Ciclosporin A Proof of Concept Study in Patients with Active, Progressive HTLV-1 Associated Myelopathy/Tropical Spastic Paraparesis

HTLV-1 is a retrovirus transmitted through body fluids that is commonly seen in the West Indies, South America and Southern Japan but rarely in the UK. Although most patients remain healthy carriers, HTLV-1 causes serious conditions such as adult T cell leukaemia/lymphoma (ATLL) and HTLV-1-associated myelopathy/Tropical Spastic Paraparesis (HAM/TSP). The infection which is life-long cannot be eradicated and treatments for the associated diseases are limited. We report the encouraging findings of the first UK Medical Research Council funded treatment study for patients with early and/or deteriorating HAM/TSP. Treatment with ciclosporin A, a drug commonly used to dampen the immune system in transplant patients, was investigated. Symptoms and signs of disease, particularly low back pain and muscle stiffness, improved by week 24 and in some patients this improvement persisted after the 48 weeks of treatment, at least to the end of the study at week 72. Most striking was the finding that the amount of HTLV-1 in the fluid around the spinal cord, called cerebrospinal fluid, was reduced during treatment. These findings justify the further study of ciclosporin A in patients with HAM/TSP

A 15-year prospective longitudinal study of disease progression in patients with HTLV-1 associated myelopathy in the UK

Background: The natural history of HTLV-1-associated myelopathy (HAM) has been mainly described in HTLV-1 endemic countries such as Japan, Brazil and Martinique. Objectives: The authors describe the natural history of the largest cohort of patients with HAM living in the UK from 1993 to 2007. Methods: Prospective, longitudinal study comparing clinical and virological outcome between first and last clinical visit. Incidence and cause of death were documented and the mortality calculated. Results: 48 patients were included: 79.2% were female, 79.2% were of Afro-Caribbean origin, and 83.3% acquired HTLV-1 through breastfeeding or unprotected heterosexual intercourse. The mean age of onset was 46 years. The median durations from onset of symptoms to diagnosis and to last follow-up were 2 and 11.6 years. The median time of follow-up was 3.8 years. The most common first recalled symptom was unilateral leg weakness. The median times from onset to unilateral, bilateral walking aid and frame or a wheelchair were 11, 11.2, 11.3 and 18 years. The overall average deterioration in timed walk in patients whose need for aid did not change was 2 s/10 m/year. Three patients progressed rapidly and were unable to walk within 2 years. Six patients were slow/non-progressors. The mortality was 2.4/100 person year follow-up. The median HTLV-1 viral load remained unchanged at 14%. Conclusions: HAM is a slowly progressing chronic disease. Timed walk deteriorates by 2 s/10 m/year, and patients remain ambulant for 10 years but become wheelchair-dependent a decade later. HTLV-1 viral load remains high and unchanged over time regardless of clinical progression

Maximum pain over time (0–72 weeks).

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

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

<p>β₂ microglobulin a marker of inflammation in peripheral venous blood (0–72 weeks).</p

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

<p>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.</p

Log₁₀ HTLV-1 proviral DNA (CSF): −2 is baseline evaluation and week 12 CSF was collected while on CsA treatment.

<p>Log₁₀ HTLV-1 proviral DNA (CSF): −2 is baseline evaluation and week 12 CSF was collected while on CsA treatment.</p

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

<p>Clinical improvement was observed despite the marked atrophy of the thoracic cord.</p

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

<p>T cell activation marker: absolute CD4⁺/CD25⁺ T cell count (0–72 weeks).</p

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

<p>Therapeutic drug monitoring of ciclosporin A: dosing and through CsA plasma concentrations.</p

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

<p>Log¹⁰ HTLV-1 proviral DNA in peripheral blood mononuclear cells (PBMCs) (0–72 weeks).</p