Therapy For SLE Research Articles

The role of non-corticosteroid related factors in osteonecrosis (ON) in systemic lupus erythematosus: a nested case-control study of inception patients

Several factors have been associated with the development of osteonecrosis (ON) in SLE but corticosteroid (CS) therapy has been the most consistent association. We sought to determine factors that predisposed to, or protected from, the development of ON in lupus patients when cumulative oral corticosteroid doses were matched between cases and controls, thereby removing presence of corticosteroid therapy and cumulative dose as risk factors. A nested case-control study of an inception cohort of SLE patients was used to determine the clinical, laboratory and therapeutic differences between patients who developed their first ON event and patients who did not develop ON, having matched these groups for their cumulative oral corticosteroid doses. Of the 570 patients seen within the first year after diagnosis 65 (11.4%) developed ON. None of the variables examined were found to confer additional ON risk in multivariate analysis. It appears that the major factor associated with the development of ON is corticosteroid therapy. Factors which may protect a majority of patients on corticosteroids from developing ON remain to be elucidated.

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.

Cognition and Immunity: Antibody Impairs Memory

Patients with lupus (SLE) experience progressive cognitive loss without evidence of CNS vascular disease or inflammation. SLE patients produce anti-DNA antibodies that crossreact with NMDA receptors and are capable of mediating excitotoxic death. We now show that mice induced by antigen to express these antibodies have no neuronal damage until breakdown of the blood-brain barrier occurs. Following administration of lipopolysaccharide (LPS) to immunized mice, antibodies gain access to the brain. They bind preferentially to hippocampal neurons and cause neuronal death with resulting cognitive dysfunction and altered hippocampal metabolism on magnetic resonance spectroscopy. Memantine, an NMDA receptor antagonist, given prior to LPS administration, prevents neuronal damage. Thus, systemic immune responses can cause cognitive impairment in the absence of an inflammatory cascade, implicating the immune system in yet another arena of human pathobiology. Furthermore, NMDA receptor antagonists prevent antibody-mediated damage and may constitute a new approach to therapy in SLE.

Nocardial infections in Japan from 1992 to 2001, including the first report of infection by Nocardia transvalensis.

In the period from 1992 to 2001, 303 cases of nocardioses were diagnosed in Japan, with the corresponding etiological agents isolated and characterized. Taxonomic analyses of these 303 strains showed that most nocardial infections were caused by members of the Nocardia asteroides group (72.3%). Speciation showed that 72 strains were N. asteroides, 31 strains were N. cyriacigeorgica, 2 strains were N. beijingensis, 81 strains were N. farcinica, and 33 strains were N. nova. Sixty-six strains of N. brasiliensis were the next most prevalent species of the total Nocardia isolates, followed by 14 strains of N. otitidiscaviarum. Infections by N. transvalensis (3 strains) and N. pseudobrasiliensis (1 strain) were also confirmed. The infections due to N. transvalensis, N. cyriacigeorgica, and N. beijingensis were the first reported in Japan. The most common factor that predisposed individuals to nocardial infection in Japan was therapy by immunosuppressive agents (22.4%), including SLE therapy (3.6%), followed by cancer (6.6%), diabetes (3.6%) and AIDS (2.0%). Nocardial infections occurred more commonly in the elderly, with most of the patients between the ages of 61 and 80 years of age. No significant difference regarding infectivity levels between the sexes was observed.

Protective effect of hydroxychloroquine in systemic lupus erythematosus. Prospective long-term study of an Israeli cohort.

Systemic lupus erythematosus-associated irreversible organ/system damage was previously associated with various clinical and demographic features. We analysed the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SLICC/ACR DI) in a cohort of 151 Israeli patients followed for a mean (+/- s.d.) period of 45.7 +/- 37.4 months. Mean score of SLICC/ACR DI at the first and last encounters were 0.17 +/- 64 and 1.64 +/- 2.1, respectively (P < 0.0001). Multiple logistic regression analyses disclosed a statistically significant positive correlation with corticosteroid and cyclophosphamide therapy. Hydroxychloroquine therapy was significantly associated with lower SLICC/ACR DI. Although the size of our study group did not allow us to find specific organs/systems which were associated with the protective effect of hydroxychloroquine, we suggest this is due to the antiatherogenic effects attributed to antimalarial therapy in SLE.

Polyvalent intravenous immunoglobulins in systemic lupus

To evaluate intravenous immunoglobulins (IVIG) treatment, which is immunomodulatory but not immunosuppressive, in SLE. IVIG indications in SLE could be categorized as already validated as for chronic polyradiculoneuropathy or thrombocytopenia; failure of classical treatment in threatening active disease; undetermined manifestation as reactive hemophagocytic syndrome which could be both disease-specific or iatrogenic, infection-related. To date, no published study has firmly established the efficacy of IVIG in SLE. IVIG therapy in SLE should be evaluated in prospective trials.

9 Opportunities for future biological therapy in SLE

The development of monoclonal antibodies and the emergence of recombinant DNA technology has made it possible to identify and selectively inhibit distinct cell subsets, surface molecules and secreted products that contribute to normal and pathological immune responses. These advances have helped to clarify the mechanisms that promote autoimmune diseases. As a result, it is now possible to contemplate rational strategies for the treatment of these diseases. Some of these strategies are designed to influence the cell surface interactions that determine whether potentially autoreactive T cells become activated or tolerant following antigen stimulation. Other strategies are designed to augment or inhibit distinct cytokines that regulate autoimmunity. All of these strategies have shown promise in animal models for systemic lupus erythematosus, and they may soon be translated into effective new therapies for people.

Intravenous immune globulin for inducing remissions in systemic lupus erythematosus.

The evidence supporting the use of long-term IVIG therapy to induce remissions in SLE is unimpressive. The single extant clinical study used an open-label design with 12 patients, no placebo control, and questionable statistical methodology. The lack of definitive clinical studies, however, is tempered by case reports documenting significant improvement and apparent lack of toxicity in patients with SLE treated with IVIG. Standard first-line therapy of active SLE should consist of nonsteroidal antiinflammatory drugs, followed by low-dose corticosteroids and antimalarial compounds. Second-line therapeutic alternatives are the cytotoxic agents methotrexate, azathioprine, or cyclophosphamide. IVIG's primary advantage over these conventional therapies is that, unlike immunosuppressant and cytotoxic drugs, IVIG has not been reported to increase the risk of opportunistic infections. Additionally, IVIG obviates the ovarian/testicular toxicity, hemorrhagic cystitis, and carcinogenicity caused by cyclophosphamide. However, IVIG therapy is extremely expensive. (Approximate average wholesale price is $1800 per dose for a 70-kg patient). Thus, IVIG treatment consisting of 0.4 g/kg/d for 5 consecutive days on a monthly basis should be reserved for patients with active SLE resistant to the first- and second-line therapies. While IVIG-induced acute renal failure is considered rare, the serious nature of this adverse event warrants close monitoring of blood urea nitrogen and serum creatinine during and several days after treatment. Preexisting renal dysfunction should be considered a relative contradiction. Further double-blind multicenter trials are warranted to determine the long-term safety, efficacy, and cost/benefit ratio of using IVIG in SLE.

Systemic lupus erythematosus with obstructive uropathy: Case report and review

We report a case of patient with documented SLE who displayed dysuria, gastrointestinal (GI) symptoms and renal insufficiency associated with the unusual occurrence of bilateral hydroureteronephrosis due to urterovesical junction stricture (obstructive uropathy). Pathologic investigations disclosed chronic interstitial cystitis (IC) with evidence of focal immune complex deposition in the blood vessel walls of the bladder. The GI symptoms and dysuria regressed with initial therapy for SLE with steroids. However, the persistent obstructive uropathy (OU) and renal insufficiency required bilateral nephrostomy followed by steroids plus intravenous pulse injection of cyclophosphamide. The obstructive uropathy was relieved even after removing the nephrostomy tube and renal function remained stable. Including this case, nineteen SLE patients associated with clinical and radiographic findings of OU were found in the world literature and reviewed to find any consistent pattern of clinical features. Most of the patients with OU in SLE were female (mean age, 31.7 yr) and orientals (63%), and had interstitial cystitis (89%) as a common underlying cause with concomitant involvement of the GI tract (89%) and WHO class IV or V advanced glomerulonephritis (67%). Despite the remarkable response (68%) to steroids in majority of OU patients associated with SLE, certain patients still required surgical correction (32%) and some even died (32%). OU, potentially reversible, was not an exception in patients with SLE, which might be overshadowed by other major organ involvement of SLE.

T cell depletion a starting point for new SLE therapies

T cell depletion a starting point for new SLE therapies

Prolactin influences autoimmune disease activity in the female B/W mouse.

Prolactin, an anterior pituitary hormone, stimulates humoral and cell-mediated immunity. This study investigated effects of manipulating prolactin levels in the autoimmune B/W mouse model of SLE. A group of B/W females was treated with daily injections of the prolactin-suppressing drug, bromocriptine. These mice had delayed elevation of anti-DNA antibodies and serum IgG; longevity was increased compared to control mice. Functioning syngeneic pituitary glands, implanted under the renal capsule, produced prolonged hyperprolactinemia in a separate group of female B/W mice. Hyperprolactinemic animals were characterized by premature albuminuria, elevated circulating gp70IC and IgG, and accelerated mortality. Analyses of thymic and splenic lymphocytes revealed no differences in lymphocyte subpopulations in mice with altered prolactin levels. This is the first report to substantiate an immunomodulatory role for prolactin in B/W mice. Further evaluation of this model may identify specific means of intervening clinically with immunosuppressive hormone-modulating therapy in SLE.

Iron deficiency in children with cyanotic congenital heart disease

scintigraphy demonstrated segmental perfusion abnormalities in 38.5% of the patients. 7 Unfortunately, nuclear studies cannot be used to define the precise cardiac abnormality, because they cannot differentiate large vessel from small vessel disease. To our knowledge, only one other patient with SLE has been reported to have had a myocardial infarction at such a young age. 8 That patient had a 2-year history of SLE and steroid therapy, as well as autopsy findings that revealed severe coronary atherosclerosis and hypertriglyceridemia. In our patient, specific evidence of coronary vasculitis, such as the presence of coronary aneurysms, was not established. However, atherosclerotic heart disease is an unlikely pathogenic mechanism, because blood pressure and serum cholesterol and serum triglyceride values were within normal limits; moreover, active disease and steroid use were limited to 1 month. In the context of a clinical presentation that included evidence of cutaneous and cerebral vasculitis, and in the absence of risk factors for atherosclerotic heart disease, coronary arteritis is the most likely mechanism of myocardial infarction in this patient. Regardless of the mechanism, we conclude that even with short duration of disease, young patients with SLE are subject to cardiac complications, including myocardial infarction. We thank Veronica Schmer, MD, and the pediatric house staff, who provided excellent care to this patient.

A case report of mitral insufficiency complicating infective endocarditis during the therapy for SLE

A case report of mitral insufficiency complicating infective endocarditis during the therapy for SLE

Intravenous Cyclophosphamide Therapy of Severe SLE

Intravenous cyclophosphamide therapy of severe systemic lupus is associated with reduction in the numbers of circulating T and B lymphocytes, suppression of T11 (CD2) receptor-mediated responses, and suppression of autoantibody production. In clinical trials, intravenous cyclophosphamide plus moderate-to low-dose daily oral prednisone appears to reduce the rate of progression of irreversible renal injury in patients who have active nephritis and definite but limited chronic changes in biopsy specimens. It may also be effective in other forms of severe lupus, although controlled trials are lacking. It may be the treatment of choice in severe lupus characterized by ongoing antibody or immune-complex mediated tissue injury.

In vitro manipulation of human anti-DNA antibody production by anti-idiotypic antibodies conjugated with neocarzinostatin.

Anti-DNA Id, 0-81, consist of 5 to 51% of Id in human anti-ssDNA antibodies; NE-1-Id shares 2 to 20% of those in anti-dsDNA antibodies. Thus, both 0-81-Id and NE-1-Id are of the cross-reactive Id that are commonly present among anti-DNA antibodies. In order to manipulate the production of anti-DNA antibodies by human PBL, we used mouse antiidiotypic mAb or those conjugated with a cytotoxic agent, neocarzinostatin. Treatment with the conjugates caused profound suppression of anti-ssDNA and anti-dsDNA antibody synthesis related to 0-81- and NE-1-Id. This was attributed to the specific killing of the clones bearing anti-DNA Id among the lymphocytes, evidenced by the indirect rosette formation tests. The Id-mediated suppression was not solely due to selective elimination of Id-positive B cells, because 50 to 92% of anti-DNA antibodies were suppressed by treatment with the conjugates. This was supported by flow cytometry analysis that showed a decrease of anti-Id-reactive cells when T cells were treated with the conjugates. This method, then, will permit an analysis of the question as to whether T cells reactive to anti-idiotypic antibodies might participate in the regulatory mechanism for anti-DNA production and, in addition, may lead to a new therapy for SLE.

Primary malignant lymphoma of the brain--clinical and pathological investigations.

Clinical and pathological studies were made on 5 patients (1 male and 4 females; average age, 58.2 years) with primary malignant lymphoma of the brain. One case had received long-term immunosuppressive therapy for SLE. The most common initial signs and symptoms were non-specific and non-localized. They included headache, disorientation and consciousness disturbance. During the course, the signs and symptoms consisted of consciousness disturbance (5 cases), hemiparesis (4 cases), headache (3 cases), dementia (2 cases), seizures (2 cases), and diplopia (1 case). The tumors on CT scans appeared as slight hyperdense areas in 3 cases, and as isodense areas in 1 case with enhancement following contrast media infusion, which was compatible with previously reported results. However, the other case showed diffuse hypodense areas without enhancement which has rarely been reported. Multiple lesions were found in 4 cases. Three cases underwent cerebral angiography which demonstrated avascular masses. Pathologically, the tumors were located in the cerebral hemispheres in 5 cases, the basal ganglia and thalamus in 3 cases, the brain stem in 2 cases, and the cerebellum in 2 cases. Three cases were classified as of the diffuse, large cell type, 1 case as small cleaved cell and 1 case as immunoblastic. Thus, the clinical diagnosis of primary malignant lymphoma of the brain still remains difficult because the symptoms and CT findings are so varied.

Present situation of SLE therapy. Central nervous disorder of SLE.

Present situation of SLE therapy. Central nervous disorder of SLE.

Cardiovascular function at rest and on exercise in patients with cryptogenic fibrosing alveolitis.

Cardiovascular complications are common in fibrosing alveolitis, but there have been few physiological studies of the pulmonary circulation in this condition, and those that have been carried out have usually depended on right heart catheterisation. This paper reports non-invasive measurements of effective pulmonary blood flow, oxygen uptake, pulmonary arteriovenous oxygen content differences, and estimates of mixed venous oxygen saturation in 20 patients with histologically proved cryptogenic fibrosing alveolitis at rest and while exercising on a motorized treadmill. Results were compared with those of 20 age and sex matched normal subjects, at rest and at an arbitrarily chosen oxygen uptake of 0.75 l/min. The latter results were obtained by linear interpolation. Effective pulmonary blood flow was normal at rest, but oxygen dispatch to the tissues (blood flow x blood oxygen content) was significantly reduced at rest (mean reduction 190 (SD 68) ml/l/min; p less than 0.01) and at an oxygen uptake of 0.75 l/min (mean reduction 128 (50) ml/l/min; p less than 0.02), reflecting the presence of systemic arterial hypoxaemia. Pulmonary arteriovenous oxygen content differences were similar in patients and normal subjects, but mixed venous saturation was lower in the patients at rest (mean % reduction 6.8 (2.6); p less than 0.02) and at an oxygen uptake of 0.75 l/min (mean % reduction 9.6 (2.9); p less than 0.002). It is concluded that the supply of oxygen potentially available to the tissues is reduced at rest and during exercise in patients with fibrosing alveolitis and hence, by analogy with normal people exercising under hypoxic conditions, that pulmonary blood flow is inappropriately low in this condition. The low mixed venous oxygen saturation may contribute to the development of pulmonary hypertension in some patients. The rebreathing technique used in this study may be of use in monitoring treatment; it could be applied many times to the same patient, and might be a suitable way of following the response to pulmonary vasodilators.

Serum interferon in systemic lupus erythematosus

Serum interferon levels were estimated in 67 samples obtained from 47 patients with SLE. Levels were increased in 70% of the samples and 72% of the patients. In the patients with active disease 81% had increased interferon levels, while in the group with clinically quiescent disease 10% had increased levels. In 20 patients retested 3 1/2 months after treatment the changes in interferon levels tended to parallel the changes in clinical disease activity in 80% of cases. Patients with active skin lesions, arthritis, and renal or haematopoietic involvement tended especially to have increased interferon levels. Interferon levels were directly related to ANA titre and inversely related to serum C3 levels, but not related to serum levels of circulating immune complexes or immunoglobulin. The interferon was shown to be of type alpha. The interferon level can be regarded as one of several parameters reflecting disease activity and may also be related to the prognosis. As it is possible that interferon may be a direct mediator of the pathophysiology of auto-immune disease, we do not recommend the use of interferon or its inducers in the therapy of SLE.

Asbestos content of lung tissue in asbestos associated diseases: a study of 110 cases.

Diseases associated with asbestos exposure include asbestosis, malignant mesothelioma, carcinoma of the lung, and parietal pleural plaques. In this study the asbestos content of lung tissue was examined in groups of cases representing each of these diseases and in several cases with non-occupational idiopathic pulmonary fibrosis. Asbestos bodies (AB), which are the hallmark of asbestos exposure, were present in the lungs of virtually everyone in the general population and present at increased levels in individuals with asbestos associated diseases. The highest numbers of AB occurred in individuals with asbestosis, all of whom had levels greater than or equal to 2000 ABs/g wet lung tissue. Every case with a content of 100,000 ABs/g or higher had asbestosis. Intermediate levels occurred in individuals with malignant mesothelioma and the lowest levels in patients with parietal pleural plaques. There was no overlap between the asbestos content of lung tissue from patients with asbestosis and those with idiopathic pulmonary fibrosis. Lung cancer was present in half the patients with asbestosis, and the distribution of histological patterns did not differ from that in patients with lung cancer without asbestosis. The asbestos body content in patients with lung cancer was highly variable. Control cases had values within our previously established normal range (0-20 ABs/g). There was a significant correlation (p less than 0.001) between AB counted by light microscope and AB and uncoated fibres counted by scanning electron microscopy. The previous observation that the vast majority of asbestos bodies isolated from human tissues have an amphibole core was confirmed.