Some issues are similar to the experience so far with HSC transplantation for other conditions such as leukaemia and solid tumour. The major one of these is the need for prospective, randomized comparative trials to confirm the impressions gained from phase 1 (safety) and phase 2 (efficacy) pilot studies.
There are examples where first impressions, either optimistic or pessimistic, were not confirmed by such trials, although many investigators had already formed an 'opinion', on the basis of their own small experience, and were therefore reluctant afterwards to randomize patients. Autologous HSC transplantation in breast cancer is a good example of this.
After many meetings of involved parties, such trial designs for MS, SSc and JIA have been generated, with the intension to extend them as multicentre studies, given the relatively low incidence of these autoimmune diseases. Outlines of these protocols are available from Basel on e-mail (firstname.lastname@example.org), and will soon be posted on the EBMT Internet page for autoimmune disease (http://gildor.conexis.es/ebmt). RA trial design is still under discussion.
Other issues are more specific to autoimmune disease, and therefore require an open-minded approach. For example, growth factors for mobilization may induce a flare of autoimmune disease, and this has been observed in JIA, MS and RA, at times possibly contributing to a fatal outcome. It is logical but not proven that cyclophosphamide given 8 days before granulocyte colony-stimulating factor could reduce such an effect, and this has been included in the second-generation study designs.
Also, cyclophosphamide 4 g/m2 for mobilization could induce a long-lasting remission of autoimmune disease, without the need to proceed to myeloablation, and this could be a point of randomization in some protocols (eg in SLE or RA). One report in RA  supports this concept. In some autoimmune diseases, cyclophosphamide may be more cardiotoxic than usual, as suggested in SSc, and alternatives may be needed for mobilizing and conditioning.
The question regarding whether allografts should be performed, especially the newer nonmyeloablative 'minigraft', has been raised if relapse rate is too high after autologous HSC transplantation. In our opinion, the point at which this option should be considered has not yet been reached, and the superiority of allo-HSC transplantation has not been proven in autoimmune disease. The risk of TRM is already higher than initially anticipated in autoimmune disease, and it is possible that this risk in allo-HSC transplantation, with its attendant risk for graft-versus-host disease, could also be higher, despite sibling fully matched donors.