Ciclosporin A proof of concept study in patients with active, progressive HTLV-1 associated myelopathy/tropical spastic paraparesis

Abstract

Introduction: Patients with HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) become progressively impaired, with chronic pain, immobility and bladder, bowel and sexual dysfunction. Tested antiretroviral therapies have not been effective and most patients are offered a short course of corticosteroids or interferon-α, physiotherapy and symptomatic management. Pathogenesis studies implicate activated T-lymphocytes and cytokines in tissue damage. We therefore tested the hypothesis that inhibition of T-cell activation with ciclosporin A would be safe and clinically beneficial in patients with early and/or clinically progressing HAM/TSP.

Materials and methods: Open label, proof of concept, pilot study of 48 weeks therapy with the calcineurin antagonist, ciclosporin A (CsA), in seven patients with 'early' (<two years) or 'progressive' (>50% deterioration in timed walk during the preceding three months) HAM/TSP. Primary outcomes were incidence of clinical failure at 48 weeks and time to clinical failure.

Results: All patients completed 72 weeks study participation and five showed objective evidence of clinical improvement after 3 months treatment with CsA. Two patients exhibited clinical failure over 6.4 person-years of follow-up to week 48. One patient had a >2 point deterioration in IPEC (Insituto de Pesquisa Clinica Evandro Chagas) disability score at weeks 8 and 12, and then stopped treatment. The other stopped treatment at week 4 because of headache and tremor and deterioration in timed walk, which occurred at week 45. Overall pain, mobility, spasticity and bladder function improved by 48 weeks. Two patients recommenced CsA during follow-up due to relapse.

Conclusions: These data provide initial evidence that treatment with CsA is safe and may partially reverse the clinical deterioration seen in patients with early/progressive HAM/TSP. This trial supports further investigation of this agent's safety and effectiveness in larger, randomised controlled studies in carefully selected patients with disease progression.

Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Figure 1. Flowchart of enrolment and follow up of patients with definite and early and/or progressing HAM/TSP.

50 patients with HAM/TSP were identified and 9 were identified as patients with early and/or deteriorating HAM/TSP, 7 of whom consented to treatment with ciclosporin A. Two patients chose to re-start ciclosporin A after 48 weeks during trial period.

Figure 2. Therapeutic drug monitoring of ciclosporin A: dosing and through CsA plasma concentrations.

Figure 3. Timed walk ranked by walking aid used (0–72 weeks).

A higher rank represents a slower walk. HC036005 walked unaided; HC036001, HC036004 one walking stick; HC036002, HC036003, HC036006, HC036007 needed 2 walking sticks. At week 0 and 2 HC036006 needed a wheelchair due to a sprained ankle.

Figure 4. Modified Ashworth Scale testing muscle spasticity (0–72 weeks).

A higher score represents increased muscle tone.

Figure 5. Maximum pain over time (0–72 weeks).

A higher score represents more pain. If pain was reported at more than one site, the higher pain score was used.

Figure 6. Log10 HTLV-1 proviral DNA in peripheral blood mononuclear cells (PBMCs) (0–72 weeks).

Figure 7. HTLV-1 proviral DNA of cerebro-spinal fluid over peripheral blood mononuclear cells (CSF/PBMC ratio) (0–12 weeks).

Figure 8. T cell activation marker: absolute CD4+/CD25+ T cell count (0–72 weeks).

Figure 9. β2 microglobulin a marker of inflammation in peripheral venous blood (0–72 weeks).

Figure 10. Magnetic resonance imaging of the thoracic chord (0–72 weeks).

Clinical improvement was observed despite the marked atrophy of the thoracic cord.