Autologous tolerogenic dendritic cells for rheumatoid and inflammatory arthritis

Abstract

Objectives: To assess the safety of intra-articular (IA) autologous tolerogenic dendritic cells (tolDC) in patients with inflammatory arthritis and an inflamed knee; to assess the feasibility and acceptability of the approach and to assess potential effects on local and systemic disease activities.

Methods: An unblinded, randomised, controlled, dose escalation Phase I trial. TolDC were differentiated from CD14+ monocytes and loaded with autologous synovial fluid as a source of autoantigens. Cohorts of three participants received 1×10⁶, 3×10⁶ or 10×10⁶ tolDC arthroscopically following saline irrigation of an inflamed (target) knee. Control participants received saline irrigation only. Primary outcome was flare of disease in the target knee within 5 days of treatment. Feasibility was assessed by successful tolDC manufacture and acceptability via patient questionnaire. Potential effects on disease activity were assessed by arthroscopic synovitis score, disease activity score (DAS)28 and Health Assessment Questionnaire (HAQ). Immunomodulatory effects were sought in peripheral blood.

Results: There were no target knee flares within 5 days of treatment. At day 14, arthroscopic synovitis was present in all participants except for one who received 10×10⁶ tolDC; a further participant in this cohort declined day 14 arthroscopy because symptoms had remitted; both remained stable throughout 91 days of observation. There were no trends in DAS28 or HAQ score or consistent immunomodulatory effects in peripheral blood. 9 of 10 manufactured products met quality control release criteria; acceptability of the protocol by participants was high.

Conclusion: IA tolDC therapy appears safe, feasible and acceptable. Knee symptoms stabilised in two patients who received 10×10⁶ tolDC but no systemic clinical or immunomodulatory effects were detectable.

Trial registration number: NCT01352858.

Keywords: Inflammation; Rheumatoid Arthritis; Synovial fluid; Treatment.

Figure 1

Overview showing tolerogenic dendritic cells (tolDC) treatment protocol. Following informed consent on day −14, an infectious disease screen was performed and synovial fluid (SF) aspirated under ultrasound guidance for use during tolDC manufacture. Participants returned 7 days later (day −7) for leucapheresis, their leucapheresis product being transferred to the good manufacturing practice facility for initiation of tolDC manufacture. After a further 7 days participants returned (day 0, baseline visit) and, following a clinical assessment and ultrasound assessment of the target knee, underwent fibre-optic arthroscopy. The target knee joint was irrigated with 1 L of normal saline, following which tolDC were administered arthroscopically. On days 7 and 14 participants returned for safety assessments. The day 14 visit also entailed an arthroscopic assessment of the target knee. If the participant remained symptomatic and/or the knee remained inflamed an arthroscopic intra-articular glucocorticoid injection was administered. The final study visit on day 91 was identical to the day +14 visit.

Figure 2

Arthroscopic synovitis scores are presented. Hypertrophy, vascularity and synovitis were scored on a 0–4 scale (17). (A) Individual patient data are illustrated for days 0 and 14 (one patient in the 10×10⁶ tolerogenic dendritic cells (tolDC) cohort declined day 14 arthroscopy). (B) Fold change is shown in hypertrophy, vascularity and synovitis scores compared with day 0. Data are plotted as the mean value for each cohort.