Safety and efficacy of first-in-man intrathecal injection of human astrocytes (AstroRx®) in ALS patients: phase I/IIa clinical trial results.

BACKGROUND: Malfunction of astrocytes is implicated as one of the pathological factors of ALS. Thus, intrathecal injection of healthy astrocytes in ALS can potentially compensate for the diseased astrocytes. AstroRx® is an allogeneic cell-based product, composed of healthy and functional human astrocytes derived from embryonic stem cells. AstroRx® was shown to clear excessive glutamate, reduce oxidative stress, secrete various neuroprotective factors, and act as an immunomodulator. Intrathecal injection of AstroRx® to animal models of ALS slowed disease progression and extended survival. Here we report the result of a first-in-human clinical study evaluating intrathecal injection of AstroRx® in ALS patients. METHODS: We conducted a phase I/IIa, open-label, dose-escalating clinical trial to evaluate the safety, tolerability, and therapeutic effects of intrathecal injection of AstroRx® in patients with ALS. Five patients were injected intrathecally with a single dose of 100 × 106 AstroRx® cells and 5 patients with 250 × 106 cells (low and high dose, respectively). Safety and efficacy assessments were recorded for 3 months pre-treatment (run-in period) and 12 months post-treatment (follow-up period). RESULTS: A single administration of AstroRx® at either low or high doses was safe and well tolerated. No adverse events (AEs) related to AstroRx® itself were reported. Transient AEs related to the Intrathecal (IT) procedure were all mild to moderate. The study demonstrated a clinically meaningful effect that was maintained over the first 3 months after treatment, as measured by the pre-post slope change in ALSFRS-R. In the 100 × 106 AstroRx® arm, the ALSFRS-R rate of deterioration was attenuated from - 0.88/month pre-treatment to - 0.30/month in the first 3 months post-treatment (p = 0.039). In the 250 × 106 AstroRx® arm, the ALSFRS-R slope decreased from - 1.43/month to - 0.78/month (p = 0.0023). The effect was even more profound in a rapid progressor subgroup of 5 patients. No statistically significant change was measured in muscle strength using hand-held dynamometry and slow vital capacity continued to deteriorate during the study. CONCLUSIONS: Overall, these findings suggest that a single IT administration of AstroRx® to ALS patients at a dose of 100 × 106 or 250 × 106 cells is safe. A signal of beneficial clinical effect was observed for the first 3 months following cell injection. These results support further investigation of repeated intrathecal administrations of AstroRx®, e.g., every 3 months. TRIAL REGISTRATION: NCT03482050.

Psoriasis and hidradenitis suppurativa: A large-scale population-based study.

BACKGROUND: The coexistence of psoriasis and hidradenitis suppurativa (HS) has been described, but the association between these conditions is yet to be firmly established. OBJECTIVE: To study the association between psoriasis and HS by using a large-scale real-life computerized database. METHODS: A cross-sectional study was conducted to compare the prevalence of HS among patients with psoriasis with that among age-, sex- and ethnicity-matched control subjects. RESULTS: A total of 68,836 patients with psoriasis and 68,836 controls were included in the study. The prevalence of HS was increased in patients with psoriasis versus in those in the control group (0.3% vs 0.2%, respectively; odds ratio, 1.8; 95% confidence interval, 1.5-2.3; P < .001). In a multivariate analysis adjusting for smoking, obesity, and other comorbidities, psoriasis was still associated with HS (odds ratio, 1.8; 95% confidence interval, 1.4-2.2; P < .001). Patients with coexistent psoriasis and HS were significantly younger (39.0 ± 15.7 vs 42.6 ± 21.2 years [P = .015]) and had a higher prevalence of obesity (35.1% vs 25.3% [P = .001]) and smoking (58.5% vs 37.3% [P < .001]) compared with patients with psoriasis alone. LIMITATIONS: Retrospective data collection. CONCLUSIONS: A positive association was observed between HS and psoriasis. Further longitudinal observational studies are necessary to establish these findings in other study populations.

Cardiac and cardiovascular morbidities in patients with psoriatic arthritis: a population-based case control study.

OBJECTIVE: To assess the prevalence of risk factors associated with cardiovascular disease (CVD) and CVD-related morbidity in a large Middle-Eastern psoriatic arthritis (PsA) cohort. METHOD: A retrospective case control study was conducted using Israel's largest health care provider's patient database from 2000 to 2013. For each patient with PsA, 10 patients with no history of psoriasis or arthritis were matched for age and sex. Analysis of CVD-related risk factors and morbidity included hypertension (HTN), hyperlipidemia (HLD), diabetes mellitus type 2 (DM-2), obesity, smoking, ischemic heart disease (IHD), congestive heart failure (CHF), cerebrovascular accident (CVA), carotid artery disease, peripheral vascular disease (PVD), aortic aneurism, valvular heart disease (VHD), and cardiomyopathy. Statistical analysis was conducted using t test and chi-square tests as appropriate. Univariate and multivariable logistic regression models assessed the association between PsA and CVD-related risk factors and morbidity. RESULTS: Three thousand one hundred sixty-one PsA patients were included, with average age 58 ± 15.0 years, of whom 53.4% were women. Increased prevalence of DM-2, HLD, HTN, and obesity (OR 1.7, 1.5, 1.5, 1.5 respectively) was noted in the PsA group. Increased prevalence of IHD (p < 0.0001), PVD (p < 0.0001), CHF (p = 0.002), VHD (p < 0.0001), and cardiomyopathy (p = 0.006) was found in the PsA group compared to the control group even after adjusting for CVD risk factors. CONCLUSIONS: A high prevalence of CVD-related risk factors and morbidity was found in this Middle Eastern PsA population, in accordance with data from other geographic regions. These results emphasize the importance of clinician awareness of the increased risk for CVD-related complications in PsA patients.

Biological treatment for psoriasis and the risk of herpes zoster: results from the Psoriasis Longitudinal Assessment and Registry (PSOLAR).

Purpose: To describe the risk of herpes zoster (HZ) in patients with psoriasis and its relation to non-biologic systemic therapies or biologic treatment. Materials and methods: Psoriasis Longitudinal Assessment and Registry (PSOLAR) is an international, prospective, registry that follows adult patients with psoriasis eligible to receive non-biologic systemic therapies or biologic therapies. Mutually exclusive therapy cohorts were defined. HZ incident rates were calculated for each therapy cohort and rates between cohorts were compared using hazard ratios (HR) adjusted for potential confounders, in new users and prevalent-exposure patients. Results: A total of 55 HZ events were identified in 10,469 patients in PSOLAR. The adjusted hazard ratio in the overall study population (new user and prevalent-exposed patients) was 2.22 (95% CI: 0.82-5.97; p = .116) for tumor necrosis factor-α (TNF) inhibitors, 2.73 (0.98-7.58; p = .054) for ustekinumab, and 1.04 (0.20-5.41; p = .966) for methotrexate versus reference (combined phototherapy, systemic steroids, topical therapy, and immunomodulators other than methotrexate). Conclusions: Exposure to ustekinumab, TNF-α inhibitors, and methotrexate was not associated with a statistically significant increased risk of HZ. However, HRs were elevated for ustekinumab and TNF-α inhibitors; a larger number of HZ events would be needed to assess the presence or absence of risk.

Melkersson-Rosenthal Syndrome: the possible role of comorbidities in the etiopathogenesis.

BACKGROUND: Melkersson-Rosenthal Syndrome (MRS) is a rare syndrome. Recently, possible association between MRS and psoriasis was reported. Our objective is to evaluate the presence of comorbidities in MRS with a focus on psoriasis-related morbidities. METHODS: We conducted a case-control study consisting of a series of 12 patients with MRS and two groups of age- and gender-matched controls: 30 patients with psoriasis vulgaris and 28 patients with acute contact dermatitis. A comparative analysis for the prevalence of comorbidities, with a focus on psoriasis-related morbidities, was done. RESULTS: Psoriasis-related morbidities including smoking, obesity, dyslipidemia, hypertension, and diabetes mellitus were recorded in 5 (42%) patients with MRS, compared to 15 (50%) patients with psoriasis and 2 (7%) patients with acute contact dermatitis. The prevalence of psoriasis-related morbidities did not differ significantly between the group of patients with MRS and the group of patients with psoriasis. On the other hand, the difference between the group of patients with MRS and the group of patients with contact dermatitis was statistically significant (P=0.01). CONCLUSIONS: The similar prevalence of psoriasis-related morbidities in MRS and in psoriasis may further support an association between MRS and psoriasis.

Psoriasis in Israel: demographic, epidemiology, and healthcare services utilization.

BACKGROUND: Updated data regarding the epidemiology of psoriasis and related healthcare utilization are lacking. OBJECTIVE: To investigate the epidemiology, comorbidities, healthcare services utilization, and drug use in a large group of patients with psoriasis from Clalit Health Services (CHS) database. METHODS: A controlled cross-sectional study was performed. Case patients were defined when there was at least one documented diagnosis of psoriasis registered by a CHS dermatologist between the years 1998-2016. The extracted data included metabolic, cardiovascular and psychiatric comorbidities; community clinic visits; in- and outpatient services utilization profiles and drug use data, which included pharmacy claims of topical and systemic treatments, including phototherapy and climatotherapy. Comparative analysis was performed by a univariate and multivariate analysis, adjusting for age, gender, obesity, and smoking. RESULTS: The study included 118,680 patients with psoriasis (prevalence of 2.69%) and 118,680 age- and gender-matched controls. Patients with psoriasis had increased prevalence of metabolic, cardiovascular, and psychiatric illnesses. Psoriasis was significantly associated with an increased healthcare utilization. The mean (SD) number of annual dermatologist clinic visits and emergency room visits was 7.2 ± 12.4 and 2.9 ± 7.7 in psoriasis patients as compared to 2.9 ± 7.9 and 2.7 ± 7.4 in the control group (P < 0.001). Topical steroids were the most applied treatment in psoriasis patients (15.5%), and topical vitamin D analogs were second in use (14.6%). Traditional systemic treatment for psoriasis was used in 3.8% of the patients, and biologic treatments were used in 1.6% of the patients. CONCLUSIONS: Our study quantifies healthcare services utilization and drug use in patients with psoriasis.

Safety and efficacy of human embryonic stem cell-derived astrocytes following intrathecal transplantation in SOD1G93A and NSG animal models.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a motor neuron (MN) disease characterized by the loss of MNs in the central nervous system. As MNs die, patients progressively lose their ability to control voluntary movements, become paralyzed and eventually die from respiratory/deglutition failure. Despite the selective MN death in ALS, there is growing evidence that malfunctional astrocytes play a crucial role in disease progression. Thus, transplantation of healthy astrocytes may compensate for the diseased astrocytes. METHODS: We developed a good manufacturing practice-grade protocol for generation of astrocytes from human embryonic stem cells (hESCs). The first stage of our protocol is derivation of astrocyte progenitor cells (APCs) from hESCs. These APCs can be expanded in large quantities and stored frozen as cell banks. Further differentiation of the APCs yields an enriched population of astrocytes with more than 90% GFAP expression (hES-AS). hES-AS were injected intrathecally into hSOD1G93A transgenic mice and rats to evaluate their therapeutic potential. The safety and biodistribution of hES-AS were evaluated in a 9-month study conducted in immunodeficient NSG mice under good laboratory practice conditions. RESULTS: In vitro, hES-AS possess the activities of functional healthy astrocytes, including glutamate uptake, promotion of axon outgrowth and protection of MNs from oxidative stress. A secretome analysis shows that these hES-AS also secrete several inhibitors of metalloproteases as well as a variety of neuroprotective factors (e.g. TIMP-1, TIMP-2, OPN, MIF and Midkine). Intrathecal injections of the hES-AS into transgenic hSOD1G93A mice and rats significantly delayed disease onset and improved motor performance compared to sham-injected animals. A safety study in immunodeficient mice showed that intrathecal transplantation of hES-AS is safe. Transplanted hES-AS attached to the meninges along the neuroaxis and survived for the entire duration of the study without formation of tumors or teratomas. Cell-injected mice gained similar body weight to the sham-injected group and did not exhibit clinical signs that could be related to the treatment. No differences from the vehicle control were observed in hematological parameters or blood chemistry. CONCLUSION: Our findings demonstrate the safety and potential therapeutic benefits of intrathecal injection of hES-AS for the treatment of ALS.

Biologic drug survival in Israeli psoriasis patients.

BACKGROUND: Drug survival is defined as the time period of treatment with a certain drug until its cessation. The role of previous exposure to traditional systemic treatments in biologic survival is still unknown. OBJECTIVE: To investigate the drug survival rates of biologic treatments in patients with psoriasis and to identify predictor factors. METHODS: Survival analysis was performed on patients with severe psoriasis who received adalimumab, infliximab, etanercept, and ustekinumab for treatment of psoriasis, drawn from the Clalit Health Services database. Multivariate analysis was performed adjusting for demographic variables; metabolic syndrome and its components; psoriatic arthritis; biologic naivety; coadministration of methotrexate, acitretin, or cyclosporine; and previous standard systemic treatment exposure. RESULTS: Among 907 patients treated with 1575 biologic treatments, ustekinumab had a significantly higher survival rate than tumor necrosis factor inhibitors. Biologic naivety and concomitant methotrexate intake were positive predictors for drug survival, whereas the female sex and the duration of previous systemic treatments were negative predictors. LIMITATIONS: Data regarding disease severity or duration could not be drawn from the Clalit Health Services database. CONCLUSION: Ustekinumab had better retention rates in comparison with other investigated biologics in patients with severe psoriasis, most of whom used it as a third line therapy.

Hidradenitis suppurativa: epidemiology, clinical features, associated comorbidities and treatment.

Hidradenitis suppurativa (HS) is a chronic relapsing suppurativa skin disease localized in the apocrine-gland-bearing areas of the body, predominantly in the axillae and groin. Although important risk factors have been identified, the pathomechanisms of the disease have not been fully understood. In the absence of proper treatment, chronic inflammation results in debilitating, and sometimes life-threatening complications. This severe and chronic disease can have detrimental effects on self-esteem and quality of life and is associated with high comorbidity, such as the metabolic syndrome and its components. Early detection and treatment in patients with HS may prevent late direct complications, such as severe scarring, and indirect complications, i.e. cardio-vascular disease. Thus appropriate screening and treatment should be prompt. No definitive treatment has been recognized, but several therapies have been found to reduce lesion severity and improve symptoms of HS. Additional research is needed for evaluation of the comparative effectiveness of topical and systemic treatments and for better understanding of the pathogenesis, natural history, and subtypes of HS.

Primary cutaneous γ/δ T-cell lymphoma. An atypical case with bone marrow granulomas.

BACKGROUND: Primary cutaneous γ/δ T-cell lymphoma is a rare variant of peripheral T-cell lymphoma which has been only recently set apart from subcutaneous panniculitis-like T-cell lymphoma and is known for its aggressive nature. MAIN OBSERVATION: We hereby report a case of primary cutaneous γ/δ T-cell lymphoma in a 35-year-old man with bone marrow granulomas, an unexpected feature in this lymphoma. The patient was treated with combination chemotherapy. Partial response was obtained, followed by relapse. Allogeneic stem cell transplantation was then carried out, and full remission was achieved. CONCLUSION: Bone marrow granulomas can be an accompanying feature in primary cutaneous γ/δ T-cell lymphoma.

Is preeclampsia a significant risk factor for long-term hospitalizations and morbidity?

OBJECTIVE: The present study was aimed to evaluate long-term morbidity of patients with hypertensive disorders of pregnancy. STUDY DESIGN: A retrospective cohort study was conducted, including women who gave birth between the years of 1988 to 1998, and had a follow-up until December 2009. Data were extracted by linking a computerized database of hospitalizations with computerized database containing maternal records from the same regional medical center. The exposed group comprised 2072 patients with mild or severe preeclampsia in one or more of their pregnancies and the comparison group included 20742 patients without preeclampsia. Excluded from the study were patients with chronic hypertension and pre-gestational diabetes before the index pregnancy. Data included subsequent hospitalizations in internal medicine, oncology, nephrology, neurology, cardiac intensive care unit, and hematology, as well as a diagnosis of chronic hypertension during the follow-up period. RESULTS: Patients with preeclampsia had significantly higher rates of chronic hypertension diagnosed after the index pregnancy as compared with patients without preeclampsia (12.5% vs. 0.9%; OR = 15.8, 95% CI 12.9-19.3; p < 0.001). Likewise, patients with preeclampsia were more likely to be hospitalized at least once (13.7% vs. 11.4%; OR = 1.2, 95% CI 1.1-1.4; p = 0.002) as compared with patients without preeclampsia. Exposed women had 582 hospitalizations (0.28 hospitalization/patient), while the non-exposed patients had a total of 4687 hospitalizations (0.23 hospitalization/patient; p < 0.001). CONCLUSION: Preeclampsia is a significant risk factor for long-term morbidity such as chronic hypertension and hospitalizations later in life.