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Novel Therapies for Systemic Lupus Erythematosus?
Author: Sara M. Mariani, MD, PhD. Highlights of the 7th International Congress on SLE and Related Conditions; May 9-13, 2004; New York, NY
Immunosuppression is achieved in patients with autoimmune diseases with different sets of drugs that have a progressively stronger effect on the underlying immune responses: from prednisone in non-organ-threatening conditions to cytotoxic drugs, such as cyclophosphamide, for more advanced disease.
Yet, Dr. Daikh of the University of California, San Francisco, said at the symposium on "New Treatments," held recently during the 7th International Congress of Systemic Lupus Erythematosus (SLE) and Related Conditions, in New York, NY: "Current therapies with traditional classes of drugs are not achieving the therapeutic challenges given by SLE. We need to improve specificity and efficacy, while reducing toxicity of treatments." More sophisticated approaches with more selective mechanisms of action and more accurate targeting are needed to improve quality of life and outcomes in patients with SLE.
Although still surrounded by uncertainty, the etiology of SLE is influenced by environmental, hormonal, and host-related factors, some of which have a genetic origin. In the past few years, great strides have been made in understanding the mechanisms that ultimately converge in the organ-damaging, autoreactive cognate immune responses seen in SLE patients.
It is through activation and collaboration of B cells, T cells, and antigen-presenting cells that a sort of immune "hyperactivity" is elicited in a predisposed individual, with the generation of pathogenic autoantibodies and circulating immune complexes. These autoreactive effectors are believed to mediate tissue damage, following binding to specific Fc receptors and activation of the complement cascade. Cytokines released by activated cells, such as interleukin (IL)-6, IL-10, interferons, and tumor necrosis-alpha also contribute to tissue damage by increasing autoimmune responses in affected organs, and thus favoring disease progression.
Identification of the cells, cell-bound receptors, and soluble mediators involved in these autoimmune reactions has thus provided an array of potential targets for more selective immunosuppressive interventions, including receptors critically involved in T-antigen-presenting cell (APC)-B-cell interactions (costimulatory molecules), such as CD28/CTLA-4 and CD40 ligands, the maturation-inducing factor BAFF/BlyS, and the complement convertases C5 and C3.
Many of the inhibitory reagents developed against these targets have been or are being tested in experimental models in mice spontaneously prone to develop autoimmunity, and, in a few cases, in transgenic or knockout mice carrying a single and well-characterized gene defect.
The lupus-prone F1 progeny of NZBxNZW mice recapitulates well the signs and lesions of human lupus with the development of immune complex-mediated nephritis, arthritis, and brain abnormalities, as seen in SLE patients. Consistently, drugs shown to be effective in controlling murine lupus in NZBxNZW mice have later proven effective in patients with SLE, indicating their value in developing new therapeutic approaches, provided, of course, that cross-species differences in reagents and systems do not affect the translation of efficacy and safety results for the human disease.
T cells have a central role in the generation and maintenance of SLE. T-cell help, in fact, is needed for the generation of target-specific autoantibodies produced by B cells, as autoantibodies are known to undergo class-switch and affinity maturation (both T-cell-dependent events). The depletion of T cells in mice effectively prevented the development of lupus, whereas a transitory or incomplete block of T-cell activity led to a reversible decrease in disease severity. Manipulation of the help given by CD4+ T cells can be achieved by inhibition of the CD40 ligand -- CD40 and CTLA-4/CD28 -- CD80/CD86 interactions that provide the costimulatory or second signals needed for activation of APCs and effective stimulation of antibody-producing B cells.[3,4]
Blocking Costimulatory Signals
The soluble, recombinant molecule CTLA4-immunoglobulin (Ig) consists of the extracellular domain of CTLA4 linked to an Ig Fc region to improve stability and bioavailability. It specifically blocks T-cell-APC interactions by preventing binding of T-cell CTLA4 to the CD80/86 receptors expressed by APCs. Studies in wild-type and autoimmunity-prone mice have shown that CTLA4-Ig was indeed able to block second signals and ameliorate the autoimmune disease.
A dose-escalation study done in psoriasis patients with CTLA4-Ig showed that about 46% of patients had > 50% reduction in their lesions at day 72 following treatment. Reductions in T-cell responsiveness accompanied response to treatment, with concomitant inhibition of antibody-dependent responses, in the absence of B-cell depletion. Autoantibody responses resumed following suspension of treatment, and relief of the inhibitory activity exerted on costimulatory T cells.
Similarly, in a randomized trial in patients with rheumatoid arthritis refractory to methotrexate, a comparison of CTLA4-Ig at 2-10 mcg/kg plus methotrexate vs methotrexate alone yielded an improvement in more than 70% of the ACR core criteria (ACR70) in 17% of patients, an ACR50 in 32% of patients, and an ACR20 in 60% of patients.
Single-agent, short-course treatment in lupus-prone mice prevented or delayed disease progression, depending on the model used, although to a lower extent than conventional treatment with cyclophosphamide. Both approaches, however, had only a transitory effect -- the disease progressed after suspension of treatment. Survival was, nonetheless, improved in mice receiving CLTA4-Ig vs control, with an effect similar to that achieved with cyclophosphamide.
Does the combination of cytotoxic and targeted therapy fare better in these animal models? Apparently yes. Survival was improved in 36% of mice treated with either cyclophosphamide or CTLA4-Ig. If both agents were given together, survival was improved in 94% of the animals.[7,8] A similar effect was seen also on advanced renal disease. Although either agent alone did not ameliorate proteinuria, a combination of the 2 agents was effective in inducing a substantial improvement in renal function.
Can the addition of CTLA4-Ig allow a reduction in the dose of cyclophosphamide used, and thus of its toxicity? Experimental data suggest that the benefit achieved with single-dose (intraperitioneal injection, 3 times/week for 2 weeks) vs continuous-dose (every 10 days) cyclophosphamide yielded similar outcomes if there was concomitant administration of CTLA4-Ig.
A number of questions still surround this experimental therapeutic approach and other similar immunomodulatory strategies:
Main concerns with immunosuppressive treatments are, in fact, in the short term, an increase in susceptibility to infections, and in the long term, a potential loss of immunosurveillance with development of immunosuppression-related tumors (as seen, for example, in Hodgkin's or transplantated patients receiving aggressive treatment protocols). A strategy to minimize these risks might be to induce global immunosuppression with an induction regimen and then use a more targeted maintenance therapy, if indeed this switch offers similar benefits and less toxicity.
Comparison of the immunomodulatory effects achieved with CTLA4-Ig vs block of the CD40 ligand pathway suggests that inhibition of CD40 may be most effective in the early stages of the disease, whereas block of CTLA4 appears to be more important in later stages. Treatment with a CD40 blocker effectively reduced activation markers on B cells and the production of autoantibodies, and it induced a decrease in the total number of circulating B cells. However, Dr. Daikh added, "the cost of such combined therapy -- a CTLA-4 plus a CD40 blocker -- could be an issue."
A physician in the audience, prompted by the thought of costs and access to these new biologic therapies, then wondered whether the idea of giving such expensive experimental treatments for a very long time (if not a lifetime, since SLE is often diagnosed in young women) would be sustainable. "We are trying to improve overall treatment both in terms of survival and quality of life", answered Dr. Daikh . Cost-benefit analysis will be needed to choose the best option(s) available for each patient
Another way to achieve down-modulation of B-cell autoimmunity is to target the B cells directly with a specific reagent. The membrane-bound molecule CD20 provides such opportunity, as it represents a B-cell-specific target. As opposed to the inhibitory approaches described before that target T-cell-APC interactions, treatment with anti-CD20 antibodies aims at inducing depletion of the recipient's B cells.
One such reagent, the anti-CD20 monoclonal antibody rituximab, has been approved for the treatment of refractory low-grade, B-cell non-Hodgkin's lymphoma, and it is being evaluated for efficacy in patients with chronic idiopathic thrombocytopenia, Wegener's granulomatosis, and rheumatoid arthritis. Its mechanism of action is thought to derive from complement-dependent cytotoxicity, cell-mediated cytotoxicity, and induction of apoptosis in antibody-targeted B cells. Resistance may occur and studies are in progress to define how to circumvent it.
Dr. Iva Gunnarsson of the Karolinska University Hospital, Stockholm, Sweden, discussed the results of an open clinical trial done in patients with severe lupus nephritis, who received 4 weekly doses of antibody (375 mg/sqm), cyclophosphamide (0.5 g/sqm), and methylprednisone (250 mg). A total of 11 women were included in the study, with a mean age of 32 years, who had failed conventional treatment. Patients received rituximab for a mean of 16 months (2-36 months).
Results presented at the symposium were from 9 patients at 6 months of follow-up. Seven of these 9 patients had nephritis, 1 had arthritis, and 1 had Quincke edema at study entry. At follow-up, patients presented a significant decrease in the Systemic Lupus Activity Measure (SLAM) score, a reduction in the daily prednisone dose from 16 mg/day to 9.4 mg/day, normalization of the C3 levels, and a reduction in autoantibodies to dsDNA. Serum IgG levels remained stable, as those for IgM and IgA. Similar results were obtained by another group in an open-label study with 2 patients.
At follow-up biopsy, there was a significant reduction in renal disease activity in some patients with decreased proteinuria, which was seen also in a patient with a former nephrotic syndrome. For example, 2 patients with stage III disease before treatment were stages II and I at follow-up, whereas 2 patients were in stage IV, 1 progressed to stage IV/V, and the other one to stage V. The patient in stage V remained stable. The activity index decreased from 5 to 1 in the IIIB patient reclassified as I after treatment; the chronicity index was, however, unchanged at 8. Circulating CD19+ cells were detectable 6 months following treatment. Skin and joint manifestations were also found improved by treatment at the 6-month follow-up. The patient with arthritis, however, relapsed at 12 months and is currently being retreated.
Treatment with rituximab was associated in this study with the development of a Herpes zoster infection in 1 patient, and an infusion reaction after the second infusion (which led to treatment discontinuation) in another patient. Two disease relapses occurred, one at 6 months and the other at 12 months.
Dr. Gunnarsson concluded that the preliminary results from this open trial in refractory patients with severe lupus nephritis are promising, and more data will be acquired to further assess its safety and efficacy. They are now treating a total of 23 patients with this approach. In her experience, anti-CD20 treatment should be given early rather than late in this subset of patients, considering the stage-related differences in efficacy seen in the patients treated so far. Skin responses were quite slow to appear, as they were noted at 8-10 months, whereas joints and the respiratory system seemed to respond more quickly to treatment.
Does polymorphism in the Fc gamma receptor RIIIa genotype affect responsiveness to rituximab treatment? Results from another study conducted in 12 SLE patients showed significant heterogeneity in B-cell depletion at 1 and 2 months after treatment. As concluded by the study authors, B-cell counts appeared highly correlated both with serum levels of the monoclonal antibody and the Fc gamma RIII genotype, thus suggesting antibody-mediated cytotoxicity and/or induction of apoptosis as effector mechanisms in these patients. If these results are confirmed in a larger number of patients, additional screening of prospective recipients may help in predicting who will be most responsive to treatment.
Autologous Stem Cell Transplant for Refractory SLE
A third potential strategy to downregulate the immune responsiveness of autoimmune patients would be to give a new immune system by stem cell transplantation. But can autologous precursor cells help in "resetting" the patient's immune system that has gone haywire, down a road of autoimmune aggression and tissue damage?
Dr. Tobias Alexander and colleagues of the University Hospital Charite, Berlin, Germany, set up an experimental autologous stem cell transplantation (ASCT) protocol for patients with life-threatening SLE, who were refractory to standard treatment with at least 2 immunosuppressive drugs, but with still adequate function of major organs. A total of 6 patients were included, 5 females and 1 male (mean age, 31 years).
Following mobilization, cells were collected by leukapheresis, enriched for CD34 expression, and reinfused in patients following ex vivo conditioning. Activity of renal disease was documented before and after treatment.
Remission was noted in 4 patients. One patient died of aspergillosis, and 1 patient (the only male) had a severe relapse 17 months after treatment, with a disease-related death. In the 4 successfully reconstituted patients, titers of anti-DNA and of antinuclear autoantibodies remained low or negative 36 months following treatment. Anti Ro/SSA and La/SSB antibodies could still be detected in 2 patients.
Reconstitution with na�ve B cells was detectable at 8 months. Reconstituted T cells, on the other hand, were CD45RA+ (na�ve cells), CD45RO+ (memory cells), or HLA-DR+ (activated cells). Analysis of the T-cell receptor genetic diversity, 2 years after the ASCT, revealed a fully reconstituted repertoire for the beta-chain variable region, with no detectable differences vs healthy controls. Reactivation of thymic activity was noted in patients who had received autologous stem cells, providing evidence of successful thymic regeneration in adult age.
Blocking Proinflammatory Cytokines -- Tumor Necrosis Factor-Alpha
Tumor necrosis factor (TNF)-alpha is 1 of the highly proinflammatory cytokines involved in the immune dysregulation seen in SLE patients. Produced by T cells, dendritic cells, and other sources, TNF-alpha has multiple activities, including the promotion of B-cell growth, activation of proinflammatory effectors, and direct tissue damage. If indeed the action of TNF-alpha tilts the internal balance in favor of autoimmunity, then blocking this cytokine should, in principle, lead to improvement of symptoms and organ damage, and offer a new therapeutic strategy for patients with SLE.
TNF-alpha blockers have been developed by preparation of soluble fusion proteins containing the extracellular domain of the TNF receptor and an Ig constant domain (TNF-R Ig) that would sequester and thus inactivate TNF (etanercept), or by generation of chimeric/humanized anti-TNF antibodies (infliximab and adalimumab). Approved for patients with rheumatoid arthritis, juvenile chronic arthritis, ankylosing spondylitis, and psoriasis, TNF blockers ameliorated inflammation, pain, and function in about two thirds of treated patients in double-blind, placebo-controlled trials. Use of such agents has, however, been associated, in a few patients, with the development of antinuclear and anti-DNA antibodies, as well as with cases of drug-induced SLE.[17,18]
Studies in patients with Crohn's disease have shown that administration of a TNF blocker induced benefit in about 60% of the patients, although such effects were transitory with relapses at suspension of treatment. Also in this case, the investigators reported development in some patients, in addition to infections, of lupus-like syndromes and demyelinating diseases.
Analysis of lymphoma prevalence in rheumatoid arthritis patients receiving anti-TNF therapies revealed a higher risk of lymphoma in these cohorts. For example, in 1 study, the standardized risk of lymphoma for the use of infliximab (with or without etanercept) was 2.6 vs 3.8 for patients receiving etanercept (with or without infliximab) vs 1.7 in patients receiving methotrexate. It is, however, still unclear whether this increase is drug-related or whether it reflects a bias in the patient-selection process. The safety and long-term effects of TNF-blocking therapies in patients with rheumatic diseases are still ongoing, together with cost-benefit analyses.[21,22]
Do anti-TNF therapies then represent a feasible therapeutic option for patients with SLE?
Dr. Josef Smolen of the Medical University of Vienna, Austria, discussed, during the symposium, further aspects of TNF action in SLE and the results from experimental and clinical studies.
In addition to its activity as a growth and differentiation factor, TNF-alpha increases the production of other proinflammatory cytokines, including IL-1, IL-6, and IL-8, and it can induce death in target cells. High concentrations of TNF-alpha were detected in lupus patients, and levels correlated with disease activity. Circulating TNF-alpha was bioactive, as shown by the induction of the adhesion molecule ICAM-1 in cultured synovial fibroblasts, and its activity was blocked by specific TNF-alpha inhibitors. Immune complexes circulating in SLE patients may contribute to the increased levels of TNF-alpha: Upon binding to macrophages, circulating immune complexes induce the release of TNF-alpha in disease-involved sites, such as the kidney or the spinal fluid.
Different lines of evidence obtained in experimental animal models, however, seem to argue against the use of TNF-alpha blockers in SLE:
About 16% of rheumatoid arthritis patients receiving a TNF-receptor (R) blocker developed anti-dsDNA and 0.2% of them a lupus-like syndrome, with resolution of symptoms at treatment suspension. Rather than being a dangerous proinflammatory cytokine, is TNF-alpha protecting from lupus-like autoimmunity?
Open-Label Trial in SLE Patients
In Dr. Smolen's view, the data on the beneficial effects of TNF blockade largely surpass those on the harmful effects deriving from the use of TNF-R-alpha antagonists.
In an open-label trial, 6 SLE patients with moderate disease activity, refractory to standard treatment, received 4 x 300 mg of infliximab on weeks 0, 2, 6, and 10 as induction therapy. Three patients had arthritis and 4 had nephritis. Remission of arthritis was seen in all 3 patients, but differently from previous trials in rheumatoid arthritis, disease recurred 6-8 weeks following drug suspension. A new treatment cycle was associated with a new remission. Disease activity was also reduced with the SLE activity and index score decreasing from 10 to 7.5. Proteinuria responded to treatment and remained low for up to 1 year in all 4 patients (also in the subject with type V renal disease). The SLE activity and index score was reduced from 10 to 5-4.
There was no effect on anti-dsDNA and C3 levels in patients 1, 3, and 5, whereas the anti-dsDNA antibody underwent a transitory increase in patient 4 and a substantial, durable increase in patient 2. A transitory increase was also noted in antihistone antibodies, which reached a lower than baseline level at the end of the trial. A patient developed antiphospholipid antibodies but no clinical manifestations. All antibodies detected were IgG. In patient 7 who had a type V renal disease, there was no effect on the disease and no changes in the titers of anti-dsDNA.
Thus, in this preliminary study, treatment with infliximab was not associated with infusion reactions or flare-ups. Several urinary tract infections were, however, noted as well as increases in circulating titers of anti-dsDNA. Treatment was associated with substantial, but transient improvements in arthritic disease, with relapse at suspension. Durable improvements (50% to 90% reductions) in proteinuria were obtained with treatment, with normalization of urinary sediment, and a 50% reduction in steroids needed at 52 weeks.
Dr. Smolen concluded by showing the painting Visioni Simultanee by Umberto Boccioni (with 2 human silhouettes looking down on 1 center from opposing perspectives) and saying that "TNF blockers may not be that dangerous in lupus." A preliminary conclusion, which some feel, will take more than preliminary, open-trial data to hold its ground and offer promise of efficacy and safety for SLE patients.
A participant in the audience commented on an anecdotal treatment of a patient with severe pneumonitis that had failed other approaches who was being treated with TNF blockers. Three months after a 3-4 week treatment, no complications occurred, but also no dramatic improvements were noted; no disease progression and apparently no toxicity-- another "painting" in need of appraisal?