High-dose chemotherapy and syngeneic stem cell transplantation in a patient with refractory rheumatoid arthritis: poor response associated with persistence of synovial abnormalities

High-dose chemotherapy (HDC) and stem cell transplantation (SCT) is an experimental treatment option for patients with refractory rheumatoid arthritis (RA). The re-infusion of stem cells with a possible intrisic cell defect may be the cause for disease relapse despite increased sensitivity to disease-modifying anti-rheumatic drugs (DMARDs). This can be avoided by a syngeneic transplantation with healthy stem cells from an identical sibling.

We treated a 44-year-old woman, who had seropositive, erosive RA, with HDC and syngeneic SCT from her healthy identical twin sister. The patient had undergone multiple joint operations and had become refractory to conventional DMARDs, etanercept and infliximab.

Outcome measures were DAS 28, rheumatoid factor titer (IgM), need for DMARD therapy and synovial inflammation for which tissue was obtained at baseline, 2, 3 and 6 months through knee arthroscopy. Stem cells from the donor were mobilized with filgrastim and collected by leukapheresis on day -1 and 0. HDC consisted of cyclophosphamide (total dose 13.4 g intravenously) combined with 1 mg/kg prednisone. On day 0 an unmanipulated graft containing 182 × 10⁹ leukocytes, containing 769 × 10⁶ CD34⁺ cells, was administered.

Before conditioning, infliximab, methotrexate and prednisone were discontinued, which resulted in a disease flare (Fig. 1). The treatment was well tolerated and the patient was discharged on day 14 without joint complaints. After 1 month disease activity flared accompanied by an acute phase response. Despite maintenance therapy with 10 mg prednisone and re-institution of methotrexate up to 22.5 mg/week she had continued active disease up to 1 year after SCT (Fig. 1). Synovial biopsies at all timepoints showed a marked infiltration with neutrophils and plasmacells, even 2 months after HDC. Immunohistological staining showed infiltration of activated T cells (CD38⁺), B cells (CD19⁺) and plasma cells (CD138⁺)

Figure 1

HDC and syngeneic SCT did not result in remission of RA. The persistence of RF, anti-CCP (IgG) and plasma cells in the synovial tissue suggests host plasma cells were not eradicated by cyclophosphamide, nor replaced by donor plasma cells (rheumatoid factor and anti-CCP negative).

Affiliations

1. Department of Rheumatology, Leiden University Medical Center, The Netherlands
   • M van Oosterhout
   • , RJ Verburg
   • , EWN Levarht
   •  & JM van Laar
2. Department of Rheumatology, Medical Center Alkmaar, The Netherlands
   • D Moolenburgh
3. Department of Pathology, Leiden University Medical Center, The Netherlands
   • I Bajema
4. Department of Hematology, Leiden University Medical Center, The Netherlands
   • RY Barge
   •  & WE Fibbe

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