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

This study was based on information from a Japanese HAM/TSP patient registry called “HAM-net.” This database was established to collect not only retrospective information such as medical and treatment histories, but also cross-sectional/prospective data such as clinical course and treatment status (UMIN trial number: UMIN000028400) [9]. The registered patients were those who met the two criteria of having a confirmed HAM/TSP diagnosis and having provided informed consent. Each subject was interviewed annually via telephone by a nurse or clinical research coordinator from the HAM-net study office. The interview phone script included patient characteristics, family and medical history, comorbidities, living backgrounds, living conditions, HAM/TSP symptoms, treatment history, and treatment status.

Our entire analysis set consisted of 486 patients enrolled sequentially in HAM-net from March 2012 to December 2016 (Fig. 1). All subjects received the initial telephone interview just after registration (Fig. 1a). The HAM-net study office confirmed that all patients were at least 20 years old, diagnosed with HAM/TSP by their physician, and more than a year had passed since onset. The 486 patients who received the initial telephone interview received up to five annual telephone interviews over an observation period of up to four years. The data cut off for this study was December 2016. Therefore, patients who were enrolled in 2016 received only the initial interview, and although they are included in the 486-patient group (Fig. 1a), they were excluded from subsequent patient cohorts which required follow-up time (Fig. 1b–e). All 257 patients in the 4-year observation group (Fig. 1e) who received five consecutive interviews were enrolled in 2012 and were included in all groups shown in Fig. 1a–e. We included a total of 486 patients (Fig. 1a) in the analyses of patient characteristics, treatment status at the time of the initial interview, and the prevalence of comorbidities.

The 434 patients (Fig. 1b) who were observed for at least one year were included in the analyses of incidence rates of comorbidities and steroid-related complications. For the analysis of incidence of steroid-related complications by steroid treatment status, the patients were divided into three patient subgroups: 185 patients who had never received steroid therapy during the observation period (untreated group), 225 patients who received steroid treatment at least one time during the observation period (steroid group), and 181 patients who received steroid treatment continuously from among the above 225 patients (continued steroid group).

As shown in Fig. 2, the analysis sets for evaluating the chronological change of motor dysfunction in the lower limbs of patients with HAM/TSP (“analysis set 2”) consisted of patients who remained after excluding those who met the exclusion/dropout criteria:

Phase I & IIa trials on anti-CCR4 antibody KW-0761 (UMIN trial number: UMIN000012655), Phase III trial on anti-CCR4 antibody KW-0761 (ClinicalTrials.gov Identifier: NCT03191526), Phase IIb trial on steroids (UMIN000023798, UMIN000024085, and UMIN000024086), and NCY-2001 clinical trial on Robot Suit HAL® (Hybrid Assistive Limb) (JMACCT ID: JMA-IIA00204 and JMA-IIA00257)

adult T-cell leukemia-lymphoma, active cancer, active tuberculosis, paralysis after stroke, Parkinsonian syndrome, rheumatoid arthritis, dementia, psychiatric disorder, and bone fracture that affects the ability to walk.

To accurately evaluate yearly changes in OMDS, the “analysis set 2” only included patients whose interval between each survey date fell within 365 ± 90 days. To clarify the influence of steroids on changes in OMDS, the analysis sets were classified into four subgroups: current steroid use, steroid-history, untreated, and miscellaneous (Table 2). Allocations into these subgroups were based on information regarding the following three parameters: history of steroid use, steroid use at the time of the initial interview, and steroid use between the initial interview and the final interview. The sub-analysis focused on patients having OMDS between 3 and 6. These are individuals who at the time of the initial interview could walk for ≥10 m with or without walking support and also have room for improvement in motor function in the lower limbs (Additional file 1: Figure S1).

The data from HAM-net used in this study consisted of information obtained from three different periods:

Age at onset, medical history, treatment history (oral steroid therapy, steroid pulse therapy, interferon-α treatment), age at which each OMDS was reached, rapid progressor status. Rapid progressor was defined as patients with progression to OMDS grade ≥ 5 within 2 years after the onset of motor symptoms as described previously [10].

Age at baseline, gender, baseline OMDS, treatment status (oral steroid therapy, steroid pulse therapy, interferon-α treatment), dose of steroids, and comorbidities, as listed following [C].

OMDS, treatment history for one year from the time of last interview (oral steroid therapy, steroid pulse therapy, interferon-α treatment), and new-onset comorbidities listed as follows: for [B] and [C], the comorbitities were uveitis, Sjogren’s syndrome, rheumatoid arthritis, all bone fractures, herpes zoster, interstitial pneumonia, tuberculosis, diabetes mellitus, cataracts, and glaucoma. All bone fractures, herpes zoster, diabetes mellitus, cataracts, and glaucoma were classified as steroid-related complications.

We first investigated the characteristics and the prevalence of comorbidities at the time of the initial interview for all 486 patients enrolled in the HAM-net (Table 3). The age at the time of the initial interview was 62.0 ± 10.7 years, the age at onset was 44.8 ± 14.9 years, the disease duration was 16.1 ± 11.3 years, and the baseline OMDS was 5.7 ± 2.3 (all shown as mean ± standard deviation). The proportion of women and rapid progressors were 74.7 and 19.8%, respectively. At the time of the initial interview, the comorbidities with high prevalence were uveitis (7.6%), Sjogren’s syndrome (3.7%), and rheumatoid arthritis (2.7%).

Next, we investigated the incidence of comorbidities in the 434 patients (Table 4) who participated in at least one annual interview (Fig. 1b). They had almost the same patient characteristics as the entire HAM-net registry. The more prevalent comorbidities were bone fractures, herpes zoster, and uveitis; the incidence rates were 55.5 (95% CI: 44.0–69.8), 10.4 (95% CI: 6.2–17.4), and 6.5 (95% CI: 3.3–12.7) per 1000 person-years, respectively (Table 4). In more detail, regarding fractures, the incidence rates of lower limb fractures, compression fractures, and upper limb fractures were 22.6, 22.4, and 3.7 per 1000 person-years, respectively. To investigate the impact of baseline OMDS on the incidence of fractures, we calculated the incidence of fractures based on OMDS (OMDS 1–4, OMDS 5, OMDS 6, and OMDS 7–13). As shown in Table 4, the OMDS categories with high incidence were OMDS 6 for all bone fractures, OMDS 7–13 for lower limb fractures, and OMDS 6 for compression fractures. The OMDS category with low incidence was OMDS 1–4 for all types of fractures. The prevalence and incidence of tuberculosis were 0.0 and 0.0 (95% CI: 0.0–2.8) per 1000 person-years, respectively. Adult T-cell leukemia-lymphoma was one of the most significant comorbidities of HAM/TSP, although its prevalence and incidence are not described here because this is the subject of a separate paper currently in preparation.

As shown in Table 5, we examined the treatment experience of patients in the HAM-net registry before the initial interview, at the time of the initial interview, and in each subsequent year. The percent of patients with a history of oral steroid therapy, methylprednisolone pulse therapy, and interferon-α treatment were 67.1, 39.3, and 35.0%, respectively. The percentages of patients who received each therapy at the time of the initial interview were 41.8, 1.4, and 2.9%, respectively. We found that in each subsequent year the percent of patients who received each treatment were 48.2–50.7% (oral steroid therapy), 3.6–7.6% (pulse therapy), and 2.6–3.5% (interferon-α treatment). Next, we examined the continuation rate of each treatment (Additional file 2: Table S1). Of the 123 subjects, 112 (91.1%) continued to take oral steroid therapy for 3 years between the 2nd and the 5th year interviews. In contrast, only 7 of 18 (38.9%) and 7 of 11 (63.6%) continued on steroid pulse therapy and interferon-α treatment, respectively, during the same period. The daily dose of oral steroid prednisolone for treated patients (n = 167) at the time of the initial interview was 7.4 ± 5.2 mg/day (mean ± standard deviation), 5.0 mg/day (median) (Additional file 2: Table S2).

As shown in Table 6, we investigated the incidence of steroid-related complications by steroid treatment status among the 434 patients that were observed for at least one-year. The incidence of bone fracture tended to be higher in the steroid groups than in the untreated group. The incidences were 48.3 (95% CI: 33.0–70.8) in the untreated group, 61.0 (95% CI: 45.1–82.5) in the steroid group, and 65.6 (95% CI: 47.4–90.8) in the continued steroid group per 1000 person-years. The rates of lower limb fractures in the three groups were 21.8, 24. 2, and 26.7, respectively, per 1000 person-years, and the rates of compression fractures were 16.1, 25.4 and 28.1, respectively, per 1000 person-years.

The incidence rate of herpes zoster also tended to be higher in the group of patients treated with steroids than in untreated patients. Per 1000 person-years, the rates were 8.8 (95%CI: 3.8–20.6) for untreated patients, 12.7 (95%CI: 6.7–24.1) for treated patients, and 12.3 (95%CI: 6.0–25.4) for continuously treated patients. In contrast, these trends were not observed for diabetes mellitus, cataracts, and glaucoma. Since the incidence of fractures varied based on OMDS (Table 4), we examined the distribution of OMDS in each of the three patient subgroups and found that OMDS tended to be skewed with the percent of OMDS 7–13 being higher in the untreated group than in the steroid treated groups (Table 6). However, the proportion of patients with OMDS ≥5 was almost similar among the three subgroups (75.1, 77.3, and 78.5%).

To assess the chronological changes in OMDS, a new analysis set that excluded patients who met the exclusion/drop-out criteria was used (Fig. 2). The baseline characteristics of the new one-year observation group (Table 7) were nearly identical to those of the entire HAM-net-registered patients. We also found no differences in gender and baseline age across the four subgroups (steroid, steroid-history, untreated, and miscellaneous). However, there was a significant difference in the baseline OMDS between the four subgroups (p < 0.001). Specifically, the untreated group had substantially lower baseline OMDSs than those of both the steroid and the steroid-history groups (5.0 vs. 5.7, 6.5). We also found differences in age at onset and disease duration across the four subgroups (p = 0.009 and p < 0.001). The steroid group had a higher onset age (47.4 years vs. 40.4 years) and a shorter disease duration (13.9 years vs. 20.6 years), compared to the steroid-history group. Interestingly, there was a tendency that the proportion of rapid progressors was high in the steroid group (26.7%) and low in the untreated group (14.1%).

Additionally, one-year changes in OMDS in the one-year observation group and its four subgroups were examined (Additional file 2: Tables S3–S7). As shown in Table 8, in the one-year observation group, the difference between baseline OMDS (5.74 ± 2.22) and OMDS at the time of the second survey (5.94 ± 2.29) was 0.20 (95% CI: 0.14–0.25), suggesting that their motor function deteriorated significantly in a year (p < 0.001). In all four subgroups, OMDS deteriorated during the one-year observation period. The magnitudes of the differences were, in decreasing order, the steroid-history group (0.26), steroid group (0.24), untreated group (0.13), and miscellaneous group (0.10). Lastly, we performed the same analyses in an analysis set limited to the patients whose OMDS were 3–6 (n = 239, Additional file 1: Figure S1b). This specific analysis set showed the same tendency as the result obtained from the 346 patients (Additional file 2: Tables S8 and S9).

As shown in Table 9, we first examined the baseline characteristics in the four-year observation group (n = 148, Fig. 2e) and its four subgroups. These 148 patients had characteristics similar to that of all 486 subjects enrolled in the HAM-net database (Table 3) except for the difference in the percentage of rapid progressors (14.2% vs. 19.8%, respectively). We found no differences in gender, age at baseline, age at onset, disease duration, and the percentage of rapid progressors across the four subgroups (Table 9). However, there was a significant difference in the baseline OMDS (p = 0.012).

We next examined the four-year changes in OMDS in the four-year observation group and its four subgroups (Additional file 2: Tables S10–S14; Additional file 3: Figure S2). As shown in Table 10, when all patients in the four-year observation group were evaluated together, the difference between baseline OMDS (5.80 ± 2.19) and OMDS at the time of the fifth survey (6.37 ± 2.31) was 0.57 (95% CI: 0.42–0.73), indicating that their motor function deteriorated significantly in four years (p < 0.001). When each subgroup was compared over time, OMDS declined during the four-year observation period. The magnitudes of the differences were, in decreasing order, the steroids-history group (0.67), steroids (0.64), miscellaneous (0.55), and the untreated group (0.41). Lastly, we performed the same analyses in an analysis set limited to the patients whose OMDS were 3–6 with similar results (Additional file 1: Figure S1e; Additional file 2: Tables S15 and S16).

We next examined the effect of interferon-α treatment on OMDS in the analysis set that could be observed for four years (n = 148, Fig. 2e) and its three subgroups (Table 11). Only 10 patients had received interferon-α treatment, of which 7 worsened (70.0%), and 3 remained unchanged (30.0%). Five of the seven patients who got worse and two of the three patients who remained unchanged were also receiving steroid therapy at the same time.