Osame Motor Disability Score Research Articles

Multicenter, randomized, double-blind, placebo-controlled phase 3 study of mogamulizumab with open-label extension study in a minimum number of patients with human T-cell leukemia virus type-1-associated myelopathy

Human T-cell leukemia virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a chronic neurodegenerative disease. This multicenter, randomized phase 3 study evaluated the efficacy and safety of 0.3 mg/kg intravenous mogamulizumab, a monoclonal antibody targeting-CC chemokine receptor 4, every 12 weeks in HAM/TSP patients. This study comprised a 24-week double-blind, placebo-controlled period, 24-week open-label period, and extension treatment period. The primary endpoint was the proportion of patients with a ≥ 1-grade improvement in the Osame motor disability score (OMDS). Secondary endpoints were changes in HTLV-1 proviral load, 10-m timed walk, cerebrospinal fluid (CSF) neopterin levels, and safety. The exploratory endpoint was CSF chemokine C-X-C motif ligand 10 (CXCL10) levels. Thirty-four and 33 patients were randomized to mogamulizumab and placebo arms, respectively. At the end of the double-blind period, no significant difference was found in the OMDS improvement rate or other secondary efficacy endpoints assessing motor activities. However, the mogamulizumab arm showed a significant decrease in HTLV-1 proviral load (− 59.39 ± 29.91% vs. placebo 2.32 ± 36.31%) and CSF neopterin (p < 0.001)/CXCL10 levels (p = 0.004). The baseline OMDS pattern and the 60–80% HTLV-1 proviral load reduction were sustained through the open-label and extension treatment periods. Although a higher incidence of rash (69.2%) was reported, the safety profile was similar compared with a previous phase 1/2a study. We found no significant difference in clinical benefit; however, mogamulizumab may provide long-term clinical benefit by preventing disease progression, as CSF neopterin/CXCL10 levels are associated with long-term prognosis in HAM/TSP.Clinical Trial Registration Number: NCT03191526 (registered date: 6-June-2017).

Use of Oral Corticosteroids to Treat HTLV-1-Associated Myelopathy (HAM) in São Paulo, Brazil

Background: During the development of human T-cell lymphotropic virus (HTLV-1)-associated myelopathy (HAM), the inflammatory phenomenon is very prominent and is a major factor in the outcome of the disease. The use of corticosteroids can modify their natural history, and in this study, we evaluated the effectiveness of using daily low-dose prednisone. Methods: This was a cross-sectional study using data collected by physicians monitoring patients with HAM at the Institute of Infectious Diseases “Emilio Ribas”, the main referral center for patients with infectious diseases in São Paulo, Brazil. The objective was to determine if daily low-dose oral prednisone would be able to stabilize the progression of HAM. The outcome measure was a change in the Osame Motor Disability Score (OMDS). Results: Fifty-four patients used treatment with oral prednisone, 5 milligrams daily. Nine cases were excluded from the study because they did not have at least two rating scales within a minimum interval of one year, and six were excluded for being co-infected with HIV and/or HCV. Thirty-nine patients met this criterion and were included for analysis. The majority were women (71.8%), the mean age was 56.51 years old (SD ± 9.74), and the median time of use of prednisone was 16 months. Thirty-two patients (82.05%) maintained the same OMDS, 5/39 (12.82%) had clinical worsening, and 2/39 (5.13%) improved. Conclusions: There was a trend toward clinical stability with the use of oral corticosteroids. However, randomized controlled trials are necessary to evaluate the use in clinical practices in all stages of HAM.

Long-term safety and efficacy of mogamulizumab (anti-CCR4) for treating virus-associated myelopathy.

Some carriers of human T-cell leukemia virus type 1 (HTLV-1), a retrovirus that primarily infects CD4+ T cells and causes lifelong infection, develop HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Current treatments for HAM/TSP are insufficient with problematic long-term side effects. This study evaluated the long-term safety and efficacy of the anti-CCR4 antibody mogamulizumab in patients with HAM/TSP over a 4-year period. We conducted an open-label, extended long-term study (UMIN trial number: UMIN000019942) of a Phase 1-2a trial with mogamulizumab for HAM/TSP (UMIN000012655). The study participants were patients with corticosteroid-resistant HAM/TSP who could walk 10 m with or without assistive tools. Mogamulizumab was administered at 0.01, 0.03, 0.1, or 0.3 mg/kg at intervals of ≥8 weeks (0.01 and 0.03 mg/kg) or ≥12 weeks (0.1 and 0.3 mg/kg). HTLV-1 proviral load, cerebrospinal fluid inflammatory markers, and clinical symptoms were summarized by descriptive statistics. Missing observations were imputed using the last-observation-carried-forward method. As a post-hoc analysis, we evaluated the therapeutic effect of mogamulizumab on gait function by comparing it with contemporary control data from a HAM/TSP patient registry. Of the 21 participants in the Phase 1-2a, 18 (86%) enrolled in the long-term study and 15 (71%) continued repeated doses of mogamulizumab for 4 years. The median dose was 0.1 mg/kg after 4 years. Seventeen of 21 participants (81%) experienced grade 1-2 skin-related adverse events. Observed grade 3 drug-related adverse effects included three cases of lymphopenia and one case each of microscopic polyangiitis, elevated levels of aspartate aminotransferase, and neutropenia. Four of 21 participants (19%) developed neutralizing antibodies. After 4 years, the peripheral blood proviral load and the number of infected cells in CSF decreased by 60.7% and 66.3%, respectively. Neopterin and CXCL10 CSF concentrations decreased by 37.0% and 31.0%, respectively. Among the 18 participants, spasticity and Osame Motor Disability Score (OMDS) improved in 17 (94%) and 4 (22%), respectively. However, 10 m walking time worsened by 7.3% on average. Comparison with the contemporary control group demonstrated that mogamulizumab inhibited OMDS progression (p = 0.02). The results of the study suggest that mogamulizumab has long-term safety and inhibitory effect on lower limb motor disability progression in corticosteroid-treated patients with HAM/TSP. This will provide a basis for the application of mogamulizumab in HAM/TSP treatment.

Efficacy of Corticosteroid Therapy for HTLV-1-Associated Myelopathy: A Randomized Controlled Trial (HAMLET-P).

Corticosteroids are most commonly used to treat HTLV-1-associated myelopathy (HAM); however, their clinical efficacy has not been tested in randomized clinical trials. This randomized controlled trial included 8 and 30 HAM patients with rapidly and slowly progressing walking disabilities, respectively. Rapid progressors were assigned (1:1) to receive or not receive a 3-day course of intravenous methylprednisolone in addition to oral prednisolone therapy. Meanwhile, slow progressors were assigned (1:1) to receive oral prednisolone or placebo. The primary outcomes were a composite of ≥1-grade improvement in the Osame Motor Disability Score or ≥30% improvement in the 10 m walking time (10 mWT) at week 2 for rapid progressors and changes from baseline in 10 mWT at week 24 for slow progressors. In the rapid progressor trial, all four patients with but only one of four without intravenous methylprednisolone achieved the primary outcome (p = 0.14). In the slow progressor trial, the median changes in 10 mWT were −13.8% (95% CI: −20.1–−7.1; p < 0.001) and −6.0% (95% CI: −12.8–1.3; p = 0.10) with prednisolone and placebo, respectively (p for between-group difference = 0.12). Whereas statistical significance was not reached for the primary endpoints, the overall data indicated the benefit of corticosteroid therapy. (Registration number: UMIN000023798, UMIN000024085)

Nanomicellar Curcumin Supplementation Improves the Clinical Manifestations of HAM/TSP Patients.

HTLV-1 infection causes a chronic, progressive, demyelinating, neuroinflammatory disease called HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Treatment of HAM/TSP patients which have high levels of proviral load and pro-inflammatory markers is a challenge for clinicians. Therefore, we aimed to investigate the immunomodulatory, anti-inflammatory, and antiviral effects of curcumin in HAM/TSP patients. In this study, 20 newly diagnosed HAM/TSP patients (2 men and 18 women) were enrolled and evaluated for clinical symptoms, HTLV-1 proviral load, Tax and HBZ expression, neopterin serum concentration, and complete blood count (CBC) before and 12weeks after treatment with nanomicellar curcumin (80mg/day, orally). Clinical symptoms such as the mean Osame Motor Disability Score and Ashworth Spasticity Scale Score were significantly improved after the treatment (P=0.001 and P=0.001). Sensory symptoms such as pain and paresthesia were significantly decreased in all of the patients (P=0.001). Furthermore, urinary disorders, including urinary frequency, incontinence, and the feeling of incomplete bladder emptying, were significantly improved (P=0.001, P=0.003, and P=0.03). However, the mean HTLV-1 proviral load (P=0.97) and CBC were similar, whereas Tax, HBZ, and neopterin levels tend to increase after the treatment (P=0.004, P=0.08, and P=0.04). Results suggest that curcumin can safely improve the clinical symptoms of HAM/TSP patients but has no observable positive effects on the HTLV-1 proviral load, Tax, and HBZ expression. Therefore, prolonged use or the use of curcumin with antiviral agents in addition to clinical signs and symptoms can reduce the HTLV-1 proviral load and the expression of functional viral factors such as Tax and HBZ.

Real-world clinical course of HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) in Japan

BackgroundAs human T-cell leukemia virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a rare chronic neurological disease, large scale studies to collect continuous clinical data have been difficult to conduct. Therefore, the incidence of comorbidities and drug utilization data remain unknown. When conducting trials to develop new drugs in rare disease such as HAM/TSP, historical control data obtained from registry studies would be useful, as cohorts in rare disease tend to be small. Long-term follow-up of patients with a chronic disease can also be challenging. In this study, we addressed the following two goals using registry data on patients (n = 486) enrolled in the Japanese HAM/TSP patient registry “HAM-net” from 2012 to 2016: 1) to clarify the epidemiological information of HAM/TSP such as the incidence of comorbidities and drug utilization and 2) to provide the real-world data on changes in lower limb motor dysfunction.ResultsIn HAM-net-registered patients, common comorbidities were fractures, herpes zoster, and uveitis, with incidences of 55.5, 10.4, and 6.5, respectively, per 1000 person-years. Every year, oral steroid treatment was administered in 48.2–50.7% of the HAM-net-registered patients and interferon-α treatment was used in 2.6–3.5% of patients. The median dose of oral prednisolone was low at 5.0 mg/day. The incidence of fractures and herpes zoster tended to be higher in the steroid-treated group than in the untreated group (fractures: 61.0 vs. 48.3, herpes zoster: 12.7 vs. 8.8, per 1000 person-years). The analysis of chronological change in Osame motor disability score (OMDS) indicated that the mean change in OMDS was + 0.20 [95% confidence intervals (CI): 0.14–0.25] per year in the one-year observation group (n = 346) and + 0.57 (95% CI: 0.42–0.73) over four years in the four-year observation group (n = 148). Significant deterioration of OMDS was noted in all subgroups with varying steroid use status.ConclusionsThis study revealed the incidence of comorbidities and drug utilization data in patients with HAM/TSP using registry data. Furthermore, this study provided real-world data on chronological changes in lower limb motor dysfunction in patients with HAM/TSP, indicating the utility of these data as historical controls.

Proposal of Classification Criteria for HTLV-1-Associated Myelopathy/Tropical Spastic Paraparesis Disease Activity.

Human T-lymphotropic virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a rare chronic neuroinflammatory disease. While the disease usually progresses slowly without remission, there is a subgroup of patients with rapid progression and another subgroup with very slow progression. However, there have been no reports to date that have successfully determined the criteria to differentiate these subgroups. Therefore, we initially conducted a statistical modeling analysis to explore representative patterns of disease progression using data from our nationwide HAM/TSP patient registration system (“HAM-net”). The latent class mixed model analysis on the retrospective data (n = 205) of disease progression measured by the change in Osame Motor Disability Score from the onset of the disease to diagnosis demonstrated three representative progression patterns of HAM/TSP. Next, to test the effect of the progression rate at the initial phase of the disease on long-term prognosis, we divided 312 “HAM-net” registered patients into three groups (rapid, slow, and very slow progressors) based on the progression rate, then analyzed long-term functional prognosis of each group using the Kaplan–Meier method. Our data clearly demonstrated that the rapid progression at the early phase of the disease is an important poor prognostic factor. Moreover, to determine the biomarkers capable of discriminating the difference in disease activity, we compared the value of potential biomarkers of HAM/TSP among rapid (n = 15), slow (n = 74), very slow (n = 7), and controls (non-HAM/TSP patients, n = 18). The cerebrospinal fluid (CSF) levels of neopterin and C-X-C motif chemokine 10 (CXCL10) were the most valuable markers to discriminate among rapid, slow, and very slow progressors. To differentiate between rapid and slow progressors, the cut-off values of neopterin and CXCL10 were determined to be 44 pmol/mL and 4400 pg/mL, respectively. Furthermore, to differentiate between slow and very slow progressors, these values were determined to be 5.5 pmol/mL and 320 pg/mL, respectively. Notably, we found that CSF levels of these markers in very slow progressors were within the reference range. Thus, we propose a new classification criteria for disease activity of HAM/TSP that may contribute to improving the treatment algorithm for HAM/TSP.

Effectiveness of Daily Prednisolone to Slow Progression of Human T-Lymphotropic Virus Type 1-Associated Myelopathy/Tropical Spastic Paraparesis: A Multicenter Retrospective Cohort Study.

Millions of people are infected with human T-lymphotropic virus type 1 (HTLV-1) worldwide; notable endemic areas include Brazil, the Caribbean islands, Iran, and Japan. A small number of those infected develop the progressive neurodegenerative disease HTLV-1-associated myelopathy (HAM), also known as tropical spastic paraparesis (TSP), which is characterized by chronic spinal cord inflammation and accompanying myelopathic symptoms. The corticosteroid prednisolone (PSL) is a classic treatment for HAM/TSP, yet its effectiveness remains controversial owing to insufficient and conflicting studies. We conducted a multicenter retrospective study using data collected by physicians monitoring patients with HAM/TSP at 7 hospitals throughout Japan. The Osame Motor Disability Score (OMDS) was used to evaluate 57 patients treated with low-dose PSL (mean 4.8mg/day) versus 29 untreated patients. Roughly half of the evaluations spanned < 3years (Short-Term) and half > 3years (Long-Term), with a mean of 3.4years. While the OMDS of most untreated patients remained unchanged in the Short-Term (87%) and worsened in the Long-Term (79%), most treated patients improved in the Short-Term (52%) and remained unchanged or improved in the Long-Term (68%). Overall, the mean change in OMDS per year was -0.13 in the Steroids group and +0.12 in the Untreated group (p < 0.01). This study addressed the effectiveness of PSL for HAM/TSP in 3 novel ways: 1) continuous low-dose administration; 2) comparison with an untreated group; and 3) Long-Term evaluation. These findings provide robust evidence supporting PSL maintenance therapy for HAM/TSP.

Evaluation of T Regulatory Lymphocytes Transcription Factors in HTLV-1-Associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP) Patients.

HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is an aggressive neurological disease. The CD4+CD25+ T cell population plays pivotal roles in the maintenance of immunological tolerance and prevention of such autoimmune diseases. In the current study, proviral load (PVL), factor forkhead box p3 (Foxp3), and glucocorticoid-induced tumor necrosis factor receptor-related protein (GITR) gene expression and regulatory T cells (Tregs) counts of 21 HAM/TSP patients and 16 HTLV-1 healthy carriers (ACs) were measured using real-time PCR, TaqMan method, and flow cytometry. The demographic, history of disease, and severity of myelopathy were assessed by a checklist and the Osame motor disability score (OMDS). The mean OMDS for HAM/TSP was 4.82±2.37 which had no significant correlation with Treg count or the expression of Foxp3, GITR, and PVL. The CD4+CD25+ cell counts had no significant differences between HAM/TSP and ACs. Findings revealed a higher PVL in HAM/TSPs (313.36 copies/104) compared to ACs (144.93 copies/104, p=0.035). The Foxp3 and GITR mRNA levels were lower in HAM/TSP patients (11.78 and 13.80, respectively) than those in healthy carriers (18.44 and 21.00, p=0.041 and 0.03, respectively). There was a significant correlation between Treg frequency and Foxp3 gene expression (R=0.67, p=0.006) and GITR and Foxp3 (R=0.84, p=0.042) in HAM/TSP patients. Furthermore, the transcription factors have strong correlations with CD4+CD25+ T cell frequencies. These findings suggest that HTLV-1 infection can modify the expression of main functional transcription factors, FOXP3 and GITR, which may lead to immune response deterioration of Tregs and consequently HAM/TSP manifestation.

HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP): A comparative study to identify factors that influence disease progression

ObjectiveHTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) can progress slowly or rapidly even though a set of symptoms such as spastic paraparesis with pathological reflexes and sweating loss of the lower extremities are commonly observed in patients. Although most of the patients are thought to be infected to HTLV-1 from their mothers by breast feeding, symptoms of HAM/TSP typically manifest in patients later in life (50–60years old in age) and also with a higher prevalence of women to men at a ratio of approximately 3:1. Probability of developing HAM/TSP and how fast an individual's disease may progress from the time of diagnosis could be multifactorial. MethodsWe reviewed the records of 150 patients with HAM/TSP admitted to Kagoshima University Hospital between 2002 and 2014. Laboratory data of cerebrospinal fluid and serum and the clinical measurements including age, age of disease onset, progression rate, duration of illness, initial symptoms, Osame's Motor Disability Score were evaluated. Rapid disease progression of the disease was defined by deterioration of motor disability by >3 grades within 2years. ResultsOf 150 HAM/TSP patients in our cohort, 114 cases (76%) were females. Patients presenting with rapid disease progression are approximately 15years older at the age of onset than those with a protracted disease course, and have increased number of cell, and elevated levels of protein as well as anti-HTLV-1 antibody titer in the CSF, suggesting a more active inflammatory process. There is no significant difference in the average values of clinical and laboratory parameters between the sexes. Furthermore, there is no apparent correlation between rate of disease progression and gender. ConclusionsOur results suggest that age and virus mediated inflammation are correlated with disease phenotypes while additional factors such as host or HTLV-1 genetics and gender may influence disease susceptibility.

Nation-wide epidemiological study of Japanese patients with rare viral myelopathy using novel registration system (HAM-net)

BackgroundAt least one million people are infected with human T-lymphotropic virus type 1 (HTLV-1) in Japan, a small percentage of whom develop HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) or adult T-cell leukemia/lymphoma (ATLL). Patients with HAM/TSP suffer from progressively worsening myelopathic symptoms, such as motor disability and bladder dysfunction, and may become wheelchair-bound or even bedridden.MethodsTo learn more about this rare, debilitating disease, we established the national registration system “HAM-net” in March 2012. We continuously obtain detailed data from enrolled patients using the registration forms and an annual telephone interview. In this retrospective study, we describe the demographics and clinical histories of 383 registered patients from all over Japan.ResultsPatients were diagnosed at a median of 53 years old, long after disease onset at 45. Most (55.3 %) were originally from the southernmost regions, Kyushu and Okinawa. The main initial symptoms were difficulty walking (81.9 %), urinary dysfunction (38.5 %), and lower limb sensory disturbances (13.9 %). Many patients reported frequent leg numbness and leg pain, and the vast majority required medical intervention for urinary symptoms and constipation. A median of 8 years elapsed from the onset of motor symptoms to Osame Motor Disability Score (OMDS) 5 (requiring unilateral support), 12.5 years to OMDS 6 (requiring bilateral support), and 18 years to OMDS 9 (unable to walk). Health Assessment Questionnaire - Disability Index (HAQ-DI) tasks related to mobility, as opposed to hand motions, were very difficult for HAM/TSP patients and well-correlated with OMDS. Scores on the MOS 36-Item Short-Form Health Survey (SF-36) indicated that physical functioning was severely impaired in HAM/TSP patients. Patients with a history of blood transfusion (19.1 %) were older and suffered from more severe disability as indicated by their high HAQ-DI scores. Patients with a family history of HAM/TSP (8.4 %) were younger and had relatively mild symptoms given their long disease durations; many (15.6 %) also had a relative with ATLL.ConclusionsThe HAM-net national registration system has been an effective tool for gathering personal and clinical data from HAM/TSP patients scattered throughout Japan. We expect to conduct many retrospective and prospective epidemiological studies using HAM-net in the future.

HAM-net national patient registration system reveals details of how Japanese patients with HTLV-1-associated myelopathy/tropical spastic paraparesis progress over time

In order to better understand and manage HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP), a rare virus-induced neurodegenerative disease, we have established a registration system known as HAM-net to gather data from patients all over Japan. In this prospective epidemiological study, we analyzed the data from the 297 registered patients who were available to be interviewed once upon registration and again one year later. On average, these patients were 63.2 years old, had experienced their first symptoms at age 44.2, and were diagnosed at age 51.3. More patients were female (74.1%) than male (25.9%). During the one-year interval between surveys, the average Health Assessment Questionnaire Disability Index (HAQ-DI) score rose significantly (P<0.001), indicating noticeably declining health. The average Osame Motor Disability Score (OMDS) also worsened (P<0.001), rising from 5.9±2.3 to 6.2±2.4. While the majority of patients (81%) experienced no change in OMDS, 53 patients (18%) worsened, and only 4 patients (1%) improved. Importantly, when compared to patients given other treatments, those treated continuously with oral steroids were less likely to experience a rise in OMDS. Fifty-four of the patients were deemed “rapid progressors,” defined as a patient who progressed from the onset of motor symptoms to at least OMDS 5 within two years, and 15 of those were “very rapid progressors,” defined as those who reached at least OMDS 6. Both rapid progressors and very rapid progressors exhibited several statistically significant traits compared to the other patients: older when motor symptoms first manifested, older when first diagnosed, higher OMDS, higher HAQ-DI score, shorter gap between disease onset and diagnosis, and shorter disease duration from onset to present day. We will continue registering new patients and analyzing changes in their health over time.

Evaluation of clinical outcome measures for HAM/TSP

HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a rare disease for which there has been no effective therapy. Therefore, there is an urgent need to develop new effective drugs. To promote new drug development, we first need to identify appropriate efficacy outcome measures and then conduct clinical trials for the treatment of HAM/TSP. In this study, we aimed to determine what outcome measures are more suitable for primary outcome measures in clinical trials for HAM/TSP patients. First, we compared some existing outcome measures such as 10-meter walk test (10mWT), Osame's motor disability score (OMDS) and Expanded Disability Status Scale (EDSS) in terms of clinical relevance, objectivity, quantifiability and so on. Second, we measured 10mWT, 2-minute walk test (2minWT), OMDS, HAQ-disability index (HAQ-DI) in 60 patients with HAM/TSP and analyzed the correlation between them. Last, we compared 10mWT with 2minWT in terms of sample size required for a clinical trial. As a result of a first comparison with some existing outcome measures, we determined that outcome measures of gait disturbance were appropriate for primary outcome measures in clinical trials because gait disturbance is most common symptoms of HAM/TSP. Among the outcome measures of gait disturbance, we selected 10mWT and 2minWT based on objectivity and quantifiability. Both 10mWT and 2minWT correlated well with OMDS (rs = 0.702 and 0.708). Likewise, both outcome measures also correlated well with HAQ-DI. Furthermore, estimated sample size required to detect a 20% improvement of 10mWT was 26 cases that was the same as that of 2minWT. In conclusion, this study suggested that both 10mWT and 2minWT are useful as primary outcome measures in clinical trials for HAM/TSP patients.

Biomarker to predict treatment response in patients with HTLV-1 associated myelopathy/Tropical spastic paraparesis (HAM/TSP)

There are only a few studies which evaluate the utility of biomarkers to predict treatment response in HTLV-1 associated myelopathy/Tropical spastic paraparesis (HAM/TSP). Therefore, we investigated biomarkers of cerebrospinal fluid (CSF) in patients with HAM/TSP treated with high-dose methylpredonisolone (SP). Eight patients with HAM/TSP, who admitted to our hospital from 2012 to 2014 for treatment of HAM/TSP, were enrolled in this study. Three patients were rapidly progressive types and five patients were slowly progressive types. We evaluated the treatment response with SP and interferon-alpha (INF-a). The CSF was collected before and after the SP treatment. As the candidates of biomarker, CXCL10, neopterin, cell count and anti-HTLV-1 antibody titer in the CSF were measured. The motor functions were evaluated using the Osame Motor Disability Score (OMDS), 10m walking time and 6 minutes walking distance. The pre-treatment CXCL10 levels in the CSF of patients with rapidly progressive types were higher compared to those with slowly progressive types and the treatment response was remarkably better in rapidly progressive types. Level of CXCL10 in the CSF before treatment is related to improvement rate of motor function after the SP treatment in all patients. These results indicate that CXCL10 level in the CSF may be a biomarker to predict treatment response with SP.

Triple Therapy with Prednisolone, Pegylated Interferon and Sodium Valproate Improves Clinical Outcome and Reduces Human T-Cell Leukemia Virus Type 1 (HTLV-1) Proviral Load, Tax and HBZ mRNA Expression in Patients with HTLV-1-Associated Myelopathy/Tropical Spastic Paraparesis.

Considering that there is no effective treatment for human T-cell leukemia virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis, this study aimed to assess the impact of triple combination therapy-interferon-α, valproic acid, and prednisolone-on clinical outcomes, main HTLV-1 viral factors, and host anti-HTLV-1 antibody response. HTLV-1 proviral load (PVL), and HBZ and Tax mRNA expression levels were measured in peripheral blood mononuclear cells of 13 patients with HTLV-1-associated myelopathy/tropical spastic paraparesis before and after treatment with 180 μg pegylated interferon once a week, 10-20 mg/kg/day sodium valproate, and 5 mg/day prednisolone for 25 weeks using a TaqMan real-time polymerase chain reaction assay. Furthermore, anti-HTLV-1 titer, Osame Motor Disability Score, Ashworth spasticity scale, and urinary symptoms (through standard questionnaire and clinical monitoring) were assessed in patients before and after the treatment. HTLV-1 PVL and HBZ expression significantly decreased after the treatment [PVL from 1443 ± 282 to 660 ± 137 copies/10(4) peripheral blood mononuclear cells (p = 0.01); and HBZ from 8.0 ± 1.5 to 3.0 ± 0.66 (p < 0.01)]. Tax mRNA expression decreased after the treatment from 2.26 ± 0.45 to 1.44 ± 0.64, but this reduction was not statistically significant (p = 0.10). Furthermore, anti-HTLV-1 titer reduced dramatically after the treatment, from 3123 ± 395 to 815 ± 239 (p < 0.01). Clinical signs and symptoms, according to Osame Motor Disability Score and Ashworth score, improved significantly (both p < 0.01). Urinary symptoms and sensory disturbances with lower back pain were reduced, though not to a statistically significant degree. Although signs and symptoms of spasticity were improved, frequent urination and urinary incontinence were not significantly affected by the triple therapy. The results provide new insight into the complicated conditions underlying HTLV-1-associated diseases.

A plasma diagnostic model of human T-cell leukemia virus-1 associated myelopathy.

ObjectiveHuman T-cell leukemia virus-1 (HTLV-1) associated myelopathy/tropic spastic paraparesis (HAM/TSP) is induced by chronic inflammation in spinal cord due to HTLV-1 infection. Cerebrospinal fluid (CSF) neopterin or proviral load are clinically measured as disease grading biomarkers, however, they are not exactly specific to HAM/TSP. Therefore, we aimed to identify HAM/TSP-specific biomarker molecules and establish a novel less-invasive plasma diagnostic model for HAM/TSP.MethodsProteome-wide quantitative profiling of CSFs from six asymptomatic HTLV-1 carriers (AC) and 51 HAM/TSP patients was performed. Fourteen severity grade biomarker proteins were further examined plasma enzyme-linked immunosorbent assay (ELISA) assays (n = 71). Finally, we constructed three-factor logistic regression model and evaluated the diagnostic power using 105 plasma samples.ResultsQuantitative analysis for 1871 nonredundant CSF proteins identified from 57 individuals defined 14 CSF proteins showing significant correlation with Osame's motor disability score (OMDS). Subsequent ELISA experiments using 71 plasma specimens confirmed secreted protein acidic and rich in cysteine (SPARC) and vascular cell adhesion molecule-1 (VCAM-1) demonstrated the same correlations in plasma (R = −0.373 and R = 0.431, respectively). In this training set, we constructed a HAM/TSP diagnostic model using SPARC, VCAM1, and viral load. Sensitivity and specificity to diagnose HAM/TSP patients from AC (AC vs. OMDS 1–11) were 85.3% and 81.1%, respectively. Importantly, this model could be also useful for determination of therapeutic intervention point (OMDS 1–3 + AC vs. OMDS 4–11), exhibiting 80.0% sensitivity and 82.9% specificity.InterpretationWe propose a novel less-invasive diagnostic model for early detection and clinical stratification of HAM/TSP.

CSF CXCL10, CXCL9, and Neopterin as Candidate Prognostic Biomarkers for HTLV-1-Associated Myelopathy/Tropical Spastic Paraparesis

BackgroundHuman T-lymphotropic virus type 1 (HTLV-1) -associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a rare chronic neuroinflammatory disease. Since the disease course of HAM/TSP varies among patients, there is a dire need for biomarkers capable of predicting the rate of disease progression. However, there have been no studies to date that have compared the prognostic values of multiple potential biomarkers for HAM/TSP.Methodology/Principal FindingsPeripheral blood and cerebrospinal fluid (CSF) samples from HAM/TSP patients and HTLV-1-infected control subjects were obtained and tested retrospectively for several potential biomarkers, including chemokines and other cytokines, and nine optimal candidates were selected based on receiver operating characteristic (ROC) analysis. Next, we evaluated the relationship between these candidates and the rate of disease progression in HAM/TSP patients, beginning with a first cohort of 30 patients (Training Set) and proceeding to a second cohort of 23 patients (Test Set). We defined “deteriorating HAM/TSP” as distinctly worsening function (≥3 grades on Osame's Motor Disability Score (OMDS)) over four years and “stable HAM/TSP” as unchanged or only slightly worsened function (1 grade on OMDS) over four years, and we compared the levels of the candidate biomarkers in patients divided into these two groups. The CSF levels of chemokine (C-X-C motif) ligand 10 (CXCL10), CXCL9, and neopterin were well-correlated with disease progression, better even than HTLV-1 proviral load in PBMCs. Importantly, these results were validated using the Test Set.Conclusions/SignificanceAs the CSF levels of CXCL10, CXCL9, and neopterin were the most strongly correlated with rate of disease progression, they represent the most viable candidates for HAM/TSP prognostic biomarkers. The identification of effective prognostic biomarkers could lead to earlier detection of high-risk patients, more patient-specific treatment options, and more productive clinical trials.

Severity score system for progressive myelopathy: development and validation of a new clinical scale

Progressive myelopathies can be secondary to inborn errors of metabolism (IEM) such as mucopolysaccharidosis, mucolipidosis, and adrenomyeloneuropathy. The available scale, Japanese Orthopaedic Association (JOA) score, was validated only for degenerative vertebral diseases. Our objective is to propose and validate a new scale addressing progressive myelopathies and to present validating data for JOA in these diseases. A new scale, Severity Score System for Progressive Myelopathy (SSPROM), was constructed covering motor disability, sphincter dysfunction, spasticity, and sensory losses. Inter-and intra-rater reliabilities were measured. External validation was tested by applying JOA, the Expanded Disability Status Scale (EDSS), the Barthel index, and the Osame Motor Disability Score. Thirty-eight patients, 17 with adrenomyeloneuropathy, 3 with mucopolysaccharidosis I, 3 with mucopolysaccharidosis IV, 2 with mucopolysaccharidosis VI, 2 with mucolipidosis, and 11 with human T-cell lymphotropic virus type-1 (HTLV-1)-associated myelopathy participated in the study. The mean ± SD SSPROM and JOA scores were 74.6 ± 11.4 and 12.4 ± 2.3, respectively. Construct validity for SSPROM (JOA: r = 0.84, P < 0.0001; EDSS: r = −0.83, P < 0.0001; Barthel: r = 0.56, P < 0.002; Osame: r = −0.94, P < 0.0001) and reliability (intra-rater: r = 0.83, P < 0.0001; inter-rater: r = 0.94, P < 0.0001) were demonstrated. The metric properties of JOA were similar to those found in SSPROM. Several clinimetric requirements were met for both SSPROM and JOA scales. Since SSPROM has a wider range, it should be useful for follow-up studies on IEM myelopathies.

Cerebrospinal Fluid Neopterin, but not Osteopontin, is a Valuable Biomarker for the Treatment Response in Patients with HTLV-I-associated Myelopathy

The concentrations of neopterin and osteopontin in the cerebrospinal fluid (CSF) were measured in patients with HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP) in order to evaluate their utility as biomarkers for the treatment response. Seven HAM/TSP patients were treated intravenously with high-dose methylprednisolone (1,000 mg/day) for 3 days. CSF samples were collected before and after the treatment. The neopterin and osteopontin concentrations were determined using high-performance liquid chromatography (HPLC) and an enzyme immunoassay, respectively. The clinical symptoms were evaluated using the Osame Motor Disability Score and the Urinary Disturbance Score. Four out of the seven patients showed an improvement in motor function with the treatment, and were therefore classed as responders. The pre-treatment CSF neopterin concentration exceeded the upper limit of normal in all seven of the patients, and tended to be higher in treatment responders as compared to non-responders. The CSF neopterin concentration was reduced following treatment in all patients. The mean CSF neopterin concentration significantly (p<0.01) decreased following treatment by almost 60% (from 124.1±79.9 nmol/L to 49.2±29.8 nmol/L). The mean CSF osteopontin concentration was significantly (p<0.01) higher in the HAM/TSP patients in comparison to the 18 HTLV-1-seronegative patients who were designated as controls (9.54±4.53 mg/L vs. 3.72±3.04 mg/L). No significant (p=0.47) reduction of the CSF osteopontin concentration was observed following the intravenous administration of high-dose methylprednisolone. These results indicate that the CSF neopterin concentration, but not the osteopontin concentration, is a potentially valuable biomarker for monitoring the treatment response in HAM/TSP patients. Furthermore, high pre-treatment CSF neopterin concentrations may be a predictive biomarker for a response to intravenous high-dose methylprednisolone therapy.

Implications of HAM/TSP functional incapacity in the quality of life

To identify the functional status and quality of life of HAM/TSP patients. We evaluated prospectively 30 HAM/TSP patients (20 females) seen in the Neuroinfection Clinic of the HUGG. The functional capacity was analyzed by the functional independence measure (FIM), the expanded disability status (EDSS) scale and the Osame's motor disability score (OMDS). The quality of life was assessed by the Short-Form Health Survey 36 (SF-36)TM. All patients need assistance device. The FIM, OMDS and EDSS scores classified 70%, 67% and 67% of the patients as dependent, respectively. The lowest scores of the SF-36 survey were found in the domains related to the physical health (D1, D2), role-emotional functioning (D7) and social functioning (D6). Our data suggest that the HAM/TSP physical impairment has an impact in the emotional and social issues, considering the limitation in the daily activities.