The Impact of the Transition From Volume to Value on Heart Failure Care: Implications of Novel Payment Models and Quality Improvement Initiatives.

In response to wide variation in quality and outcomes as well as escalating health care costs, the U.S. health care system is moving away from a volume-based payment system to a quality- and value-based system. Medicare, the largest insurer and payer of health care, has accelerated the movement toward value-based care with the development and implementation of myriad alternate payment models and pay-for-performance programs as part of the Affordable Care Act. Given that heart failure affects a significant number of Medicare patients and that these patients account for a disproportionate amount of health care utilization and spending, heart failure has become a focal point for these initiatives. In this article, we highlight 4 such programs beyond the Hospital Readmission Reduction Program (HRRP) which financially penalizes hospitals for excess readmissions. Specifically, we focus on Hospital Value-Based Purchasing (HVBP), Bundled Payments for Care Improvement (BPCI), the Merit-Based Incentive Payment System (MIPS), and Accountable Care Organizations (ACOs). The HVBP and BPCI programs aim to improve quality and cost efficiency primarily among patients who are hospitalized, and the MIPS program has taken similar aim in the ambulatory setting. Finally, ACOs encourage active population health management across the continuum of care as providers bear financial risk for enrolled patients. Given broader discussions about health care reform, the specific policies and programs meant to accelerate the transition from volume to value may be altered. However, the underlying drivers for reform will persist, and heart failure is a clinical condition that by comparison will be subject to greater scrutiny.

Risk factors for the development of deformity in patients with spinal infection.

OBJECT: Bacterial spinal infections are infrequent but may lead to significant morbidity and death. Apart from neurological complications, infections may also lead to bone destruction resulting in deformity of the spine. However, the incidence of spinal deformities and risk factors is not well characterized in the literature. METHODS: A retrospective cohort study was conducted using electronic medical records at a single institution. All patients were over 18 years of age and had a clinically and radiologically documented spinal infection that was treated surgically during the period 2006-2013. Infections were classified according to anatomical location including disc, bone, and/or epidural space. Deformities included kyphosis and/or subluxation. The authors analyzed risk factors for developing at least 1 deformity between the time of infection and operation using the Fisher exact test and chi-square test. Change in visual analog scale (VAS) scores preoperatively versus postoperatively was also analyzed using the paired t-test. RESULTS: The study included 48 patients. The most common types of spinal infections were osteomyelitis and discitis (31%); osteomyelitis, discitis, and spinal epidural abscess (SEA; 27%); SEA only (15%); and osteomyelitis only (13%). Overall, 21 (44%) of 48 patients developed a spinal deformity. Anatomical location of infection (bone and/or disc and/or epidural space) was significantly associated with development of deformity (p < 0.001). In particular, patients with SEA had lower odds of deformity compared with patients without SEA (odds ratio 0.2, 95% confidence interval 0.05-0.9; p < 0.001). No other factor was significantly associated with deformity. Pain measured by VAS score tended to improve by a mean of 1.7 ± 2.7 points (p < 0.001) when comparing preoperative to postoperative scores. CONCLUSIONS: In this cohort of patients, 44% developed at least 1 deformity, predominantly kyphosis. The only variable significantly associated with deformity was infection location. Patients with SEA alone demonstrated lower odds of developing a deformity compared with patients without SEA. Other analyzed variables, including age, body mass index, time from initial diagnosis to surgery, and comorbidities, were not found to be associated with development of deformity. Surgical intervention resulted in pain improvement.

Garetosmab in Fibrodysplasia Ossificans Progressiva: Clinical Pharmacology Results from the Phase 2 LUMINA-1 Trial.

Here, we report the clinical pharmacology data from LUMINA-1 (NCT03188666), a Phase 2 trial that evaluated garetosmab (a monoclonal antibody against activin A) in patients with fibrodysplasia ossificans progressiva. Forty-four patients were randomly assigned to intravenous 10 mg/kg of garetosmab or placebo every 4 weeks in a double-blind 28-week treatment period, followed by a 28-week open-label treatment period with garetosmab, and subsequent open-label extension. Serum samples were obtained to assess pharmacokinetics (PK), immunogenicity, and bone morphogenetic protein 9 (BMP9). Comparative exposure-response analyses for efficacy and safety were performed with trough concentrations (Ctrough ) of garetosmab prior to dosing. Steady-state PK was reached 12-16 weeks after the first dose of garetosmab, with mean (standard deviation) Ctrough of 105 ± 30.8 mg/L. Immunogenicity assessments showed anti-garetosmab antibody formation in 1 patient (1/43; 2.3%); titers were low, and did not affect PK or clinical efficacy. Median concentrations of BMP9 in serum were approximately 40 pg/mL at baseline. There were no meaningful differences in PK or BMP9 concentration-time profiles between patients who did and did not experience epistaxis or death. The comparative exposure-response analyses demonstrated no association between Ctrough and efficacy or safety. PK findings were consistent with prior data in healthy volunteers and were typical for a monoclonal antibody administered at doses sufficient to saturate target-mediated clearance. There were no trends that suggested patients with higher serum exposures to garetosmab were more likely to experience a reduction in heterotopic ossification or adverse events. Garetosmab is being further evaluated in the Phase 3 OPTIMA trial.

How Activin A Became a Therapeutic Target in Fibrodysplasia Ossificans Progressiva.

Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disorder characterized by episodic yet cumulative heterotopic ossification (HO) of skeletal muscles, tendons, ligaments, and fascia. FOP arises from missense mutations in Activin Receptor type I (ACVR1), a type I bone morphogenetic protein (BMP) receptor. Although initial findings implicated constitutive activity of FOP-variant ACVR1 (ACVR1FOP) and/or hyperactivation by BMPs, it was later shown that HO in FOP requires activation of ACVR1FOP by Activin A. Inhibition of Activin A completely prevents HO in FOP mice, indicating that Activin A is an obligate driver of HO in FOP, and excluding a key role for BMPs in this process. This discovery led to the clinical development of garetosmab, an investigational antibody that blocks Activin A. In a phase 2 trial, garetosmab inhibited new heterotopic bone lesion formation in FOP patients. In contrast, antibodies to ACVR1 activate ACVR1FOP and promote HO in FOP mice. Beyond their potential clinical relevance, these findings have enhanced our understanding of FOP's pathophysiology, leading to the identification of fibroadipogenic progenitors as the cells that form HO, and the discovery of non-signaling complexes between Activin A and wild type ACVR1 and their role in tempering HO, and are also starting to inform biological processes beyond FOP.

Characterization of flare-ups and impact of garetosmab in adults with fibrodysplasia ossificans progressiva: a post hoc analysis of the randomized, double-blind, placebo-controlled LUMINA-1 trial.

Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare disorder, characterized by progressive heterotopic ossification (HO) and painful soft-tissue inflammatory flare-ups. This was a post hoc analysis from a phase 2 (NCT03188666) trial in which adults with FOP received intravenous anti-activin A antibody garetosmab 10 mg/kg or placebo every 4 wk over 28 wk (Period 1), followed by a 28-wk open-label treatment and extension (Periods 2 and 3). Here we describe flare-ups, their relationship to new HO lesions, and the impact of garetosmab on flare-ups. Volume of new HO lesions was measured by CT. Patient-reported flare-ups were defined by any 2 of the following: new onset of pain, swelling, joint stiffness, decrease in movement, or perceived presence of HO. Flare-ups were experienced by 71% (17/24) of placebo-treated patients, 59% (10/17) of whom developed a new HO lesion irrespective of flare-up location; 24% of flare-ups location-matched new HO lesions. Twenty-nine new HO lesions occurred in the placebo cohort by week 28, of which 12 (41%) occurred in the same location as new or ongoing flare-ups. A higher volume of newly formed heterotopic bone (week 28) occurred in placebo-treated patients who had experienced a prior flare-up vs those without (median [Q1:Q3] of 16.6 [12.0:31.1] vs 3.2 cm3). Garetosmab was previously shown to decrease patient-reported flare-up frequency in Period 1; here, garetosmab reduced the median (Q1:Q3) duration of patient-reported flares (15.0 [6.0:82.0] vs 48.0 [15.0:1.00] d) and the severity of flare-ups vs placebo. Frequency of corticosteroid use was numerically reduced in those treated with garetosmab (40.0%) vs placebo (58.3%). In this analysis, 71% of placebo-treated adults with FOP experienced flare-ups over 28 wk, which were associated with an increased volume of newly formed heterotopic bone. Garetosmab reduced the severity and duration of flare-ups, with effects sustained during the entire trial.

Fibrodysplasia ossificans progressiva (FOP) is a very rare genetic disorder caused by mutations in the ACVR1 gene. People with FOP experience growth of new bone in places where bone does not usually develop. Soft tissues (like skeletal muscles) and connective tissues (like tendons and ligaments) are gradually replaced by bone beyond the normal skeleton­a process called heterotopic ossification (HO). People with FOP experience flare-ups, which are painful swellings of the soft tissues. In this clinical study in people with FOP, we looked at the number of flareups, whether flareups were linked to new HO lesions, and the impact of garetosmab (a monoclonal antibody) on flareups. At random, about half the patients received placebo, or inactive drug, with the other half receiving garetosmab, the study drug. Of the patients who received placebo, 71% had flare-ups and 59% percent of those who had flare-ups also had a new HO lesion, which was not always related to the location of the flare-up. We have previously shown that garetosmab reduces the number of flareups patients report. In this study, we show that garetosmab reduces the length and pain severity of flare-ups too. The treatment effects were maintained for the whole study.

Effect of GLP-1 agonists on weight loss in patients with polycystic ovary syndrome and obesity: A single-center study.

Background: Weight loss of >5% in patients with polycystic ovary syndrome and obesity (PCOS-O) is believed to improve underlying drivers of the syndrome. Weight loss facilitated by GLP-1 agonists in patients with PCOS-O is not well characterized. In this single-center retrospective study, we determined weight loss in patients with PCOS-O with GLP-1 monotherapy versus metformin. Methods: In this brief report, electronic records of 183 adult patients with PCOS-O were reviewed between January 2020 and April 2021. We identified 12 and 19 patients that were treated with metformin and GLP-1 monotherapy respectively. One patient in each cohort had diabetes mellitus. Weights were reviewed at baseline (prior to therapy initiation) and at six-month follow-up. We analyzed change in weight from baseline and proportion with >5% and 10% weight loss using Fisher exact t-test and chi-square test. Univariate linear regression was used to identify correlations between treatment and weight loss. Results: Baseline characteristics were similar between metformin (n = 12) and GLP-1 (n = 19) cohorts with the exception of mean days on medication. Following six months of treatment, mean weight loss was 4.9 kg (4.8%) and 9.1 kg (9.8%) in the metformin and GLP-1 cohorts (p = 0.13) respectively. Similar trends were seen in BMI with reductions of 1.8 kg/m2 (4.7%) and 3.5 kg/m2 (9.7%). A significantly greater proportion of patients achieved 5% and 10% weight loss with GLP-1 treatment (84.2% and 57.8%, p = 0.01 and p = 0.02) compared to metformin. Univariate linear regression analysis demonstrated a trend towards greater weight loss in patients treated with GLP-1 monotherapy (Coeff: 4.15, 95% CI: 1.3-9.7, p = 0.13) versus metformin. Conclusion: Our study shows improvements in weight with GLP-1 monotherapy versus metformin as demonstrated by overall weight loss and proportion of patients achieving >5% weight loss. Further prospective randomized controlled studies are needed to establish GLP-1 weight loss efficacy in patients with PCOS-O and clinically related outcomes.

Disseminated Herpes Simplex Virus-2 (HSV-2) as a Cause of Viral Hepatitis in an Immunocompetent Host.

BACKGROUND Herpes simplex virus-2 (HSV-2) affects nearly 1 in 5 adults in the United States. Complications such as viral hepatitis and dissemination are rare in immunocompetent hosts. In this report, we describe a case of viral hepatitis secondary to disseminated HSV-2 in an immunocompetent patient with recurrent fevers and elevated aminotransferases. CASE REPORT A 57-year-old man with a history of type 2 diabetes and hypertension was admitted with a right index finger lesion concerning for an abscess. He underwent successful incision and drainage and was started on ampicillin-sulbactam. On Day 2 of hospitalization, he developed recurrent fevers and elevated aminotransferases and inflammatory markers. An extensive infectious, rheumatologic, and malignancy workup were pursued without immediate findings. Imaging demonstrated cirrhotic morphology of the liver and splenomegaly, but lab markers were intact for liver synthetic function. On Day 7 of hospitalization, fever frequency decreased, and HSV-2 titers resulted, with positive IgM and negative IgG. He subsequently developed erythematous, raised lesions in multiple dermatomes. Nucleic acid amplification testing of biopsied lesions was positive for HSV-2, confirming viral hepatitis secondary to disseminated HSV-2. He was started on intravenous acyclovir and discharged on valacyclovir following improvement in symptoms. CONCLUSIONS We report a case of viral hepatitis secondary to disseminated HSV-2 in an immunocompetent host. Up to 25% of cases occur in immunocompetent hosts and many patients do not develop characteristic skin lesions. Early diagnosis and treatment of viral hepatitis secondary to disseminated HSV remains vital to minimize morbidity and mortality.

Outcomes of Kidney Transplant Recipients With Posttransplant Genitourinary Infectious Complications: A Single Center Study.

OBJECTIVES: Long-term outcomes of kidney transplant recipients with postoperative genitourinary tract infections are not well characterized. In this single center retrospective study, we aimed to investigate the long-term effects of early posttransplant genitourinary infections under a protocol that included 1 month of antibiotic prophylaxis on graft failure and patient outcomes. MATERIALS AND METHODS: Electronic medical records of 1752 recipients of kidney-alone transplant between January 2000 and December 2008 were reviewed. Of these, 344 patients had postoperative genitourinary tract infections within 6 months of transplant. Infections included urinary tract infections, recurrent urinary tract infections, and pyelonephritis. All patients received 1-month of treatment with antibiotic prophylaxis for genitourinary infections after graft placement. Kaplan-Meier survival curves and multivariable regression modeling were performed to determine survival outcomes. RESULTS: In the 344 patients with postoperative infections, the most common cause was Escherichia coli (34.9%). Kaplan-Meier graft survival results showed no significant differences (P = .08) among those with and those without postoperative urinary tract infections; however, patient survival (P = .01) was significantly different. Multivariate analysis demonstrated no significant trend regarding graft failure (hazard ratio: 1.28; 95% confidence interval, 0.95-1.71; P = .09) or patient death (hazard ratio: 1.33; 95% confidence interval, 0.98-1.79; P = .06) in patients with and without genitourinary infections. The major cause of graft failure was infection in the infection cohort (17.4%). CONCLUSIONS: Kidney transplant recipients who develop urinary tract infections within 6 months of transplant may be at increased risk of graft failure or patient death; however, further studies are needed to elucidate the relationship between posttransplant infections and long-term outcomes.

Variation in practice patterns and outcomes across United Network for Organ Sharing allocation regions.

BACKGROUND: The number of heart transplants performed is limited by organ availability and is managed by the United Network for Organ Sharing (UNOS). Efforts are underway to make organ disbursement more equitable as demand increases. HYPOTHESIS: Significant variation exists in contemporary patterns of care, wait times, and outcomes among patients undergoing heart transplantation across UNOS regions. METHODS: We identified adult patients undergoing first, single-organ heart transplantation between January 2006 and December 2014 in the UNOS dataset and compared sociodemographic and clinical profiles, wait times, use of mechanical circulatory support (MCS), status at time of transplantation, and 1-year survival across UNOS regions. RESULTS: We analyzed 17 096 patients undergoing heart transplantation. There were no differences in age, sex, renal function, and peripheral vascular resistance across regions; however, there was 3-fold variation in median wait time (range, 48-166 days) across UNOS regions. Proportion of patients undergoing transplantation with status 1A ranged from 36% to 79% across regions (P < 0.01), and percentage of patients hospitalized at time of transplantation varied from 41% to 98%. There was also marked variation in MCS and inotrope utilization (28%-57% and 25%-58%, respectively; P < 0.001). Durable ventricular assist device implantation varied from 20% to 44% (P < 0.001), and intra-aortic balloon pump utilization ranged from 4% to 18%. CONCLUSIONS: Marked differences exist in patterns of care across UNOS regions that generally trend with differences in waitlist time. Novel policy initiatives are required to address disparities in access to allografts and ensure equitable and efficient allocation of organs.

ACE inhibitor-associated intestinal angioedema in orthotopic heart transplantation.

Angiotensin-converting enzyme inhibitor induced angioedema commonly involves the head and neck area. We report a case of angiotensin-converting enzyme inhibitor induced intestinal angioedema in a heart transplant recipient on mTOR immunosuppression. A 36-year-old Caucasian woman with history of heart transplantation on sirolimus, tacrolimus and prednisone presented to the Emergency Department with abdominal pain, one day following lisinopril initiation. A computer tomography scan demonstrated diffuse bowel wall thickening consistent with pancolitis and edema. She was subsequently diagnosed with angiotensin-converting enzyme inhibitor induced angioedema. Patients on mTOR immunosuppression are at higher risk for this potentially life-threatening side effect. Knowledge of this interaction is critical for providers prescribing mTOR agents.

Outcomes of Kidney Transplant Recipients With Percutaneous Ureteral Interventions: A Single-Center Study.

BACKGROUND: Long-term outcomes of kidney transplantation recipients with percutaneous ureteral management of transplant ureteral complications are not well characterized. METHODS: Electronic records of 1753 recipients of kidney-alone transplant between January 2000 and December 2008 were reviewed. One hundred thirty-one patients were identified to have undergone percutaneous ureteral management, with placement of percutaneous nephrostomy tube or additional intervention (nephroureteral stenting and/or balloon dilation). Indications for intervention included transplant ureteral stricture or ureteral leak. Kaplan-Meier survival curves and multivariable regression modeling were performed to determine survival outcomes. RESULTS: Kaplan- Meier graft survival (P = 0.04) was lower in patients with percutaneous ureteral intervention for transplant ureteral complication. Graft survival at 1, 5, and 10 years was 94.3% 78.3%, and 59.1% for no intervention and 97.2%, 72.1%, and 36.2% for intervention cohort. Patient survival (P = 0.69) was similar between cohorts. Multivariate analysis demonstrated no association with graft failure (hazard ratio, 1.21; 95% confidence interval, 0.67-2.19; P = 0.53) or patient death (hazard ratio, 0.56; 95% confidence interval, 0.22-1.41; P = 0.22) in intervention group. The major cause of graft failure was infection for percutaneous ureteral intervention group (20.4%) and chronic rejection for those without intervention (17.3%). CONCLUSIONS: Kidney transplant recipients with percutaneous ureteral interventions for ureteral complications do not have a significant difference in graft and patient survival outcomes. Therefore, aggressive nonoperative management can be confidently pursued in the appropriate clinical setting.

Long-Term Outcomes of Kidney Transplant Recipients with Bladder Dysfunction: A Single-Center Study.

BACKGROUND: Long-term outcomes of kidney transplantation recipients with bladder dysfunction or prior bladder surgery are not well characterized. MATERIAL AND METHODS: Electronic records of 1753 recipients of kidney-alone transplant between January 2000 and December 2008 were reviewed. We found that 1652 recipients had normal bladder function, 80 had bladder dysfunction, and 21 had bladder substitute or urinary diversion. Kaplan-Meier survival curves and multivariable regression modeling were performed to determine survival outcomes. RESULTS: Kaplan-Meier graft survival (p=.11) and patient survival (p=.18) were lower in recipients with bladder surgery but not statistically significant. Multivariate analysis demonstrated inferior graft survival (HR 3.57, 95% CI 1.06-12.1, p =0.04) and a trend towards inferior patient survival (HR 3.19, 95% CI .71-14.5, p=0.13) in reci-pients with bladder surgery. The major cause of graft failure was chronic rejection for normal function (17.1%) and bladder dysfunction (28.5%), and infection for bladder surgery (28.5%). Post-operative urinary infectious and surgical complications were higher in recipients with bladder dysfunction (35%) and substitutes (52.3%) compared with normal function (12.8%). CONCLUSIONS: Kidney transplant recipients with prior bladder surgery have an increased risk of graft failure and an increased risk of infectious urinary complications. These risks should be considered in recipient selection and post-transplant management.

Sports participation with arachnoid cysts.

OBJECT There is currently no consensus on the safety of sports participation for patients with an intracranial arachnoid cyst (AC). The authors' goal was to define the risk of sports participation for children with this imaging finding. METHODS A survey was prospectively administered to 185 patients with ACs during a 46-month period at a single institution. Cyst size and location, treatment, sports participation, and any injuries were recorded. Eighty patients completed at least 1 subsequent survey following their initial entry into the registry, and these patients were included in a prospective registry with a mean prospective follow-up interval of 15.9 ± 8.8 months. RESULTS A total 112 patients with ACs participated in 261 sports for a cumulative duration of 4410 months or 1470 seasons. Of these, 94 patients participated in 190 contact sports for a cumulative duration of 2818 months or 939 seasons. There were no serious or catastrophic neurological injuries. Two patients presented with symptomatic subdural hygromas following minor sports injuries. In the prospective cohort, there were no neurological injuries CONCLUSIONS Permanent or catastrophic neurological injuries are very unusual in AC patients who participate in athletic activities. In most cases, sports participation by these patients is safe.

Perioperative characteristics and complications in obese patients undergoing anterior cervical fusion surgery.

In the USA, obesity rates have significantly increased in the last 15 years. Mirroring this trend, a large proportion of patients undergoing spinal surgery are obese. Concern exists for increased complications due to surgical challenges posed by obese patients and their often-prevalent comorbidities. Studies have shown associations between body mass index (BMI) and perioperative complications in lumbar and thoracolumbar fusion surgeries; however, few studies have evaluated the impact of obesity on anterior cervical fusion surgery. As such, this study aimed to evaluate complications and perioperative characteristics in obese patients undergoing anterior cervical fusion. We queried medical records to identify patients with BMI >30 who underwent anterior cervical fusion surgery. A total of 69 patients were included and subdivided based on obesity class: Class 1 (BMI 30-35), Class 2 (BMI 35-40), and Class 3 (BMI >40). Subgroup analysis included comorbidities, diagnosis, procedure, levels treated, and length of hospital stay. Overall mean BMI was 35.1, mean age was 54.3 years, and 43 (63.3%) were men. Disc herniation was the most common diagnosis. Length of stay differed significantly among obesity subgroups (p=0.02). Mean length of stay was 2.8, 3.5, and 4.0 days for Classes 1, 2, and 3, respectively. Three (4.3%) complications were observed, comprising of urinary tract infection, wound dehiscence, and neck hematoma. Complication rates by class were 5.5%, 0%, and 16.6% for Classes 1, 2, and 3, respectively (p=0.17). We found that obese patients undergoing anterior cervical spine surgery experience relatively few complications. Hospital stay, however, appears to lengthen with increased BMI.

Radiation safety and spine surgery: systematic review of exposure limits and methods to minimize radiation exposure.

BACKGROUND: Ionizing radiation is typically used during spine surgery for localization and guidance in instrumentation placement. Minimally invasive (MI) surgical procedures are increasingly popular and often require significantly more fluoroscopy, placing surgeons at risk for increased radiation exposure and radiation-induced complications. This study provides recommendations for minimizing risk of radiation-induced injury to spine surgeons and summarizes studies addressing radiation exposure in spine procedures. METHODS: The PubMed database was queried for relevant articles pertaining to radiation exposure in spine surgery. RESULTS: Discectomy, percutaneous pedicle screw placement, MI transforaminal lumbar interbody fusion, MI lateral lumbar interbody fusion, and vertebroplasty/kyphoplasty procedures were assessed. The highest radiation doses were seen with MI pedicle screw placement, MI transforaminal lumbar interbody fusion, vertebroplasty and kyphoplasty, and percutaneous endoscopic lumbar discectomy. Use of lead aprons and thyroid shields reduces effective dose by several orders of magnitude. Proper operator positioning also minimizes radiation exposure. Lead gloves decrease dose to the surgeon's hand from scatter if the hand is out of the x-ray beam most of the time. If prolonged exposure of the hand cannot be avoided, the technician should collimate the surgeon's hand out of the beam or use instruments to position the hand farther from the beam. In addition to using less fluoroscopy, pulsed fluoroscopy can decrease overall dose in a procedure. CONCLUSIONS: Spine surgeons should reduce their exposure to radiation to minimize risk of potential long-term complications. Strategies include minimizing fluoroscopy use and dose, proper use of protective gear, and appropriate manipulation of fluoroscopic equipment.

SOD1 in cerebral spinal fluid as a pharmacodynamic marker for antisense oligonucleotide therapy.

BACKGROUND: Therapies designed to decrease the level of SOD1 are currently in a clinical trial for patients with superoxide dismutase (SOD1)-linked familial amyotrophic lateral sclerosis (ALS). OBJECTIVE: To determine whether the SOD1 protein in cerebral spinal fluid (CSF) may be a pharmacodynamic marker for antisense oligonucleotide therapy and a disease marker for ALS. DESIGN: Antisense oligonucleotides targeting human SOD1 were administered to rats expressing SOD1G93A. The human SOD1 protein levels were measured in the rats' brain and CSF samples. In human CSF samples, the following proteins were measured: SOD1, tau, phosphorylated tau, VILIP-1, and YKL-40. PARTICIPANTS: Ninety-three participants with ALS, 88 healthy controls, and 89 controls with a neurological disease (55 with dementia of the Alzheimer type, 19 with multiple sclerosis, and 15 with peripheral neuropathy). RESULTS: Antisense oligonucleotide-treated SOD1G93A rats had decreased human SOD1 messenger RNA levels (mean [SD] decrease of 69% [4%]) and decreased protein levels (mean [SD] decrease of 48% [14%]) in the brain. The rats' CSF samples showed a similar decrease in hSOD1 levels (mean [SD] decrease of 42% [14%]). In human CSF samples, the SOD1 levels varied a mean (SD) 7.1% (5.7%) after additional measurements, separated by months, were performed. The CSF SOD1 levels were higher in the participants with ALS (mean [SE] level, 172 [8] ng/mL; P<.05) and the controls with a neurological disease (mean [SE] level, 172 [6] ng/mL; P<.05) than in the healthy controls (mean [SE] level, 134 [4] ng/mL). Elevated CSF SOD1 levels did not correlate with disease characteristics in participants with ALS or controls with dementia of the Alzheimer type, but they did correlate with tau, phosphorylated tau, VILIP-1 and YKL-40 levels in controls with dementia of the Alzheimer type. CONCLUSIONS: SOD1 in CSF may be an excellent pharmacodynamic marker for SOD1-lowering therapies because antisense oligonucleotide therapy lowers protein levels in the rat brain and rat CSF samples and because SOD1 levels in CSF samples from humans are stable over time.