones with the ability to escape therapy and drive subsequent tumor expansion. In order to better understand molecular susceptibilities of MB cells post BMI1 inhibition, we undertook an in vitro genome-wide CRISPR/Cas9 screening to identify context-specific MB regulatory pathways to be synergistically targeted along with BMI1. By comparing the results of the in vitro genome wide CRISPR/Cas9 screen to the essential genes in human neural stem cells (hNSCs), we identified several context specific regulators of mTOR, AKT and PLK1 pathways. The combined treatment alongside PTC-596 has demonstrated synergistic efficacy against MB cells with minimal toxicity to hNSCs in vitro and is currently being evaluated in preclinical studies. This study provides the foundation for clinical validation of small-molecule inhibitors synergistic with PTC-596 to improve the durability of remissions and extend survival of patients with treatment-refractory Group 3 MB.

DOP71 Efficacy, safety, and tolerability of ustekinumab in paediatric patients with moderately to severely active Crohn’s disease: Results from, UniStar, a phase 1 study

Abstract Background Ustekinumab (UST) is approved for the treatment of adults with moderate to severe Crohn’s disease (CD). The objective of this study was to evaluate the pharmacokinetics (PK), safety, and efficacy of UST in paediatric patients with moderately to severely active CD who had failed treatment with corticosteroids (CS) and/or immunomodulators (IM) and/or anti-tumour necrosis factor (TNF) therapies. Here, we report the safety and efficacy results through Week 16; PK results are reported separately. Methods This was a Phase 1, multicentre, 16-week, double-blind induction dose-ranging study (NCT02968108) in patients aged 2 to &amp;lt;18 years (body weight [BW] ≥10 kg) with a Paediatric CD Activity Index (PCDAI) score &amp;gt;30 and at least an abnormal C-reactive protein &amp;gt;3.0 mg/l or faecal calprotectin &amp;gt;250 µg/g), or ulcerations in the ileum or colon upon ileocolonoscopy despite adequate treatment with CS ± IM ± anti-TNF therapy. Patients were randomised (1:1) and stratified by weight and prior anti-TNF use for induction to one of 2 weight range-based intravenous (IV) doses: 130mg vs. 390 mg if BW ≥40 kg and 3 mg/kg vs. 9 mg/kg if BW &amp;lt;40 kg. At week 8, all patients received a single subcutaneous (SC) UST maintenance dose of 90mg if BW ≥40 kg or 2 mg/kg if BW &amp;lt;40 kg. Results Forty-four patients (59% ≥40kg BW; &amp;gt;90% anti-TNF exposed) were randomised (n = 23 lower dose; n = 21 higher dose) and treated with UST. Baseline characteristics are summarised in Table 1. At week 16, in the lower dose and higher dose groups, 52%/52% achieved clinical response (reduction in PCDAI ≥15) and 22%/29% had clinical remission (PCDAI ≤10), respectively (Table 2). In addition, 32% and 28% of patients showed endoscopic response (reduction in Simple Endoscopic Score for CD of ≥50%), respectively. Through week 16, 73% of patients reported ≥1 adverse event (AE; 82.6% lower dose vs. 62% higher dose); 2 discontinued due to AEs (1 in each group). Serious AEs occurred in 16% of patients (26% lower dose and 5% higher dose, with CD exacerbation being the most frequent (13%/5%, respectively). Infections occurred in 41% of patients (1 was serious, which was intestinal abscess that spontaneously resolved with sequelae). No injection site reactions, opportunistic infections, malignancies, or deaths were reported. No antibodies to UST were observed. Conclusion As early as 3 weeks and through 16 weeks, both the lower and higher doses of UST (IV week 0 and SC at week 8) improved clinical and endoscopic disease activity in this previously treatment-refractory group of children with CD. The safety profile was consistent with that for UST in adults with CD.

P714 Real-world effectiveness of vedolizumab in ulcerative colitis: Week 52 results from the Swedish multi-centre, prospective, observational SVEAH UC study

Abstract Background Clinical trials may not readily reflect clinical practice. We aimed to assess the clinical effectiveness of vedolizumab in a real-world cohort of patients with ulcerative colitis (UC). Methods This is a prospective, observational, multi-centre cohort study. Eligible patients had active UC confirmed by a Mayo endoscopic subscore ≥2 at initiation of vedolizumab and had started treatment from 1/6/2015. Exclusion criteria included concurrent participation in a clinical trial in which UC treatment is dictated and contraindications to vedolizumab. All patients provided a written consent. Data on clinical characteristics, treatment patterns, disease activity and the short health scale were recorded at baseline and prospectively, using an electronic Case Record Form, integrated with the Swedish National Quality Registry for IBD (SWIBREG). The primary outcomes were A) clinical response, defined as a decrease in partial Mayo score of ≥2 and a reduction of ≥25 % from baseline, with a decrease ≥1 on the rectal bleeding score or an absolute rectal bleeding score of 0 or 1, at week 12 and B) clinical remission, defined as a partial Mayo score &amp;lt;2, at week 52. Continuous data are presented as median (interquartile range). Differences between baseline and follow-up visits were assessed by the Wilcoxon-signed rank test. Results In total, 117 eligible UC patients were included during the study period 1/6/2015 to 2/6/2018. Clinical and demographical characteristics of patients are shown in Table 1; 101/117 (86%) patients had failed prior anti-TNF therapy. The drug persistence rate was 106/117 (91%) at 12 weeks and 79/117 (68%) at 52 weeks. The clinical response rate at 12 weeks was 59/117 (50%) and the clinical remission rate at 52 weeks was 57/117 (49%). Altogether, 35/117 (30%) had an endoscopic Mayo score ≤1 at 12 weeks and 41/117 (35%) at 52 weeks. However, data on endoscopy were not available for 42 vedolizumab treated patients at 12 weeks and 30 at 52 weeks. Among patients who continued vedolizumab, the median partial Mayo score decreased from 4 (3–5) at baseline to 1 (0–2) at 52 weeks (p &amp;lt; 0.0001). Correspondingly, the median faecal calprotectin decreased from 646 (333–1130) µg/g to 162 (42–382) µg/g (p = 0.0002) and the median C-reactive protein from 5.0 (2.1–8.0) mg/L to 3.5 (1.6–5.0) mg/L (p = 0.008). Consistently, quality of life improved in vedolizumab treated patients, with a significant reduction of the overall short health scale score at 52 weeks (p &amp;lt; 0.0001). Conclusion Vedolizumab treated patients with UC represented a treatment-refractory group. Long-term (52 weeks) effectiveness of vedolizumab can be achieved, in terms of clinical- and inflammatory activity as well as in quality of life. The study was financially supported by Takeda.

Clinical effectiveness of golimumab in Crohn’s disease: an observational study based on the Swedish National Quality Registry for Inflammatory Bowel Disease (SWIBREG)

Objective: The effectiveness of golimumab in Crohn’s disease (CD) is largely unknown as it is not approved for the treatment of the disease. We aimed to identify the population of CD patients treated with golimumab in Sweden, to assess the effectiveness of golimumab (defined as the drug retention rate), and to identify predictors of drug discontinuation.Methods: Patients with CD who received at least one injection of golimumab were identified through the Swedish National Quality Registry for Inflammatory Bowel Disease, which includes prospectively collected clinical information. Cox regression models were used to identify predictors of golimumab discontinuation.Results: The study cohort involved 94 patients of whom the majority (96.8%) had previously discontinued at least one anti-tumour necrosis factor (anti-TNF) agent. The drug retention rate at 12 weeks was 85.1%. Predictors of golimumab discontinuation at 12 weeks were previous surgery (adjusted HR = 7.52, 95% CI: 1.12–50.36), concomitant corticosteroid use at baseline (adjusted HR = 5.70, 95% CI: 1.13–28.68) and female sex (adjusted HR = 6.59; 95% CI: 1.04–41.62). The median duration of follow-up was 89 (IQR: 32–158) weeks. The drug retention at the most recent follow-up was 35.1%. Predictors of golimumab discontinuation at the most recent follow-up were corticosteroid use at baseline (adjusted HR = 2.60, 95% CI: 1.17–5.79) and female sex (adjusted HR = 2.24; 95% CI: 1.19–4.23).Conclusion: Patients with CD treated with golimumab were a treatment-refractory group. Despite this, more than one-third of the patients appeared to have had clinical benefit after a median follow-up of more than 1.5 years.

Trajectories of depressive symptoms in the acute phase of psychosis: Implications for treatment

Depression is common in schizophrenia and associated with negative outcomes. Previous studies have identified heterogeneity in treatment response in schizophrenia. We aimed to investigate different trajectories of depression in patients suffering from psychosis and predictors of change in depressive symptoms during antipsychotic treatment. Two hundred and twenty-six patients >18 years acutely admitted due to psychosis were consecutively included and the follow-up was 27 weeks. The Calgary Depression Scale for Schizophrenia (CDSS) sum score was the primary outcome. Latent growth curve (LGCM) and Growth Mixture Models (GMM) were conducted. Predictors were the Positive sum score of the Positive and Negative Syndrome Scale for Schizophrenia (PANSS), Schizophrenia spectrum/non-spectrum psychoses, gender and being antipsychotic naive at inclusion. We found support for three depression-trajectories, including a high- (14.7%), a low depression-level (69.6%) class and a third depressed class quickly decreasing to a low level (15.7%). Change in CDSS was associated with change in PANSS positive score in all time intervals (4 weeks: b = 0.18, p < 0.001, 3 months: 0.21, p < 0.023, 6 months: 0.43, p < 0.001) and with a diagnosis within schizophrenia spectrum but not with antipsychotic naivety or gender. The schizophrenia-spectrum patients had less depressive symptoms at inclusion (−2.63, p < 0.001). In conclusion, an early responding and a treatment refractory group were identified. The treatment-refractory patients are candidates for enhanced anti-depressive treatment, for which current evidence is limited. The post-psychotic depression group was characterized by depressive symptoms in the acute phase as well. We could not identify differentiating characteristics of the depression trajectories.

P758 Clinical effectiveness of vedolizumab: Interim analysis of the Swedish observational study on vedolizumab assessing effectiveness and healthcare resource utilisation in patients with Crohn’s disease (SVEAH CD)

Clinical trials may not appropriately reflect real-world clinical practice. Therefore, we aimed to assess the clinical effectiveness of vedolizumab in a real-world Crohn’s disease (CD) cohort. This is a prospective, observational, multi-centre cohort study. Eligible patients had active CD confirmed by The presence of ulcers at colonoscopy, contrast enhancement, bowel thickening, or combs sign at magnetic resonance imaging, C-reactive protein (CRP) >upper threshold, Hs-CRP >2.87 mg/l or f-Calprotectin >200 µg/g at initiation of vedolizumab therapy and had started treatment with vedolizumab from 1/6/2015. Exclusion criteria included concurrent participation in a clinical trial in which IBD treatment is dictated by a study protocol and contraindications to vedolizumab. All patients provided a written consent. Data on clinical characteristics, treatment, disease activity and the short health scale (SHS) were recorded at baseline and prospectively, using an electronic Case Record Form, integrated with the Swedish National Quality Registry for IBD (SWIBREG). Data on the patients who had completed the 52 week follow-up are presented. The primary outcome at week 52 was clinical remission, defined as a Harvey Bradshaw Index (HBI) <5. Continuous data are presented as median (interquartile range). Differences between baseline and week 52 were assessed by the Wilcoxon-signed rank test. In total, 169 CD patients had been included by 19/09/2017. Clinical characteristics of patients (n = 104) who had completed the 52 week study period are shown in Table 1; 95/104 (91%) patients had failed prior anti-TNF therapy. At week 52, 71/104 (68%) were still on treatment with vedolizumab and 45/104 (43%) had achieved clinical remission. Among the 71 patients who had continued vedolizumab treatment, a decrease in the median HBI [6 (3–10) vs. 3 (2–5.5); n = 68; p < 0.001], median CRP [4.0 (2.0–10) g/l vs. 3.0 (1.4–5.0) g/l; n = 67; p = 0.01] and median f-Calprotectin [561 (139.5–830) vs. 232.5 (77.5–464) µg/g; n = 36; p = 0.09] was observed from baseline to week 52. Consistently, quality of life improved, defined by a significant reduction of the overall SHS score (n = 68; p < 0.001). Vedolizumab treated patients represented a treatment-refractory group. Significant improvements in clinical- and inflammatory activity, as well as in quality of life, were observed in patients who continued treatment through to week 52. The study was financially supported by Takeda.

Identification of factors associated with treatment refractoriness of oral lesions in pemphigus vulgaris.

The oral mucosal lesions of patients with pemphigus vulgaris are known to show more treatment refractoriness than skin lesions. To identify which clinical and laboratory parameters may indicate treatment refractoriness of oral lesions in pemphigus vulgaris. This was a prospective study of 50 adults with pemphigus vulgaris and oral lesions; patients were given treatment appropriate for overall disease severity. Treatment refractoriness was defined arbitrarily as less than 75% reduction in oral objective Autoimmune Bullous Skin Disorder Intensity Score (ABSIS) after treatment for 6 months. Of 46 patients who completed the study, 17 (37%) were treatment refractory whereas 29 (63%) were treatment responsive. At baseline, the treatment refractory group had a significantly longer mean duration of disease (P = 0·02) and mean duration of oral lesions (P = 0·01), a higher percentage of lesions in the retromolar trigone (P = 0·05) and on the occlusion line along the buccal mucosa (P = 0·04), a higher percentage of deep/crateriform ulcers (P < 0·001) and erosions with a lichenoid hue (P < 0·001). Herpes simplex virus (HSV) DNA positivity, assessed by polymerase chain reaction in oral tissue scrapings (P = 0·02), was also significantly higher in the treatment refractory group. No other factors we tested for were statistically significant. Treatment refractoriness of oral lesions was significantly associated with duration of disease/oral lesions; specific morphology and location of oral lesions; and the presence of HSV DNA in the oral cavity. These factors may forewarn the treating physician about a refractory course of oral lesions that may help with counselling patients.

Long-term effectiveness of vedolizumab in inflammatory bowel disease: a national study based on the Swedish National Quality Registry for Inflammatory Bowel Disease (SWIBREG)

Objectives: Clinical trials have demonstrated the efficacy of vedolizumab in inflammatory bowel disease (IBD). However, these findings may not reflect the clinical practice. Therefore, we aimed to describe a vedolizumab-treated patient population and assess long-term effectiveness.Materials and methods: Patients initiating vedolizumab between 1 June 2014 and 30 May 2015 were identified through the Swedish National Quality Registry for IBD. Prospectively collected data on treatment and disease activity were extracted. Clinical remission was defined as Patient Harvey Bradshaw index <5 in Crohn’s disease (CD) and Patient Simple Clinical Colitis Activity index <3 in ulcerative colitis (UC).Results: Two-hundred forty-six patients (147 CD, 92 UC and 7 IBD-Unclassified) were included. On study entry, 86% had failed TNF-antagonist and 48% of the CD patients had undergone ≥1 surgical resection. After a median follow-up of 17 (IQR: 14–20) months, 142 (58%) patients remained on vedolizumab. In total, 54% of the CD- and 64% of the UC patients were in clinical remission at the end of follow-up, with the clinical activity decreasing (p < .0001 in both groups). Faecal-calprotectin decreased in CD (p < .0001) and in UC (p = .001), whereas CRP decreased in CD (p = .002) but not in UC (p = .11). Previous anti-TNF exposure (adjusted HR: 4.03; 95% CI: 0.96–16.75) and elevated CRP at baseline (adjusted HR: 2.22; 95% CI: 1.10–4.35) seemed to be associated with discontinuation because of lack of response. Female sex was associated with termination because of intolerance (adjusted HR: 2.75; 95% CI: 1.16–6.48).Conclusion: Vedolizumab-treated patients represent a treatment-refractory group. A long-term effect can be achieved, even beyond 1 year of treatment.

The Validity of a Scoring System in Predicting Intravenous Immunoglobulin Treatment Failure in Children With Kawasaki Disease

Background: Between 10 and 20% of children with Kawasaki disease (KD) will not respond to intravenous immunoglobulin (IVIG) treatment, and are prone to coronary abnormalities. A variety of predicting scoring systems, including the Kobayashi system, have been proposed, but have not yet been evaluated using Iranian patients. Objectives: To evaluate the Kobayashi scoring system with regard to predicting response to IVIG treatment in Iranian children. Patients and Methods: All patients who received a final diagnosis of KD at Aliasghar children’s hospital between 1982 and 2013, and who met the inclusion criteria, were enrolled in this retrospective cohort study. We excluded patients with missing data, abnormal echocardiographic finding on admission, late admission, atypical or afebrile cases, and those who had received an insufficient amount of IVIG. We compared demographic and echocardiographic data before IVIG, and within 7 days of treatment, as well as C reactive protein (CRP), sodium, aspartate aminotransferase, platelet levels, neutrophil percentage, age of patients, and duration of fever before IVIG administration, in treatment responders and non-responders. Results: Of the 141 cases, 97 patients met the criteria and were enrolled. Of these, 19 (19.6%) did not respond to IVIG. A total of 61.8% of patients were male, and the mean patient age was 36.9 months (SD = 32.1 months). Echocardiographic evaluation revealed early coronary involvement in 15.3% of patients, and coronary abnormalities were diagnosed in 10% of patients within the first 10 days of presentation and concurrent with their IVIG treatment. A between-groups comparison of quantitative CRP, absolute neutrophil count, and platelet count showed that platelet count alone was significantly higher in nonresponders (P = 0.04). With regard to items of Kobayashi scoring system, data were present for just 41 cases, but a significant difference between the two groups was shown, with the treatment-refractory group having a significantly higher score (P = 0.002). Receiver-operating characteristic curve analysis revealed that the optimum cut-off point for our population would be 2, which makes the sensitivity of the test equal to 75%, with a specificity of 60%. Conclusions: This preliminary study showed that patients with KD and a high Kobayashi score are at greater risk of being unresponsive to IVIG treatment. Further studies, preferably multicenter evaluations, are required in order to understand the exact application of various scoring systems in the management of people with KD in Iran.

Induced production of anti-etanercept antibody in collagen-induced arthritis

Etanercept is a widespread biological drug for the treatment of rheumatoid arthritis, which inhibits tumor necrosis factor-α (TNF-α). Recently, the presence of antibodies targeting TNF-α inhibitors such as infliximab and adalimumab, was reported. However, few reports have studied etanercept in a mouse model of arthritis. We investigated the induction of anti-etanercept antibody production, along with the antibody's potential interfering effects on the biological function of etanercept, in mice with collagen-induced arthritis (CIA). CIA mice received an intraperitoneal injection of etanercept (25, 100 or 400 µg per mouse). The degree of inflammation and cartilage erosion was evaluated, and the number of osteoclasts in the ankle joints was assessed by TRAP staining. The level of pro-inflammatory cytokines in the serum was measured. To analyze the anti-osteoporotic effect of etanercept, microfocal computed tomography analyses of femurs and tibias were performed. Etanercept treatment decreased both the incidence and severity of arthritis in a dose-dependent manner, except for the highest dose of 400 µg. The mice that were treated with 25 and 100 µg etanercept showed an improvement in inflammation, cartilage damage, and even bone loss. However, mice treated with 400 µg etanercept showed no significant improvement in any of the tested parameters. Using a customized enzyme-linked immunosorbent assay (ELISA), the presence of the anti-etanercept antibody was detected in the serum in this treatment-refractory group. The therapeutic effect of etanercept was reduced in the CIA mice that developed the anti-etanercept antibody. In conclusion, the production of an anti-etanercept antibody can be induced in CIA mice, and this antibody can considerably reduce the anti-arthritic and anti-osteoporotic effects of etanercept.

Decrease ADHD Symptoms, and Pounds May Follow

Back to table of contents Previous article Next article Clinical & Research NewsFull AccessDecrease ADHD Symptoms, and Pounds May FollowJoan Arehart-TreichelJoan Arehart-TreichelSearch for more papers by this authorPublished Online:3 Apr 2009https://doi.org/10.1176/pn.44.7.0018aQuite a bit of research has linked depression and obesity. Now some researchers have coupled attention-deficit/hyperactivity disorder (ADHD) to obesity as well.Moreover, they have found that treating ADHD in obese individuals who have it seems to help them lose weight.“This is an intriguing and potentially important preliminary study,” Michael Devlin, M.D., a Columbia University psychiatrist and eating disorders authority, told Psychiatric News. Its findings suggest that a number of obese people have ADHD and that treating their ADHD can help them lose weight. The lead investigator was Lance Levy, M.S., a Toronto nutritional scientist who runs a private referral practice for obesity management. Results were published online on February 17 in the International Journal of Obesity.Levy and his coworkers found that over a quarter of 75 severely obese patients referred to their practice reported having ADHD symptoms as children and as adults. Screening of an additional 190 consecutively referred severely obese patients revealed that over a third had ADHD. Furthermore, most of these patients had tried to lose weight but had failed to do so.Levy and his colleagues thus suspected that some of the symptoms triggered by ADHD—say, inattention, restlessness, distractibility, impulsivity, and novelty seeking—might have sabotaged the weight-loss efforts of patients who had ADHD. Indeed, other research has shown that the personality trait of novelty seeking is strongly associated with obesity in the general population and with obese individuals' difficulty in losing weight (Psychiatric News, May 18, 2007). So Levy and his coworkers launched a study to see whether ADHD treatment might help obese persons achieve long-term weight loss.The subjects were 78 severely obese individuals who had been diagnosed for ADHD through clinical interviews. All had tried to lose weight for at least a decade, but had failed. All of the subjects were offered medication treatment for their ADHD. Sixty-five of them accepted medication treatment; the remaining 13 did not. The researchers then followed all of the subjects for at least a year to see whether there was any difference in weight loss between the 65 subjects who were receiving ADHD medication and the 13 subjects who were not. At the end of that period, the group that had received medication had lost 12 percent of their initial weight, whereas the group that had not received medication had gained 3 percent of their initial weight. This difference was highly significant statistically.“ADHD should be considered a primary cause of weight-loss failure in the obese,” Levy and his coworkers concluded in their study report.“ Screening for ADHD should become part of the diagnostic assessment for the management of severe obesity.”The study had some weaknesses, Devlin pointed out. For example, it did not include a randomized, control group. It is possible that the psychostimulants used to treat ADHD in 65 of the subjects promoted weight loss not by treating ADHD but by suppressing appetite and increasing energy expenditure.“It is also important,” he noted, “to recognize that the participant pool consisted of severely obese treatment-refractory individuals seeking further treatment, so the results cannot be generalized to all obese individuals.”Nonetheless, he said, “that about a third of the severely obese treatment-refractory group were diagnosed with ADHD based on a careful assessment is very thought provoking.... For me, the one thing that this study points to is the utility of carefully identifying and treating both medical and psychiatric comorbid conditions and the degree to which this can improve weight outcomes in those with severe and/or treatment-refractory obesity.”The study had no outside funding.An abstract of “Treatment of Refractory Obesity in Severely Obese Adults Following Management of Newly Diagnosed Attention-Deficit/Hyperactivity Disorder” is posted at<www.nature.com/ijo/journal/vaop/ncurrent/abs/ijo20095a.html>.▪ ISSUES NewArchived

Policy makers ignoring science and scientists ignoring policy: the medical ethical challenges of heroin treatment

A decade of research in Switzerland, The Netherlands, Germany, and Spain now constitutes a massive body of work supporting the use of heroin treatment for the most difficult patients addicted to opiates. These trials concur on this method's safety and efficacy and are now serving as a prelude to the institution of heroin treatment in clinical practice throughout Europe.While the different sampling and research protocols for heroin treatment in these studies were important to the academic claims about specific results and conclusions that could be drawn from each study, the overall outcomes were quite clear – and uniformly positive. They all find that the use of prescribed pharmaceutical heroin does exactly what it is intended to do: it reaches a treatment refractory group of addicts by engaging them in a positive healthcare relationship with a physician, it reduces their criminal activity, improves their health status, and increases their social tenure through more stable housing, employment, and contact with family.The Canadian trial (NAOMI), now underway for over a year, but not yet completed, now faces a dilemma about what to do with its patients who have successfully completed 12 months of heroin and must be withdrawn from heroin and transferred to other treatments in accordance with the research protocol approved by Government of Canada, federal granting body and host institutions. The problem is that the principal criterion for acceptance to NAOMI was their history of repeated failure in these very same treatment programs to which they will now be referred.The existence of the results from abroad (some of which were not yet available when NAOMI was designed and initiated) now raises a very important question for Canada: is it ethical to continue to prohibit the medical use of heroin treatment that has already been shown to be feasible and effective in numerous medical studies throughout the world? And while this is being worked out, is it acceptable to require patients who have been successfully treated with heroin in Canada, to be forced to move back to less effective treatments (treatments that failed to be efficacious in the past)?This essay discusses this dilemma and places it in the broader context of ethics, science, and health policy. It makes the case for continuation of the current successful patients in heroin treatment and the institution of heroin treatment to all Canadian patients living with active addictions who qualify.

No seizure exacerbation from risperidone in youth with comorbid epilepsy and psychiatric disorders: a case series.

The aim of this study was to study risperidone use in pediatric patients with comorbid epilepsy and psychiatric disorders. We retrospectively reviewed the outpatient psychopharmacology medical records of patients with epilepsy, aged 19 and younger, who received risperidone for psychiatric disorders. Twenty-one (21) youths (mean age, 12.0 +/- 4.2 years) met our criteria for review. Mean risperidone dosage was 2.4 +/- 3.5 mg/day. Target symptoms included severe aggression, severe agitation, psychosis, and self-injurious behavior. Diagnoses included attention-deficit hyperactivity disorder (ADHD), learning disorder, and impulse control disorder. Seizure type was partial complex in 12 patients, generalized in 6 patients, neonatal in 1 patient, myoclonic in 1 patient, and unclassified in 1 patient. The average number of previous psychotropic trials was 3.5 +/- 3.0. Using a definition of response of a Clinical Global Impressions (CGI) improvement score of 2 or less, 15 patients (71%) were considered responders. Adverse effects were none to slight in 16 patients, moderate in 4 patients, and severe in 1 patient. Seizures did not worsen in any patient. Risperidone was associated with a clinically significant global improvement, without seizure exacerbation in youths with epilepsy and psychiatric disorders. Despite the limitations of the study design, the 71% responder rate is noteworthy in this treatment-refractory group.

Psychiatric Care Lowers IBS Treatment Costs

Back to table of contents Previous article Next article Clinical & Research NewsFull AccessPsychiatric Care Lowers IBS Treatment CostsMark MoranMark MoranSearch for more papers by this authorPublished Online:21 Mar 2003https://doi.org/10.1176/pn.38.6.0029Both psychotherapy and paroxetine appear to improve health-related quality of life for patients with irritable bowel syndrome (IBS), and at no additional cost.“Improvement in overall health-related quality of life is possible even if the pain does not greatly improve,” said Francis Creed, M.D., a professor of psychological medicine at the university department of psychiatry at Manchester Royal Infirmary in Manchester, England.“If patients with severe IBS do not respond to usual treatment, an SSRI antidepressant or referral to psychotherapy is worth trying,” Creed told Psychiatric News. “Exploration of psychological problems, even if they are not very severe, may well lead to improvement in health-related quality of life.”Creed and colleagues published results comparing psychotherapy and paroxetine for IBS in the February issue of Gastroenterology.In the study, 257 subjects treated at seven British hospitals for IBS were randomized to receive either psychotherapy, 20 mg of paroxetine for a period of three months, or treatment as usual—defined as whatever treatment was deemed appropriate by the patient’s treating physician.Psychotherapy consisted of one two-hour and seven 45-minute sessions of “psychodynamic interpersonal therapy” delivered over three months.Creed and colleagues found at one-year follow-up that abdominal pain was similar in all three groups. But both psychotherapy and paroxetine were superior to treatment as usual in improving the physical aspects of health-related quality of life, as measured by the SF36 Health Survey.Importantly, psychotherapy—but not paroxetine—was associated with a significant reduction of health care costs compared with treatment as usual. Psychotherapy was associated with a total cost of $976 (U.S. dollars) compared with paroxetine at a cost of $1,252.Treatment as usual was associated with a cost of $1,663, according to the study.Creed says that many patients with irritable bowel syndrome typically don’t seek treatment at all or use over-the-counter products that may not be helpful. Most patients who do seek help from a gastroenterologist achieve some success with dietary modifications and antispasmodic or other medical therapies.Yet a sizable cohort remains that is not helped, Creed says. And it is among this treatment-refractory group that the highest prevalence of psychiatric illness is found.Mind-Body InteractionCreed and others say IBS is a condition that highlights the mental and emotional component of much medical illness, refuting the traditional dichotomy of mind and body. Among clinic patients with IBS, approximately 50 percent have significant anxiety and depression, Creed said.“For some patients there is primarily an infective, dietary, or other cause,” she told Psychiatric News. “For a small number of people it is primarily anxiety and depression. For the majority, however, there is a physical component together with a psychological component.”Constantine Lyketsos, M.D., a professor of psychiatry and behavioral sciences at Johns Hopkins University School of Medicine, called the study “extremely important,” noting that there have been few controlled cost-effectiveness studies of the best way to treat IBS.Study Proves Treatment Value“This study is showing not only that treatment works and which treatments work, but also the effect on cost,” Lyketsos told Psychiatric News. “In this particular case, it appears that it actually reduces health care costs to treat IBS in a particular way.”Lyketsos, who is chair of APA’s Committee on Consultation-Liaison Psychiatry and Primary Care Education, emphasized that the study demonstrates the value of psychiatric treatment of a condition typically thought of as medical illness. “Those of us in psychosomatic medicine have known this, and this study provides controlled-trial evidence to drive it home,” he said.Lyketsos said that while in most cases there is no known organic cause for the condition, the suffering and distress experienced by patients are real. “The issue is the functioning of the gut, which is affected by the patient’s perceptions,” he said. “The problem isn’t in the gut necessarily, but how the brain interacts with the gut.”At press time, Lyketsos said that the American Board of Medical Specialties is expected to endorse psychosomatic medicine as a new psychiatric subspecialty (Psychiatric News, September 6, 2002).“This study is an example of what this new field is going to do for psychiatry,” he said. “There is going to be more of this kind of work at the research and clinical levels to show how psychiatric care of medically ill patients makes a difference.”An abstract of the study, “The Cost-Effectiveness of Psychotherapy and Paroxetine for Severe Irritable Bowel Syndrome,” is posted on the Web at www2.gastrojournal.org under the February issue. ▪ ISSUES NewArchived

Treatment refractory schizophrenia.

Treatment resistance constitutes a significant dilemma in schizophrenia since it affects a substantial number of patients, their families and the health care professionals involved in their care. Nonresponsiveness needs to be approached as a multidimensional syndrome by specifying which symptoms in the spectrum of positive symptoms, negative symptoms, excitement/hostility, cognitive symptoms, and anxiety/depression are failing to respond to treatment. This review presents some of the clinical, demographic and biological correlates of nonresponse, in addition to compliance issues, psychosocial factors or side effects and as-yet-untreated comorbidities as a source for nonresponse. The effects of the atypicals clozapine, olanzapine, risperidone and quetiapine as compared to typicals are reviewed using available double-blind studies in this treatment refractory group of schizophrenia patients. The limited number of reports on the comparison of atypical compounds amongst each other are critically presented. Given that a subset of patients still do not respond to these agents, clinicians are using various augmentation strategies. We review studies with augmentation strategies which remain difficult to interpret given the open label and uncontrolled nature of most of these studies.

Treatment-refractory schizophrenia: Update on concepts and interventions

Until recently, clinicians have had little reason for enthusiasm in the treatment of a significant proportion of the population with schizophrenia. Approximately 15% of these patients are unresponsive to traditional antipsychotic therapy. Defining this severely ill, treatment-refractory group of patients can be a difficult task. Despite the complexity of the undertaking, it is important that such patients be identified so that their treatment can be optimized. There is increasing evidence that new, atypical antipsychotic agents can not only ameliorate both positive and negative symptoms of schizophrenia, but can also improve patients' vocational, social, and cognitive functioning as well as their overall quality of life. Free of the limitations imposed by conventional antipsychotics, patients are now able to effectively partake in many available treatments. Psychiatric rehabilitation now becomes an achievable reality. The advent of atypical antipsychotics has clearly shown that there is a much greater potential for recovery from schizophrenia than we had previously thought possible.