Treatment Of SLE Research Articles

Management of systemic lupus erythematosus: a brief update on recent advances

AbstractSystemic lupus erythematosus (SLE) has remained one of the most baffling autoimmune rheumatic diseases since it was described in the 19th century. It is a multisystemic, chronic condition that affects individuals with life‐threatening irreversible end‐organ damage and debilitating clinical features. The course of SLE varies from periods of quiescence to ones of exacerbation that may involve any organ system in almost any combination. In particular, SLE typically attacks young women at their childbearing years, which makes the therapeutic goals and pharmacological management challenging. The management of patients with SLE in Asia is further complicated by the facts that these patients tend to have a more severe disease, do not have ready access to medical treatment, are not able to afford expensive drugs, especially novel immunosuppressive and biologic agents, and are more susceptible to serious infective complications. In this article, we will provide a brief update on the currently available drug treatment for SLE, and recent advances in this area. The emphases are on early recognition and monitoring of disease complications and the judicious use of immunosuppressive drugs.

B-cell depletion as a treatment for refractory SLE

B-cell depletion as a treatment for refractory SLE

Chinese antirheumatic remedy for the treatment of SLE

Chinese antirheumatic remedy for the treatment of SLE

A Mimic of p21WAF1/CIP1 Ameliorates Murine Lupus

Systemic lupus erythematosus (SLE) is a progressive autoimmune disease characterized by the production of high levels of affinity-matured IgG autoantibodies to dsDNA and, possibly, visceral involvement. Pathogenic autoantibodies result from the activation and proliferation of autoreactive T and B lymphocytes stimulated by epitopes borne by nucleosomal histones. To inhibit the proliferation of autoreactive cells and abrogate the development of SLE, a novel tool, cell cycle inhibiting peptide therapy, was used. Thus, a peptidyl mimic of p21WAF1/CIP1 that inhibits the interaction between cyclin-dependent kinase 4 and type D cyclins abrogated the in vitro proliferative response of T cells to histones and T-independent and T-dependent proliferative responses of B cells. The WAF1/CIP1 mimic also abrogated the in vitro production of total and anti-dsDNA IgG Abs by B cells. Similarly, the p21WAF1/CIP1 construct inhibited the ex vivo T and B cell proliferative responses to histones and decreased the numbers of activated/memory B and T spleen cells. The alterations in the balance of spleen cell subsets resulted from proapoptotic effects of the p21WAF1/CIP1)construct on activated splenocytes. Finally, in vivo, four i.v. injections of the p21WAF1/CIP1 mimic were sufficient to inhibit the progression of the lupus-like syndrome in (NZB x NZW)F1 mice. The levels of anti-dsDNA IgG autoantibodies and the incidence and severity of renal involvement were lower in treated mice than in nontreated mice. Those observations open new avenues for the treatment of SLE and prompt us to evaluate the potential interest of peptidic therapy in human SLE.

Systemischer Lupus Erythematodes – Mythos und Dogma

In this short review, four different aspects of SLE are discussed. The ACR criteria for SLE were established for the differentiation of SLE from other autoimmune diseases and not for the direct diagnosis of SLE. Treatment of SLE is continuously re-evaluated thanks ongoing clinical research. Best clinical practice should be based on experienced and continuous knowledge in the field rather than on dogmatic treatment schemes. SLE is not one disease, but a series of clinical pictures associated into a syndrome. Finally, do not forget that patients with the SLE syndrome suffer almost always from debilitating fatigue.

BILAG 2004. Development and initial validation of an updated version of the British Isles Lupus Assessment Group's disease activity index for patients with systemic lupus erythematosus

To devise a more discriminating version of the British Isles Lupus Assessment Group (BILAG) disease activity index and to show that it is reliable. A nominal consensus approach was undertaken by members of BILAG to update and improve the BILAG lupus disease activity index. The index has been revised following intense consultations over a 1-yr period. It has been assessed in two real-patient exercises. These involved patients with diverse clinical features of SLE, including gastrointestinal, hepatic and ophthalmic problems, which the earlier versions of the index did not fully take into account. Reliability in terms of the ability to differentiate patients was assessed by calculating intraclass correlation coefficients. The level of agreement between physicians was determined by calculating the ratio of estimates of the standard error (SE) attributable to the physicians to the SE attributable to the patients. Good reliability and high levels of physician agreement were observed in one or both exercises in the constitutional, mucocutaneous, neurological, cardiorespiratory, renal, ophthalmic and haematological systems. In contrast, the musculoskeletal system did not score as well, although providing more clear-cut glossary definitions should greatly improve the situation. Some significant changes in the BILAG disease activity index to assess patients with SLE are proposed. The process of demonstrating validity and reliability has started with these two exercises assessing real patients. Further validation studies are under way. BILAG 2004 is likely to be valuable in clinical trials assessing new therapies for the treatment of SLE, as it provides a more comprehensive system-based disease activity measure than has been available previously.

Abnormalities of Stromal Cells in Autoimmune Systemic Lupus Murine Model.

Mice of the BXSB strain develop autoimmune systemic lupus-like syndrome characterized by thrombocytopenic purpura, coronary vascular disease with myocardial infarction, glomerulonephritis, and autoantibodies. Defects in hematopoietic cells and lymphocytes have been reported in these strains. We have analyzed mesenchymal stem cells (MSCs) purified from autoimmune prone BXSB to determine whether stromal, and not only hematopoietic cells contribute to the development of autoimmune pathology in these mice. MSCs are progenitors within the bone marrow stroma that spontaneously differentiate into adipose, bone, cartilage, and stromal tissue. Stromal progeny of MSCs support engraftment of hematopoietic stem cells (HSCs) and promote hematopoiesis. We have previously demonstrated the capacity of bone marrow transplanted from healthy mice into autoimmune prone mice to prevent and treat the autoimmune pathology and reverse associated abnormalities. MSCs were purified from autoimmune BXSB bone marrow, and from normal C57Bl/6 mouse strains. Initially, adherent stromal cell populations from both murine cultures proliferated at similar rate, however fewer colony forming unit-fibroblasts (CFU-Fs) were obtained in cultures from BXSB stroma. After few passages, C57/Bl 6 stroma continued to reach 70% confluency within 2 weeks of splitting, while BXSB stromal culture continued to survive but stagnated and did not reach confluency. Both MSCs harvested from BXSB and C57/Bl6 lacked hematopoietic progenitors and did not develop CFU-E, CFU-GM, or CFU-GEMM when cultured in methyl cellulose medium supplemented with the appropriate hematopoietic growth factors. To examine interaction between diseased stroma and healthy marrow cells, stroma from autoimmune BXSB and healthy C57Bl/6 mice were separately placed in the bottom chambers of transwell plates. The top chambers contained marrow cells from healthy GFP-transgenic B6 mice and were separated by nylon mesh membrane (5μ pores) from the bottom chambers. More marrow cells migrated to the autoimmune MSCs well as shown by flow cytometry. This suggests that the autoimmune affected MSCs produce cyokines/mediators, or have cellular structure defects that attract healthy marrow cells. To investigate the latter possibility, we looked for expression of gap junction protein Connexin 43 which is important for MSC-HSC interaction and possibly subsequent expansion and proliferation. While healthy MSCs from C57/Bl6 mice expressed connexin 43, this expression was minimal in MSCs purified from autoimmune mice as shown by both immunostaining and Western blot analysis. These results indicate that marrow-derived MSCs have defective structure and function when compared with MSCs from healthy mouse strains. These data support the hypothesis that co-transplantation of MSCs along with HSCs for the treatment of advanced SLE and other autoimmune disease is imperative to restore healthy stromal cells in the diseased marrow, and to support hematopoiesis and promote tissue repair.

Lupus and desoxyribonuclease.

The dominant autoantigen in SLE is the nucleosome and immune complexes involving nucleosomes are the major cause of tissue damage. Nucleosomes can be broken down in vivo with Desoxyribonuclease 1. DNase 1 from humans and mice is inhibited by actin and it is proposed that the release of platelet actin at inflammatory sites is one mechanism which causes nucleosomes to become antigenic. Rats whose DNase 1 is not inhibited by actin do not get lupus. Treatment of NZB/W mice with recombinant DNase slows the onset of their disease if given early and improves the renal disease if given later. This disease can also be entirely prevented by treatment with dexamethasone. Mice whose DNase 1 gene is knocked out are known to develop lupus and to be otherwise normal. DNase 1 especially in its mutant actin and salt resistant forms remains an attractive candidate for the treatment of SLE.

Factors associated with anxiety, depression and suicide ideation in female outpatients with SLE in Japan.

The subjects consisted of 84 female SLE outpatients who were all over 20 years of age. These patients were able to maintain relatively stable physical conditions and lead normal daily lives, and they were regularly treated at the outpatient clinic. All subjects were Japanese. Psychological features (trait anxiety, state anxiety, depression and suicide ideation) were evaluated using psychological tests, and the relationships between the respective psychological features and background factors were statistically evaluated using stepwise multiple logistic regression analyses. In this study, we found that 'the self-evaluation of not having understood SLE at the time of starting SLE treatment' was the background factor significantly affecting depression or trait anxiety. 'No spouse' had a statistically significant effect on depression, and 'self-awareness as problems of side-effects due to steroids' had a statistically significant effect on state anxiety. We also found 'human relations among family members' and 'high daily steroid dosage' to be significantly correlated with suicide ideation. However, there were no correlations between the psychological features and 'disease activity at the time of investigation' or 'history of neuropsychiatric diseases'. In female SLE outpatients, performing psychological approaches focusing on 'understanding SLE at the beginning of treatment', 'the human relationships among family members', or 'issues related to steroid therapy' may be useful for the early treatment or prevention of various major mental problems.

Differential effect of corticosteroid therapy on the cytoplasmic cytokine expression in CD4 and CD8 positive T cells from lupus patients

Due to their different antiinflammatory and immunmodulatory effects corticosteroids are widely used in the treatment of SLE. Literature data support both Th1 and Th2 dominance in lupus. There are only few reports about cytokine profile of CD8+ T cells in SLE. In the present study we examined by flow cytometry the cytoplasmic IFNγ, IL-4 and IL-10 expression in CD4+ and CD8+ T cells from six active, untreated, newly diagnosed SLE patients, who received after that 1 mg/kg methylprednisolon. Pretreatment expression of IFNγ was lower, while IL-4 and IL-10 expressions were higher in CD4+, but not in CD8+ T cells of patients than in control cells. Corticosteroid treatment increased IFNγ and decreased IL-4 and IL-10 expressions in patients' CD4+ cells, but had no significant effect on the cytoplasmic cytokine expression of CD8+ cells. In conclusion, present results indicate that corticosteroid therapy does not influence INFγ, IL-4 and IL-10 expression in CD8+ T cells of lupus patients, and it may have pathogenic significance.

ROLES OF PROLACTIN AND GONADOTROPIN-RELEASING HORMONE IN RHEUMATIC DISEASES

PRL is capable of influencing immune responses and is a cytokine in all likelihood. Circulating PRL is elevated in a number of autoimmune diseases, and about 20% of SLE patients are hyperprolactinemic. The serum PRL concentration often does not reflect disease activity in SLE. The PRL-suppressing drug bromocriptine has been reported to benefit small numbers of patients with reactive arthritis and inflammatory eye disease, and bromocriptine may be beneficial in treating SLE. In NZB/NZW mice, bromocriptine was beneficial and prolonged life. Bromocriptine therapy favorably modified disease in human SLE. In a preliminary open-label study, SLE patients treated with bromocriptine for 6 months had significant improvement in disease activity. These responses were corroborated by masted therapeutic studies. Daily treatment with low-dose bromocriptine prevented lupus flares, and bromocriptine was as effective as hydroxychloroquine in treating active nonorgan-threatening disease. The reports of the efficacy of bromocriptine treatment of SLE are encouraging. Additional studies may confirm the findings reported in this review and may lead to further use of hormonal modification to treat lupus and other autoimmune diseases. For the present, it is important to understand that treatment with dopamine agonists such as bromocriptine is experimental and best confined to therapeutic trials. In the experience of the authors, bromocriptine should not be relied on to treat severe life-threatening autoimmune disease. If bromocriptine is used to treat SLE and is then discontinued, the patient should be observed carefully for rebound hyperprolactinemia and the development of a lupus flare. GnRH is produced by lymphocytes and exerts immunomodulatory actions. Thus, GnRH resembles a cytokine. GnRH can be shown to exert gender-restricted immune actions in vitro and in vivo. The authors' preliminary observations are consistent with the possibility that gender-related differences in expression of the GnRH receptor or in GnRH signal transducers may contribute to gender-related differences in immune responsiveness to GnRH. These differences in G proteins may contribute to the gender-related differences in immunity and expression of autoimmune disease.

NEW THERAPIES FOR SYSTEMIC LUPUS ERYTHEMATOSUS

New therapies for the treatment of SLE have gained increased attention, as demonstrated by a growing number of new modalities being studied. These modalities include novel biologic agents that target specific immunologic responses and more traditional pharmaceutical agents. This article summarizes these new therapies and briefly discusses their mechanisms of action and the most recent research performed to characterize their safety and efficacy.

DEHYDROEPIANDROSTERONE IN SYSTEMIC LUPUS ERYTHEMATOSUS

DHEA has shown promise for the treatment of SLE in three controlled and several uncontrolled clinical trials, including one large multicenter study comprising nearly 200 patients. The main benefits of DHEA seem to be a decrease in corticosteroid requirements and improved overall symptomatology. Intriguing aspects of DHEA treatment in SLE that require further study are a possible bone protective effect and improvements in cognitive function. The most frequent side effect is mild acneiform dermatitis, and long-term concerns include lowered HDL cholesterol.

HEMATOPOIETIC STEM CELL TRANSPLANTATION FOR SYSTEMIC LUPUS ERYTHEMATOSUS

Many institutions worldwide are conducting clinical studies using immunoablative therapy followed by hematopoietic stem cell transplantation for the treatment of SLE. Interpretation of these studies will be complicated by the differences in patient selection, conditioning regimens, and the method of stem cell collection. A major concern with this approach is that autoreactive effector cells will be re-infused with the autologous graft. The recent demonstration that immunoablative therapy (cyclophosphamide 200 mg/kg) can be safely delivered without the need for stem cell rescue offers a potential way to circumvent this problem. Early results employing immunoablative therapy, with or without stem cell rescue, are encouraging; however, longer follow-up and additional patients are necessary to validate this approach.

The preparation of immunoadsorbents and their adsorption properties for anti-DNA antibodies in SLE serum

By using the hydroxyethyl crosslinked chitosan beads as the support, a novel immunoadsorbent was prepared by conjugating DNA onto the beads via the CNBr activation. The influence of conditions on the immobilization capacity of DNA was studied in detail. The adsorption experiments were performed by adding the immunoadsorbents to the SLE serum. The results showed that this type of immunoadsorbent could cut down the anti-DNA antibody levels by 65.33% at most in serum. Because the chitosan has good blood compatibility, this type of immunoadsorbent is hopeful for the treatment of SLE by hemoperfusion in the future.

Prospective Randomized Trial of Two Different Immunoadsorbers in Severe Systemic Lupus Erythematosus

Experiences with extracorporeal therapy in systemic lupus erythematosus have been published over the last 20 years and more. In addition to plasmapheresis, specific adsorption columns have been developed to deplete pathogenic antibodies and immune complexes in the plasma of patients with SLE. We conducted a prospective randomized trial to compare the efficacy of a disposable adsorption column, which contained a specific ligand, phenylalanine (IMPH-350|Pt, Diamed, Köln, Germany) with a regenerable Ig-adsorbing column containing sheep anti-human antibodies (Ig-Therasorb|Pt, Therasorb, München, Germany). Twenty SLE patients inadequately controlled with corticosteroids, anti-malarials, azathioprine or cyclosporine A, had strong evidence of disease in general, or an organ related SLAM score. They were randomized to receive either a perfusion of IMPH-350, or Ig-Therasorb, immunoadsorbed with 2.5ml of plasma, three times each. The treatment regime was repeated after 4 weeks when the response was limited or non-existent. Response was defined as a reduction in the SLAM score of at least 30%. SLAM scores in the IMPH group decreased from 14.3±5.6 to 9.2±6.2 after 1 month and to 9.4±3.9 after 6 months; corresponding scores in the Ig-Therasorb group were 18.3±5.5 to 11.2±7.6, decreasing to 9.2±2.9. After 1 month, 8/10 patients in both groups showed a response; after 6 months, 5/10 patients in the IMPH-350 group and 8/10 in the Ig-Therasorb group fulfilled the response criteria. Reduction of dsDNA antibodies directly after treatment was 50.8±6.6% in the IMPH-350 group and 61.0±8.0% in the IgTherasorb group. Results indicate that immunoadsorption is an additional option in the treatment of severe SLE. Choice of type of immunoadsorber and immunosuppressive treatment has to take into account the severity and chronicity of common disease activity and organ involvement, as well as economic aspects.

Soluble CD16 in the Treatment of Murine Lupus Nephritis

To determine if soluble CD16 (sCD16) could alter the expression of lupus-like disease, groups of 10 female NZB/NZW mice (age 16–20 weeks) were given sCD16 three times a week for 5 weeks (control; 100 μg; 200 μg/dose) after onset of proteinuria. Results of this study indicate that the administration of sCD16 after onset of disease lowered anti-DNA levels, delayed the development of proteinuria, and significantly prolonged survival while the mice were on treatment. These results indicate that sCD16 alters the expression of autoantibodies and the progression of renal disease in NZB/NZW mice, suggesting that therapies directed at Fc receptors may be useful in the treatment of SLE.

Neuropsychiatric systemic lupus erythematosus before and after immunosuppressive treatment: a FDG PET study

At its inception, morphological imaging, like magnetic resonance imaging (MRI), is often not useful in neuropsychiatric systemic lupus erythematosus (NPSLE), although the disease clinically shows cerebral symptoms. Functional imaging, like positron emission tomography (PET), may be a method that offers some advantages. We report a 53-year-old white man with decreased memory and visual disturbances who met four of the American Rheumatism Association (ARA) criteria for the classification of SLE. He was investigated before and after 3 months of therapy using PET and F-18-fluoro-2-deoxy-D-glucose (FDG). Treatment consisted of prednisone (25 mg/day, tapered to 10 mg/day) and cyclophosphamide (daily 100 mg for 3 weeks followed by a drug-free interval of 1 week). For the control group, 15 clinically and neurologically healthy volunteers (5 male, 10 female, aged 48 +/- 7 years) were investigated. All study participants additionally had a cranial MRI. In both controls and the SLE patient, cranial MRI was negative. However, the patient showed a significant hypometabolism in the region parieto-occipital on both sides and the parietal region on the right side before treatment. After treatment metabolism in these regions was within normal limits. Hence, FDG-PET could help to verify brain-onset of SLE earlier and may be a powerful tool for controlling SLE treatment.

The Dilemma of Diagnosis and Treatment of Neuropsychiatric SLE

The Dilemma of Diagnosis and Treatment of Neuropsychiatric SLE

Immunomodulating effects of synchronised plasmapheresis and intravenous bolus cyclophosphamide in systemic lupus erythematosus.

Recent studies have suggested that synchronised plasmapheresis and intravenous pulse cyclophosphamide therapy reduce disease activity in SLE patients. The aim of the present study was to examine the immunomodulating effects of this therapy and compare it with changes seen with cyclophosphamide alone. Four patients with active SLE were studied. Two were treated with synchronised therapy and two received cyclophosphamide only for up to 26 weeks. Disease activity was measured by the SLE disease activity index (SLEDAI). Immunological studies were performed immediately prior to each treatment. Patients in both treatment groups improved as reflected by a fall in mean SLEDAI scores: synchronised therapy 33.5 to 11; cyclophosphamide only 13.5 to 4.5. Following synchonised therapy only there was a prompt and sustained increase in the mean percentage of CD8+ cells (20.8 to 54.8) which resulted in a fall in the CD4:CD8 ratio (1.95 to 0.62). With both treatment modalities there was a fall in the proportion of CD20+ cells (B lymphocytes) (synchronised therapy 10.5 to 3.2; cyclophosphamide only 5.6 to 2.2). However, only synchronised therapy resulted in a fall in the in vitro production of immunoglobulins which was unchanged or increased following cyclophosphamide alone. These results suggest that although both treatment modalities are efficacious in the treatment of active SLE they produce different immunomodulatory effects. Thus, both therapies reduce the number of circulating B lymphocytes whereas synchronised therapy also modifies cellular immunity by promoting the emergence of a phenotypic suppressor T lymphocyte population.