Analysis of autonomic outcomes in APOLLO, a phase III trial of the RNAi therapeutic patisiran in patients with hereditary transthyretin-mediated amyloidosis

Hereditary transthyretin-mediated (hATTR) amyloidosis is a progressive, debilitating disease often resulting in early-onset, life-impacting autonomic dysfunction. The effect of the RNAi therapeutic, patisiran, on autonomic neuropathy manifestations in patients with hATTR amyloidosis with polyneuropathy in the phase III APOLLO study is reported. Patients received patisiran 0.3 mg/kg intravenously (n = 148) or placebo (n = 77) once every 3 weeks for 18 months. Patisiran halted or reversed polyneuropathy and improved quality of life from baseline in the majority of patients. At baseline, patients in APOLLO had notable autonomic impairment, as demonstrated by the Composite Autonomic Symptom Score-31 (COMPASS-31) questionnaire and Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QOL-DN) questionnaire autonomic neuropathy domain. At 18 months, patisiran improved autonomic neuropathy symptoms compared with placebo [COMPASS-31, least squares (LS) mean difference, - 7.5; 95% CI: - 11.9, - 3.2; Norfolk QOL-DN autonomic neuropathy domain, LS mean difference, - 1.1; - 1.8, - 0.5], nutritional status (modified body mass index, LS mean difference, 115.7; - 82.4, 149.0), and vasomotor function (postural blood pressure, LS mean difference, - 0.3; - 0.5, - 0.1). Patisiran treatment also led to improvement from baseline at 18 months for COMPASS-31 (LS mean change from baseline, - 5.3; 95% CI: - 7.9, - 2.7) and individual domains, orthostatic intolerance (- 4.6; - 6.3, - 2.9) and gastrointestinal symptoms (- 0.8; - 1.5, - 0.2). Rapid worsening of all study measures was observed with placebo, while patisiran treatment resulted in stable or improved scores compared with baseline. Patisiran demonstrates benefit across a range of burdensome autonomic neuropathy manifestations that deteriorate rapidly without early and continued treatment.The study was funded by Alnylam Pharmaceuticals, Inc. Medical writing services provided by Kristen Brown (PhD) of Adelphi Communications Ltd, Macclesfeld, UK were funded by Alnylam Pharmaceuticals, Inc. in accordance with Good Publication Practice (GPP3) guidelines. We would like to thank Anastasia McManus (Alnylam Pharmaceuticals, Inc.) for her assistance during preparation of this manuscript.info:eu-repo/semantics/publishedVersio

Musculoskeletal manifestations associated with transthyretin-mediated (ATTR) amyloidosis: a systematic review

Abstract Background Hereditary and wild-type transthyretin-mediated (ATTRv and ATTRwt) amyloidoses result from the misfolding of transthyretin and aggregation of amyloid plaques in multiple organ systems. Diagnosis of ATTR amyloidosis is often delayed due to its heterogenous and non-specific presentation. This review investigates the association of musculoskeletal (MSK) manifestations with ATTR amyloidosis and the delay from the onset of these manifestations to the diagnosis of ATTR amyloidosis. Methods This systematic review utilized Medline and EMBASE databases. Search criteria were outlined using a pre-specified patient, intervention, comparator, outcome, time, study (PICOTS) criteria and included: amyloidosis, ATTR, and MSK manifestations. Publication quality was assessed utilizing Joanna Briggs Institute (JBI) critical appraisal checklists. The search initially identified 7,139 publications, 164 of which were included. PICOTS criteria led to the inclusion of epidemiology, clinical burden and practice, pathophysiology, and temporality of MSK manifestations associated with ATTR amyloidosis. 163 publications reported on ATTR amyloidosis and MSK manifestations, and 13 publications reported on the delay in ATTR amyloidosis diagnosis following the onset of MSK manifestations. Results The MSK manifestation most frequently associated with ATTR amyloidosis was carpal tunnel syndrome (CTS); spinal stenosis (SS) and osteoarthritis (OA), among others, were also identified. The exact prevalence of different MSK manifestations in patients with ATTR amyloidosis remains unclear, as a broad range of prevalence estimates were reported. Moreover, the reported prevalence of MSK manifestations showed no clear trend or distinction in association between ATTRv and ATTRwt amyloidosis. MSK manifestations precede the diagnosis of ATTR amyloidosis by years, and there was substantial variation in the reported delay to ATTR amyloidosis diagnosis. Reports do suggest a longer diagnostic delay in patients with ATTRv amyloidosis, with 2 to 12 years delay in ATTRv versus 1.3 to 1.9 years delay in ATTRwt amyloidosis. Conclusion These findings suggest that orthopedic surgeons may play a role in the early diagnosis of and treatment referrals for ATTR amyloidosis. Detection of MSK manifestations may enable earlier diagnosis and administration of effective treatments before disease progression occurs

Additional file 1 of Musculoskeletal manifestations associated with transthyretin-mediated (ATTR) amyloidosis: a systematic review

Additional file 1: Supplement 1. PICOTS criteria for study inclusion and exclusion in the SLR. Supplement 2. Ovid® search strategies for EMBASE and Medline (run on November 3rd, 2021). Supplement 3. Case studies excluded from the systematic literature with ATTR MSK manifestatio

Treatment response and neurofilament light chain levels with long-term patisiran in hereditary transthyretin-mediated amyloidosis with polyneuropathy: 24-month results of an open-label extension study

Longitudinal changes in neurofilament light chain (NfL) levels were evaluated alongside prespecified clinical assessments 24 months into the patisiran Global open-label extension (OLE) study in patients with ATTRv amyloidosis with polyneuropathy. All patients enrolled in the Global OLE, from phase III APOLLO and phase II OLE parent studies, received patisiran. Assessments included measures of polyneuropathy (modified Neuropathy Impairment Score+7 (mNIS+7)), quality of life (QOL; Norfolk QOL-Diabetic Neuropathy questionnaire (Norfolk QOL-DN)), and plasma NfL. Patients receiving patisiran in the parent study (APOLLO-patisiran, n = 137; phase II OLE-patisiran, n = 25) demonstrated sustained improvements in mNIS+7 (mean change from parent study baseline (95% confidence interval): APOLLO-patisiran −4.8 (−8.9, −0.6); phase II OLE-patisiran −5.8 (−10.5, −1.2)) and Norfolk QOL-DN (APOLLO-patisiran −2.4 (−7.2, 2.3)), and maintained reduced NfL levels at Global OLE 24 months. After initiating patisiran in the Global OLE, APOLLO-placebo patients (n = 49) demonstrated stabilized mNIS+7, improved Norfolk QOL-DN, and significantly reduced NfL levels. Patisiran continued to demonstrate an acceptable safety profile. Earlier patisiran initiation was associated with a lower exposure-adjusted mortality rate. Long-term patisiran treatment led to sustained improvements in neuropathy and QOL, with NfL demonstrating potential as a biomarker for disease progression and treatment response in ATTRv amyloidosis with polyneuropathy.</p

TUR-PSO: A cross-sectional, study investigating quality of life and treatment status of psoriasis patients in Turkey

Psoriasis is a common inflammatory disease that has a severe impact on quality of life. There is lack of data regarding epidemiological and clinical features of psoriasis patients in Turkey, a country with a population of 76million. The aim of this study was to define the demographic and clinical characteristics, quality of life and treatment patterns of psoriasis patients in Turkey. A cross-sectional observational study was conducted at 40 centers, chosen from geographically diverse locations in Turkey. Patients diagnosed with psoriasis were assessed by investigators who were specialists of dermatology using standardized study questionnaire forms. Dermatology Life Quality Index (DLQI) and EuroQol-5 dimension (EQ-5D) forms were also filled out by each patient. 3971 psoriasis patients were included in this study. 24.2% of plaque psoriasis patients had moderate to severe psoriasis (Psoriasis Area and Severity Index, 10). Mean DLQI was 7.03 +/- 6.02; quality of life was moderately, severely or very severely affected in 49.2% of patients. The most severely affected component of EQ-5D was anxiety/depression. Among all patients, 22.9% were not receiving any treatment, 39.8% were receiving only topical treatment, 11.5% were on phototherapy, 26.1%, were taking conventional systemic agents and 4.1% were on a biologic treatment. 31.3% of psoriasis patients with moderate to severe disease were treated with only topical agents and only 30.5% of moderate to severe psoriasis patients were receiving systemic therapy. Moderate to severe psoriasis has a considerable impact on quality of life. Treatment in Turkey of patients with moderate to severe psoriasis is insufficient

TUR-PSO: A cross-sectional, study investigating quality of life and treatment status of psoriasis patients in Turkey

WOS: 000371889000011PubMed ID: 26365805Psoriasis is a common inflammatory disease that has a severe impact on quality of life. There is lack of data regarding epidemiological and clinical features of psoriasis patients in Turkey, a country with a population of 76million. The aim of this study was to define the demographic and clinical characteristics, quality of life and treatment patterns of psoriasis patients in Turkey. A cross-sectional observational study was conducted at 40 centers, chosen from geographically diverse locations in Turkey. Patients diagnosed with psoriasis were assessed by investigators who were specialists of dermatology using standardized study questionnaire forms. Dermatology Life Quality Index (DLQI) and EuroQol-5 dimension (EQ-5D) forms were also filled out by each patient. 3971 psoriasis patients were included in this study. 24.2% of plaque psoriasis patients had moderate to severe psoriasis (Psoriasis Area and Severity Index, 10). Mean DLQI was 7.03 +/- 6.02; quality of life was moderately, severely or very severely affected in 49.2% of patients. The most severely affected component of EQ-5D was anxiety/depression. Among all patients, 22.9% were not receiving any treatment, 39.8% were receiving only topical treatment, 11.5% were on phototherapy, 26.1%, were taking conventional systemic agents and 4.1% were on a biologic treatment. 31.3% of psoriasis patients with moderate to severe disease were treated with only topical agents and only 30.5% of moderate to severe psoriasis patients were receiving systemic therapy. Moderate to severe psoriasis has a considerable impact on quality of life. Treatment in Turkey of patients with moderate to severe psoriasis is insufficient.PfizerPfizerThis study was sponsored by Pfizer, employees of Pfizer contributed to the design of the study, interpretation of the results and development of the manuscript. Editorial assistance with manuscript development was provided by Susanne Gilbert of ACUMED (New York, NY, USA) and was funded by Pfizer. The authors acknowledge the contributions of the investigators: Dr Esra Ozsoy Adisen, Dr Vahide Baysal Akkaya, Dr Aye Esra Koku Aksu, Dr Hamza Aktas, Dr Aynur Akyol, Dr Sema Altun, Dr Ilknur Altunay, Dr Aysegul Altuntas, Dr E. Esra Arpag, Dr Burcak Bozdemir Aral, Dr Safak Arslan, Dr Gokcen Balci, Dr Emel Bulbul Baskan, Dr Cemal Bilac, Dr Ferihan Uslu Bilgin, Dr Ilgul Bilgin, Dr Omer Calka, Dr Burcin Dogan, Dr Tugba Ekmekci, Dr H. Meral Eksioglu, Dr Sevinc Elinc, Dr Mustafa Teoman Erdem, Dr Bema Sanli Erdogan, Dr Ayten Ferahbas, Dr Gonca Gokdemir, Dr Seyma Celik Gulecol, Dr Asli Gulel, Dr Ulas Guvenc, Dr Asli Hapa, Dr Seval Dogruk Kacar, Dr Basak Kandi, Dr Isin Kilic Karaarslan, Dr Yelda Karincaoglu, Dr Aylin Haskok Kazanci, Dr Sevgi Kilic, Dr Yildiz Kilinc, Dr Saliha Can Kirbas, Dr Rafet Koca, Prof. Dr Mukadder Kocak, Dr Selma Korkmaz, Dr Adem Kosklu, Dr Ergun Kusku, Dr Nurdan Seda Kutlu, Dr Hamdi R. Memisoglu, Dr Ahmet Metin, Dr Inci Mevlitoglu, Dr Ozgul Mustu, Dr Tuba Ozceyhan, Dr Mustafa Ozdemir, Dr Ayes Sebnem Ozkan, Dr Serap Ozturkcan, Dr Hatice Ozyigit, Dr Mustafa Turhan Sahin, Dr Muzaffer Sahin, Dr Mehmet Sakman, Dr Sezai Sasmaz, Dr Neslihan Sendur, Doc. Dr Nilgun Senturk, Dr Gamze Serarslan, Dr Engin Sezer, Dr Funda Tas, Dr Nazan Sengun Taslidere, Dr Nergiz Turan, Dr Muge Turkmen, Dr Isin Zehra Uluc, Dr Cahit Yavuz, Dr I. Halil Yavuz, Dr Savas Yayli, Dr Eylem Yilmaz, Dr Yasar Yilmaz, Dr Tulin Yuksel and Dr Ilknur Yorgun

Neurofilament light chain (NfL) as a biomarker of hereditary transthyretin-mediated amyloidosis

To identify changes in the proteome associated with onset and progression of ATTRv amyloidosis, we performed an observational, case-controlled study which compared proteomes of patients with ATTRv amyloidosis and healthy controls. Plasma levels of >1,000 proteins were measured in patients with ATTRv amyloidosis with polyneuropathy who received either placebo or patisiran in the APOLLO study and in healthy controls. The impact of patisiran on the time profile of each protein was determined by linear mixed model at 0, 9, and 18 months. Neurofilament light chain (NfL) was further assessed using an orthogonal quantitative approach. Levels of 66 proteins were significantly changed with patisiran vs placebo, with NfL change most significant (p < 10−20). Analysis of changes in protein levels demonstrated that the proteome of patisiran-treated patients trended toward healthy controls at 18 months. Healthy controls' NfL levels were 4-fold lower than in patients with ATTRv amyloidosis with polyneuropathy (16.3 vs 69.4 pg/mL, effect: −53.1 pg/mL, 95% CI [–60.5 to −45.9]). NfL levels at 18 months increased with placebo (99.5 vs 63.2 pg/mL, 36.3 pg/mL, [16.5–56.1]) and decreased with patisiran treatment (48.8 vs 72.1 pg/mL, −23.3 pg/mL, [–33.4 to −13.1]) from baseline. At 18 months, improvement in modified Neuropathy Impairment Score +7 following patisiran significantly correlated with reduced NfL (R = 0.43, [0.29–0.55]). Findings suggest NfL may serve as a biomarker of nerve damage and polyneuropathy in ATTRv amyloidosis, may enable earlier diagnosis of patients with ATTRv amyloidosis, and facilitate monitoring of disease progression. This study provides Class III evidence that NfL levels may enable earlier diagnosis of polyneuropathy in patients with ATTRv amyloidosis and facilitate monitoring of disease progression.This supplementary data comprises: Table e-1 A comprehensive list of all proteins that significantly changed between placebo- and patisiran-treated hereditary transthyretin (ATTRv) amyloidosis patients over time during the APOLLO study Table e-2 Comparisons of levels of neurofilament light chain (NfL) between healthy controls and placebo- or patisiran-treated patients at baseline, 9 months, or 18 months Table e-3 Comparisons of levels of NfL in baseline APOLLO patients at different polyneuropathy disability (PND) scores Table e-4 Comparisons of levels of NfL in baseline APOLLO patients that were in the prespecified cardiac subpopulation or not to healthy controls Table e-5 Comparisons of levels of NfL in healthy controls and placebo- or patisiran-treated patients at baseline or 18 months between groups

Perceptions of Painful Diabetic Peripheral Neuropathy in South-East Asia: Results from Patient and Physician Surveys

<p><strong>Article full text</strong></p> <p><br> The full text of this article can be found <a href="https://link.springer.com/article/10.1007/s12325-017-0536-5"><b>here</b>.</a><br> <br> <strong>Provide enhanced digital features for this article</strong><br> If you are an author of this publication and would like to provide additional enhanced digital features for your article then please contact <u>[email protected]</u>.<br> <br> The journal offers a range of additional features designed to increase visibility and readership. All features will be thoroughly peer reviewed to ensure the content is of the highest scientific standard and all features are marked as ‘peer reviewed’ to ensure readers are aware that the content has been reviewed to the same level as the articles they are being presented alongside. Moreover, all sponsorship and disclosure information is included to provide complete transparency and adherence to good publication practices. This ensures that however the content is reached the reader has a full understanding of its origin. No fees are charged for hosting additional open access content.<br> <br> Other enhanced features include, but are not limited to:<br> • Slide decks<br> • Videos and animations<br> • Audio abstracts<br> • Audio slides<u></u></p