LEIDEN, The Netherlands—Intensive immunosuppression followed by T-cell-depleted autologous hematopoietic stem cell transplantation (ASCT) may be a safe and effective option for children with refractory progressive juvenile idiopathic arthritis (JIA) who have failed prior treatment including biologic therapy, according to a new report in Arthritis & Rheumatism.1

"This approach offers a fair chance of long-lasting improvement in patients with severe progressive disease," conclude researchers led by D.M.C. Brinkman, MD, with the department of pediatrics at Leiden University Medical Centre, The Netherlands.

In the new phase II clinical study, 22 patients with refractory progressive JIA underwent pretreatment with intensive immunosuppression followed by ASCT. Pretreatment consisted of a combination of antithymocyte globulin, cyclophosphamide, and low-dose total body irradiation. Hematopoietic stem cells were harvested from the patients' bone marrow, depleted of T-cells, and kept frozen until transplantation. Patients were followed up over a median period of 80 months.

Reconstitution of hematologic values to normal range in patients was rapid, but the recovery of immune system parameters, especially normalization of CD4+, CD45RA+ naïve T-cells, occurred at >e;6 months after ASCT. This prolonged period of immune deficiency resulted in a large number of viral infections and may have contributed to the development of macrophage activation syndrome (MAS), which occurred 18 days post-ASCT and lead to death in two patients.

Intensive immunosuppression followed by ASCT resulted in sustained complete remission or marked improvement in 15 of 22 patients with progressive refractory JIA. After ASCT, eight of the 20 evaluable patients reached complete clinical remission, seven were partial responders, and five experienced a relapse of their disease. In one patient, the relapse occurred 7 years after ASCT.  Two of the patients whose disease relapsed died from infections that developed after restarting immunosuppressive medication during follow-up.

Protocol modified midstream due to adverse events

After fatal complications due to MAS were observed in some patients, the protocol was amended to ensure less profound depletion of T-cells, better control of systemic disease before transplantation, antiviral prophylaxis after transplantation, and slow tapering of corticosteroids. No additional ASCT-related deaths were observed among the 11 patients who received the modified treatment.

The role of biologic therapy in JIA

The study was initiated before the advent of biologics. "Biologic therapy has thus far been established as a safe and effective approach to treat refractory JIA. However, there will remain a number of treatment failures, and therefore the potential for use of ASCT will now be limited to patients in whom prior treatment has failed," the study authors write.

ASCT not a panacea, but it can be an important option

"These children with intractable disease suffer from both their disease and severe side effects of medication needed to at least partially control their arthritis [such as] severe short stature, osteoporosis and fracture, cataracts, and multiple others," said Kathleen A. Haines, MD, the section chief of pediatric immunology at Hackensack University Medical Center, in New Jersey. "For these children, who are a small minority of JIA cases, ASCT is currently their only hope of improvement, notwithstanding the risk of the therapy," Dr. Haines told CIAOMed.

Two thirds of the evaluable cases in the study were either in complete remission or responsive to therapy; however, it clearly is not a panacea as one third of patients relapsed, she commented.

"Whether new biologic therapies would have helped these difficult cases remains to be seen, although we hope that it will be the case. There are certainly ones that need to be studied and perhaps if we discover the precise immunologic imbalance in these children, better targeted therapies will be designed," Dr. Haines, who has had one patient who underwent ASCT for systemic JIA, concluded. She has a colleague with an NIH planning grant to prepare a proposal to study ASCT in JIA in the US.

Reference

1. Brinkman DMC, de Kleer IM, ten Cate R, et al. Autologous stem cell transplantation in children with severe progressive systemic or polyarticular juvenile idiopathic arthritis.  Long-term follow-up of a prospective clinical trial. Arthritis Rheum. 2007;56:2410-2421.