Because estrogenic hormones have been implicated in the pathogenesis of SLE, several investigators have studied the efficacy of administering androgenic hormones or luteinizing hormone-blocking agents. Danazol is useful in some patients, 117, 118 especially those with thrombocytopenia (see previous discussion). There has been recent interest in DHEA, which reduced the activity of SLE and was steroid-sparing in an open trial and in a controlled prospective trial. 10, 11 These agents are not effective in severe SLE; however, they probably have steroid-sparing properties in some individuals with mild disease. Doses of DHEA from 50 to 200 mg daily can be used to reduce SLE activity and steroid requirements in patients with relatively mild disease; the major side effect of this intervention is acne, which occurs in 10 to 30 percent of patients.
REGULATION OF T CELL AND B CELL INTERACTIONS
Biologic interventions that suppress B cell activation—either by direct effects on B cell receptors or on helper T cells—have been effective in mouse models of lupus. These interventions include interrupting idiotypic circuits, binding B cell receptors with nucleotides on a framework that prevents binding to fragment crystallizable (Fc) receptors with activation of second signals, interrupting expansion of B cells with a fusion protein that binds Blys growth factor, inactivating helper T cells through antibody blockade of surface molecules cell determinant (CD) 4 or CD3, inactivating second-signal molecules on T cells such as CD40L and CTLA4, blocking recognition of antigen presented in class II major histocompatibility complex (MHC) gene products on surfaces of APCs, inhibiting cytokines that, among other functions, increase B cell maturation and secretion of autoantibodies, including IL-6 and IL-10, and replacing bone marrow of lupus mice with allogeneic marrow from mice resistant to lupus. 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141 Activation of T cells requires two signals delivered by APCs: one antigen-specific signal via the T cell receptor and a second nonspecific signal by linking of additional surface molecules. For T cell activation, linkage between CD28 on T cells and B7.1 or B7.2 (CD80 and CD86) on APC is required. There is at least one additional signal, between CTLA4 on T cells and CD80 and CD86 on APC, that may in some cases give a negative signal that stops T cell activation. The interaction between CD28 and its ligands, B7.1 and B7.2, can be interrupted by administration of the experimental fusion protein CTLA4-Ig. 135, 136, 137 For T cell activation that leads to B cell activation, the second signal requires links between CD40L (CD154) on T cells and CD40 on B cells. This interaction can be interrupted by administration of the experimental monoclonal antibody, anti-CD154. 136 Blys is a surface molecule with increased expression on activated T cells; interaction between soluble Blys and its receptor on B cells expands activated B cells and increases autoantibody production. 133, 134
Most of these biologics have been studied in phase I or phase II studies in patients with SLE, but development is not far enough along to recommend their use in patients at this time. There is also interest in treatment with a monoclonal antibody to CD20, which eliminates most mature B cells for several months. 142 A promising biologic in the treatment of human SLE is La Jolla Pharmaceuticals 394 (LJP 394, "Riquent") a "tolerogen" consisting of four small nucleotides held in an "X" configuration by a tetrameric scaffold. 143, 144 The idea is to bind anti-DNA B cell receptors, but not Fc gamma receptors, so that second signals are not activated. Administration of LJP 394 intravenously to SLE patients with high antibodies to DNA reduces the quantities of those antibodies. One phase II prospective, randomized, placebo-controlled study of patients with recent flares of lupus nephritis but stable disease at the time of treatment suggested reduction of renal flares in the treatment group. 145a
A small series of SLE patients with diffuse membranoproliferative nephritis resistant to treatment with glucocorticoids and cytotoxics was treated with total lymph node irradiation, which inactivates both B and T lymphocytes over the short term, and some T cells for many months. 146 After 10 years of follow-up, approximately 20 percent of patients had good renal function without immunosuppressive therapies. This therapy is not popular currently, but it might be considered for individuals who have not responded to the many alternative therapies now available.
INTRAVENOUS GAMMA GLOBULIN
Administration of IV gamma globulin may have favorable effects on active SLE. 147 Such treatment may solubilize immune complexes and provide anti-idiotypic downregulation of autoantibody production, thus interfering with T cell and B cell signaling. In addition to the utility of this treatment in the management of lupus-induced thrombocytopenia, 113 there are reports of improvement (and of worsening) of dermatitis and nephritis. 144, 147
IMMUNOABLATION WITH OR WITHOUT AUTOLOGOUS STEM CELL TRANSPLANTATION
The idea of these therapies is to induce disease remission in patients with SLE. Thus, the increased short-term danger of infections and bleeding during periods of inadequate numbers of leukocytes and platelets is offset by the possibility that over the long-term patients will not require chronic immunosuppressive therapies, including glucocorticoids. There is at least one report studying administration of immunoablative doses of cyclophosphamide (200 mg/kg divided into four daily IV doses) without subsequent transfer of stem cells. 76 The majority of patients showed excellent improvement in the disease activity of SLE, and over a period of 2 years the flare rate approximated 30 percent. The advantage of this approach is the avoidance of the manipulations required to mobilize stem cells into the peripheral blood (usually done by administration of cyclophosphamide and G-CSF); this mobilization process is associated with increased risk for infections, bleeding, and death. On the other hand, many experts suggest that providing autologous stem cells after immunoablation is safer than not doing so. In this experimental procedure stem cells are induced in the peripheral blood, then harvested and cultured. 73, 74, 75 Therapies that completely ablate bone marrow and much of the immune system are administered (usually consisting of very-high-dose cyclophosphamide, and total body irradiation or antithymocyte globulin), stem cells are reinfused, and stem cell growth factor is administered. Peripheral leukocytes are repopulated in an average of 10 days, with platelets reaching safe levels by a mean of 14 days. The advantage of this approach is that, ultimately, post-treatment immunosuppression is not required: The disadvantage is the well-known dangers of immunoablation during the harvest period, then of immunoablation during the period around the administration of the stem cells, as well as the risk of flaring SLE with administration of G-CSF. Several patients with SLE have been treated with this approach in Europe and in the United States. 73, 74, 75, 75a To date, short-term follow-up (approximately 3 years) has suggested that the great majority of patients with autologous stem cell therapy respond with greatly diminished disease activity; 50 to 75 percent achieve "remission" requiring no immunosuppression, or therapy with only antimalarials or low-dose prednisone (10 mg or less), and 25 to 35 percent flare by 3 years. Flares may be easier to control than the severe disease that led the patient to be a candidate for stem cell transplantation. Mortality rates (including deaths during the induction period) are reported as 3 to 8 percent. The ultimate utility of this therapy, particularly its ability to induce long-standing remissions, is being studied.
Print
Email
Save
