Cerebrospinal Fluid CXCL10 as a Candidate Surrogate Marker for HTLV-1-Associated Myelopathy/Tropical Spastic Paraparesis

Abstract

Human T-cell leukemia virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a debilitating, progressive disease without effective treatment; therefore, development of disease modifying therapy that improves long-term functional outcomes is an unmet need for patients. However, it is virtually impossible to consider this as a primary endpoint in clinical trials owing to the prolonged disease course. Therefore, development of surrogate markers that help predict the effectiveness of new interventions is essential. Currently, several candidate surrogate markers have been identified for HAM/TSP. Cerebrospinal fluid (CSF) C-X-C motif chemokine 10 (CXCL10) is involved in the pathogenesis of HAM/TSP and was shown to correlate with disease progression. However, it remains unclear whether changes in CSF CXCL10 levels are observed in response to treatment and whether these correlate with prognosis. Here we investigated several markers, including CSF CXCL10, in this respect. Data pertaining to patient characteristics and results of motor function evaluation and CSF examination of 13 HAM/TSP patients who received steroid treatment were retrospectively analyzed. Osame motor disability scores (OMDS), 10 m walking time, and CSF levels of CXCL10, neopterin, total protein, cell counts, and anti-HTLV-1 antibody titer were compared before and after steroid therapy. Levels of all CSF markers, with the exception of cell count, were significantly decreased after treatment. Nine of the 13 patients (69.2%) showed improvement in OMDS and were considered responders. Pre-treatment CSF levels of CXCL10 and anti-HTLV-1 antibody titer in responders were higher than those in non-responders (p = 0.020 and p = 0.045, respectively). Patients who continued low-dose oral prednisolone maintenance therapy after methylprednisolone pulse therapy showed sustained improvement in OMDS and CSF CXCL10 and neopterin levels lasting for 2 years. In contrast, OMDS and the CSF marker levels in patients who discontinued treatment returned to pre-treatment levels. This rebound phenomenon was also observed in patients who discontinued oral prednisolone therapy independently of pulse therapy. Our findings suggest that CSF CXCL10 may serve as a therapy-response and therapy-predictive marker for HAM/TSP. In addition, since decrease in CSF CXCL10 level was associated with good functional prognosis, CSF CXCL10 is a potential surrogate marker for treatment of HAM/TSP.

Keywords: CXCL10; HAM/TSP; HTLV-1; biomarker; cerebrospinal fluid; neopterin.

FIGURE 1

Effects of steroid therapy on Cerebrospinal fluid (CSF) markers. Left: Comparison of pre-treatment levels of the following five CSF markers with those approximately 2 weeks after steroid therapy (mean ± standard deviation (SD): 2.5 ± 0.9 weeks from the first day of pulse therapy): C-X-C motif chemokine 10 (CXCL10), neopterin, total protein, anti-HTLV-1 antibody (Ab) titer, and cell count. Post-treatment CSF markers were not available for one or two patients among the 13 patients who received methylprednisolone pulse therapy (n = 12: CXCL10, neopterin, and anti-HTLV-1 antibody titer; n = 11: total protein and cell count). Right: Comparison of the same five CSF markers between two time points (mean ± SD: 16.4 ± 5.7 months) in five patients who did not receive any steroid treatment and interferon alpha treatment. Statistical analysis was performed using a Wilcoxon signed rank test. Ab, antibody.

FIGURE 2

Comparison of pre-treatment marker values between responders and non-responders to steroid therapy. Responders (n = 9) refer to patients who showed improved Osame motor disability scores (OMDS) by one or more grade 1 month after the start of steroid therapy. Non-responders (n = 4) refer to patients who did not show any change in OMDS. The pre-treatment values of five CSF markers (CXCL10, neopterin, total protein, anti-HTLV-1 antibody titer, and cell count) and HTLV-1 proviral load in Peripheral blood mononuclear cells (PBMCs) were compared between responders and non-responders. Data were analyzed by Mann–Whitney U test. Ab, antibody; PVL, proviral load; PBMC, peripheral blood mononuclear cells.

FIGURE 3

Differences in time course of motor function and CSF markers with and without maintenance therapy using oral prednisolone after methylprednisolone pulse therapy. These graphs demonstrate the time course of (A) OMDS and 10 m walking time and (B) CSF CXCL10 concentration and CSF neopterin concentration in eight HAM/TSP patients who received maintenance therapy (left) and five HAM/TSP patients who did not receive maintenance therapy (right). The data of the 10 m timed walk were obtained from seven patients, as one of eight patients who received maintenance therapy was unable to walk 10 m. Among the five patients who did not receive maintenance therapy, patient no. 1 repeatedly received methylprednisolone pulse therapy every 2 months. The arrowhead indicates the time of administration. Patient no. 4 received oral prednisolone therapy after the third CSF test because of the clinical deterioration with high levels of CXCL10 and neopterin. OMDS, Osame motor disability score.

FIGURE 4

Time course of motor function and CSF markers in patients received and subsequently discontinued oral prednisolone therapy. These graphs demonstrate the time course of (A) OMDS and 10 m walking time and (B) CSF CXCL10 concentration and CSF neopterin concentration in four HAM/TSP patients treated with low-dose prednisolone from before treatment to after treatment discontinuation. The pre-treatment data of the 10 m walking time in patient no. 22 could not be obtained. OMDS, Osame motor disability score; PSL, prednisolone.