Rheumatoid Arthritis: Fibbe WE

Verburg RJ, Toes RE, Fibbe WE, Breedveld FC, van Laar JM. · Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands. · Hum Immunol. · Pubmed #12121670 No free full text.

Abstract: A new treatment approach, involving intense immunosuppression and autologous hematopoietic stem cell transplantation (SCT), has emerged in recent years for the treatment of severe, refractory rheumatic autoimmune diseases including rheumatoid arthritis (RA). The rationale of this strategy is based on the concept of immunoablation by intense immunosuppression with subsequent regeneration of naïve T lymphocytes derived from reinfused hematopoietic progenitor cells. Patients with a therapy-refractory, progressively erosive disease who are at risk of functional disability and early mortality are considered eligible for treatment with autologous SCT. The goal is long-term improvement of disease activity and quality of life. However, when offering SCT to RA patients these benefits should be balanced against toxicities and treatment-related mortality. In several patients with intractable RA, long-term remissions were observed with this strategy, but failures have been reported as well. Only small numbers of RA patients have been treated thus far. Although different treatment protocols have been used, high dose chemotherapy as a means to achieve immunoablation has been invariably used in all studies. In this review we discuss background, clinical results, protocols, and future prospects of high dose chemotherapy and autologous SCT for RA.

van Laar JM, Verburg RJ, Fibbe WE, Breedveld FC. · Department of Rheumatology, Leiden University Medical Center, The Netherlands. · J Rheumatol Suppl. · Pubmed #11642499 No free full text.

Abstract: Ten patients with active, destructive rheumatoid arthritis refractory to antirheumatic therapy enrolled in a study to evaluate the effects of intensive immunosuppression followed by autologous stem cell transplantation. Intensive immunosuppression was achieved with high dose cyclophosphamide as part of the mobilization (4 g/m2) and conditioning (200 mg/kg) regimen. The autologous stem cell products were enriched for CD34+ cells to minimize the chance of reinfusing autoreactive lymphocytes. Eight patients completed all consecutive treatment steps, one patient withdrew after mobilization because of improvement, one patient was taken off study because of pulmonary embolism. The treatment appeared feasible and safe, and marked sustained clinical improvement was observed in 6 patients, 2 of whom were previously unresponsive to tumor necrosis factor blocking therapy. In 5 patients disease modifying antirheumatic drugs were successfully withdrawn after transplantation. The treatment induced significant lymphopenia, with low levels of naive CD4+ T cells in particular, without clinical sequelae. Titers of rheumatoid factor dropped but did not normalize.

Verburg RJ, Kruize AA, van den Hoogen FH, Fibbe WE, Petersen EJ, Preijers F, Sont JK, Barge RM, Bijlsma JW, van de Putte LB, Breedveld FC, van Laar JM. · Leiden University Medical Center, The Netherlands. · Arthritis Rheum. · Pubmed #11315914 links to  free full text

Abstract: OBJECTIVE: To assess the feasibility, safety, and efficacy of high-dose chemotherapy and autologous hematopoietic stem cell transplantation (HSCT) in patients with severe, refractory rheumatoid arthritis (RA). METHODS: Fourteen patients (3 male, 11 female, mean age 43 years, mean disease duration 10 years) with active, destructive, refractory RA entered the study. Autologous hematopoietic stem cells were collected by leukapheresis after mobilization with a single infusion of cyclophosphamide (CYC; 4 gm/m2) and subcutaneous injections of filgrastim (granulocyte colony-stimulating factor). Immunomagnetic selection of CD34+ cells from the leukapheresis products was performed to deplete potentially autoreactive lymphocytes. The conditioning regimen consisted of intravenous administration of high doses of CYC (cumulative dose 200 mg/kg), with subsequent reinfusion of the graft. Patients were monitored for disease activity, disability, adverse effects, and hematopoietic and immunologic reconstitution. RESULTS: All 14 patients completed the mobilization and leukapheresis procedures successfully, and 12 proceeded to receive conditioning and transplantation. Engraftment occurred in all of these patients, with rapid hematologic recovery. No major unexpected toxicity was observed. Marked improvement of disease activity was recorded in 8 of 12 patients at >50% of the visits, with a followup ranging from 7 months to 21 months. The clinical responders included 2 patients who had previously failed treatment with tumor necrosis factor (TNF) blocking agents. CONCLUSION: High-dose chemotherapy followed by autologous HSCT is feasible and safe, and can result in long-term improvement of disease activity in patients whose condition previously did not respond to conventional antirheumatic drugs or TNF blocking agents. The persistence of active disease in some patients may reflect the heterogeneity of the underlying disease process.

van Oosterhout M, Verburg RJ, Levarht EW, Moolenburgh JD, Barge RM, Fibbe WE, van Laar JM. · Department of Rheumatology, Leiden University Medical Centre, PO Box 9600, 2300 RC Leiden, The Netherlands. · Ann Rheum Dis. · Pubmed #16284342 links to  free full text

Abstract: BACKGROUND: Immunoablative therapy combined with haematopoietic stem cell transplantation (SCT) is a possible treatment for patients with severe rheumatoid arthritis (RA).Case report: A patient with rheumatoid factor positive, progressively erosive RA, refractive to treatment, was treated with high dose cyclophosphamide, followed by reinfusion of an unmanipulated peripheral blood graft derived from her identical twin sister. The clinical response was unsatisfactory, necessitating reinstitution of treatment with disease modifying antirheumatic drugs, which was associated with persistence of host serum autoantibodies and a cellular infiltrate in synovium, notably of plasma cells.Discussion: The effectiveness of syngeneic SCT may be critically dependent on the degree of immunoablation achieved or on the composition of the graft.