Lupus

Lupus nephritis remains the most common severe manifestation of SLE with increased risk of death and end-stage renal disease. Although, recent research has focused on the choice of immunosuppressive in its treatment, other factors, including the quality and delivery of healthcare, the management of glucocorticoids and co-morbidity are probably of more importance. There has been significant progress in induction regimes with the successful use of mycophenolate mofetil, low dose intravenous cyclophosphamide and development of sequential regimens whereby cyclophosphamide is followed by an alternative immunosuppressive. However, the attention on the day-to-day management of lupus nephritis in the clinic has merited less attention. In this article, we aim to address more widely the major issues which are encountered regularly in the long-term management of these patients. The overall goals are the reduction of mortality and preservation of renal function.

The role of tumour necrosis factor (TNF-α) signalling adapters in lupus nephritis (LN) is poorly understood. This study investigated renal expression of TNF-α and TNF signalling adapter proteins, including TNF receptor-associated death domain protein (TRADD), receptor-interacting protein (RIP) and TNF receptor-associated factor-2 (TRAF-2) in patients with LN. The renal expression of proliferating cell nuclear antigen (PCNA) and CD68 was also measured. The study showed that glomerular and tubular expression of TNF-α, TRADD, RIP and TRAF-2 was significantly up-regulated in class III and IV LN in which the intense staining was observed on the crescents, proximal and distal tubules and interstitial mononuclear cells. The number of PCNA-positive cells and CD68-positive cells (macrophages) was increased obviously in class III and IV LN. There was a correlation between the expression levels of TNF-α, TRADD, RIP, TRAF-2 and the number of PCNA-positive or CD68-positive cells and active index of renal pathology. These findings suggest that TNF-α and TNF-α adapters in patients with LN play a role in immunopathogenic injury via transmitting abnormal cell proliferating and proinflammatory signals. The findings have provided further insights into the role of TNF-α and its adapter proteins in the pathogenesis of LN and have important therapeutic implications.

To determine the frequency and clinical correlates of asymptomatic pericardial effusion (PE) in patients with systemic lupus erythematosus (SLE), echocardiography and electrocardiography were performed in 50 consecutive patients with SLE. Among 50 patients with SLE, 12 patients (24%) had PE and 17 patients (34%) had hypoalbuminaemia. Patients with PE had a significantly lower serum albumin (P < 0.001), higher incidence of proteinuria (P = 0.003), higher C-reactive protein (P = 0.036) and pulmonary artery systolic pressure (P = 0.011) and tended to have a higher incidence of PR-segment depression (P = 0.082) compared with those without PE. When four variables (PR-segment depression, C-reactive protein, serum albumin and pulmonary artery systolic pressure) were used in the multivariate analysis, serum albumin (P = 0.005, odds ratio = 0.016) and pulmonary artery systolic pressure (P = 0.010, odds ratio = 1.106) emerged as significant variables related to the occurrence of asymptomatic PE. Thus, an increase in hydrostatic pressure of the right heart cavities and a decrease in colloid osmotic pressure were important factors associated with the presence of asymptomatic PE in patients with SLE.

Patients with antiphospholipid syndrome (APS) have an increased risk for the development of thrombotic complications. Recent studies indicate that osteoprotegerin (OPG) acts as an important molecule in the development of vascular diseases. The aim of the present study was to examine the association between serum OPG levels and APS manifestations in patients with SLE. Seventy-nine patients with SLE and ninety-two healthy controls, matched for age and sex, were included in this study. Serum levels of OPG, monocyte chemoattractant protein(MCP)-1 and soluble E-selectin were determined by ELISA. At the time of serum sampling, various clinical and laboratory parameters were assessed. We found that serum levels of OPG were significantly higher in patients with SLE than in healthy controls (1236 ± 82 vs 967 ± 37 pg/mL, P = 0.003). Particularly, serum OPG levels were significantly higher in SLE patients with APS than those without (1615 ± 191 vs 1171 ± 91 pg/mL, P = 0.006). Serum OPG levels correlated with titres of IgG anti-cardiolipin antibody (P = 0.026) and anti-β₂-glycoprotein I antibody (P < 0.001). Moreover, serum OPG also correlated with serum levels of sE-selectin (P = 0.002), which is an endothelial cell activation marker, and MCP-1 (P = 0.003), a well known chemokine implicated in thrombogenesis. Collectively, serum OPG levels were increased in SLE patients with APS and correlated with titres of antiphospholipid antibodies, suggesting that OPG might be linked to the development of APS.

Mycophenolate mofetil (MMF) has proved to be an efficacious and safe therapy in adult lupus nephritis. Recently, this drug has been suggested as a possible new alternative treatment also for juvenile-onset SLE (juvenile-SLE). A multicenter study has been performed to evaluate the efficacy and safety of MMF in controlling the disease activity in children and adolescents with juvenile-SLE. Our results show that MMF was effective in reducing the disease activity or as a steroid-sparing agent in 14 of 26 patients (54%), stabilised the disease in 8 (31%) and was ineffective in 4 (15%). In particular, in patients without renal involvement, a good response was registered in 9 of 13 patients (69%). Among those patients with renal involvement, MMF was effective in 5 of 13 patients (38%), partially effective in 4 (31%) and ineffective in 4 (31%). No severe side effects have been observed; only two patients stopped the drug because of severe diarrhoea and abdominal pain. With the limits of a retrospective study, MMF seems to be effective and safe for the treatment of juvenile-SLE, especially in patients with no renal involvement.

The aetiology of systemic lupus erythematosus (SLE) is thought to involve both genetic and environmental factors. In other complex diseases, analysis of large multi-case families has resulted in insights into biological mechanisms. We have sought to characterise the members of an extended Indigenous family, five of whom have been diagnosed with SLE. Pedigree members were evaluated using the Lupus Screening Questionnaire, clinical interviews and medical records. Participants contributed blood and urine samples for laboratory analysis. A Mendelian pattern of inheritance was not observed. The five affected members (all female) shared two American College of Rheumatology criteria (positive ANA and arthritis) but showed a wide variety of other SLE manifestations. Disease onset, severity and progression were discordant. Including the five individuals with SLE, 15 blood relatives and two non-consanguineous spouses had autoimmune manifestations. Autoimmune haemolytic anaemia (one case), idiopathic thrombocytopenic purpura (ITP) (one case) and hypothyroidism (two cases) were observed in non-SLE affected individuals. Anti-nuclear antibodies were present in 12 blood relatives and one non-consanguineous spouse. Infections (especially of the skin) were observed to be common in the kindred. The lack of clear Mendelian inheritance or phenotypic concordance makes a rare monogenic explanation for SLE unlikely in this family. The finding of familial autoimmunity associated with SLE further supports the hypothesis that a common genetic pathway can precipitate autoimmunity, with further genes and possible environmental factors interacting to produce the eventual phenotype. Future genetic linkage studies may reveal a rare ‘autoimmune gene’ variant in this kindred.

The purpose of this study is to determine whether two distinct histopathological–immunopathological lesions, which have been reported in severe lupus nephritis, diffuse global glomerulonephritis (GN) (WHO IV) and a segmental and necrotising GN (WHO III) can be reported to coexist in a single patient. We examine the evidence of coexistence of these disparate lesions and the prognostic significance in a group of patients with severe lupus nephritis who have been subjected to a common therapeutic regimen by protocol. The simple, reproducible parameter indicating the presence of glomerular capillary necrosis was the presence of crescents. We, therefore, reviewed 39 renal biopsies with diffuse global lupus GN (WHO IV) (Churg, J, Sobin, LH. Lupus nephritis. Renal disease, classification and atlas of glomerular diseases. New York: Igaku-Shoin; 1982. p. 127–149). and used crescents as a surrogate for glomerular necrosis. Peripheral capillary immune deposits were less prominent in WHO IV with crescents compared with those without and resembled the reduced immune deposits seen in severe segmental GN (WHO III ≥ 50%). Patients with WHO IV with crescents had decreased survival without end-stage renal disease (P = 0.02), fewer remissions (P = 0.04) and more adverse outcomes (12/22 vs 3/17) (P = 0.02) than those without crescents, and this was similar to patients with WHO III ≥50%. We conclude that, on the basis of immunological and morphological features, WHO IV with crescents appears to be the result of two distinct pathogenetic mechanisms. We propose that diffuse global lupus GN, associated with crescents, is best described as WHO class IV + WHO class III.

Despite their unproven efficacy and safety concerns, complementary and alternative therapies (CAT) are used by a high proportion of patients with systemic lupus erythematosus (SLE). A prospective survey of past and present CAT use was done on 192 patients (36.5 ± 12.7 years; 106 ± 85 months of disease duration; 94% women) with an SLE diagnosis according to ACR criteria. Quality of life [Short Form 36 (SF-36)] and cumulated damage (SLICC/ACR) were compared between CAT users and non-users. In all, 103 (53.6%; 95% CI: 46.8–60.9) patients were CAT users (median: two remedies/patient): two (1%) in the alternative mode (CAT instead of allopathic treatment); 101 (52.6%) in the complementary mode (CAT in addition to allopathic treatment). A univariate analysis showed CAT users to have higher cumulated damage (P = 0.01) levels, as well as lower physical function (P = 0.05), social function (P = 0.05) and bodily pain (P = 0.02) domain scores in the SF-36 survey. After adjustment for disease duration with a linear model, only differences in bodily pain (P = 0.04) and cumulated damage (P = 0.05) remained statistically significant. CAT use is apparently associated with lower health status in patients with SLE from Yucatan, Mexico. Because the study was cross-sectional, more research is needed to define the directionality of this association.

Autoimmune diseases have several etiologies. Acute Chlamydia pneumoniae (C. pneumoniae) infection may be involved in the pathogenesis of several autoimmune diseases. In this study, 82 patients with several autoimmune diseases and 70 controls were enrolled, and acute C. pneumoniae infection has been evaluated by monitoring the levels of IgM antibody. Chlamydia pneumoniae IgM positive results were observed in 29% (P < 0.05) of the patients with several autoimmune diseases and in 10% of the controls. Chlamydia pneumoniae IgM positive cases were more frequent among the patients with rheumatoid arthritis (RA; 30%, P < 0.05), systemic lupus erythematosus (SLE; 28.0%, P < 0.05), dermatomyositis/polymyositis (23%, NS), myeloperoxidase-antineutrophil cytoplasmic autoantibody (MPO-ANCA)-associated vasculitis (33%, NS), adult onset of Still’s disease (29%, NS) and giant cell arteritis/Takayasu arteritis (50%, NS) than among the controls. This positive frequency was statistically significant in RA and SLE. These results suggest that acute C. pneumoniae infection is probably involved in the pathogenesis of autoimmune diseases.

The use of TNF alpha (TNFα) inhibitors has made a strong impact on the management of rheumatoid and psoriatic arthritis, ankylosing spondylitis and Crohn disease. Side effects of these agents include the development of autoantibodies and a lupus-like syndrome (drug-related lupus, DRL). Here, a case of a patient who developed DRL while receiving infliximab therapy which resolved spontaneously upon discontinuation of the agent and did not recur with subsequent institution of adalimumab is described. A discussion on the possible pathogenic mechanisms involved in the development of drug-related autoimmunity and differences between the agents is also included.

We describe a case of neonatal lupus erythematosus in a term female infant who presented at birth with mild, scattered facial erythema and ice-pick lesions at lateral and superior borders of her face. These lesions then progressed to an erythematous raccoon-like mask following exposure to the sun. Initial blood work performed at four-months-old showed speckled anti-nuclear antibody titers of 1:320, with negative anti-Ro/SSA and La/SSB negative and a positive anti-RNP. The infant had no evidence of cardiac, haematological or hepatobilary involvement initially or throughout her course of evaluation. The patient’s mother was asymptomatic throughout the investigation of the infant but through blood work and evolvement of symptoms, she was diagnosed with mixed connective tissue disease.

It is often difficult to make a diagnosis of pleuritis associated with rheumatic diseases because of lack of specific diagnostic tools. We report a patient with lupus pleuritis from which tuberculous pleuritis was distinguished by Mycobacterium tuberculosis-specific enzyme-linked immunospot assay of pleural exudate mononuclear cells. After the diagnosis of lupus pleuritis, the patient was successfully treated with prednisolone.

The aim of this study was to assess the bone mineral density (BMD) of premenopausal patients with systemic lupus erythematosus (SLE) on corticosteroids (CS) and to determine the influence of CS and other risk factors on BMD. A total of 98 premenopausal patients with SLE were recruited from outpatient clinics in two teaching hospitals. Risk factors for osteoporosis were determined, and BMD was measured using dual-energy x-ray absorptiometry. The mean age of the patients was 30.05 ± 7.54 years. The mean dose of prednisolone at time of BMD measurement was 18.38 ± 10.85 mg daily. Median duration of CS use was 2.5 years (range 0–20). Median cumulative dose of CS was 9.04 g (range 0.28–890.0). Six patients (6.1%) had osteoporosis, 41 (41.9%) had osteopenia and 51 (52.0%) had normal BMD. Lumbar spine T score correlated with cumulative CS dose (P = 0.019). Duration of CS intake correlated with femoral neck T score (P = 0.04) and trochanter T score (P = 0.008). There was no correlation between BMD and race, SLE Disease Activity Index score, smoking and self-reported calcium intake or exercise. Only 52% of these patients had normal BMD. The duration and cumulative dose of CS intake was significantly correlated to BMD, but not the other commonly assessed risk factors. These findings suggest that premenopausal patients with SLE on CS should have their BMD measured at regular intervals to fully assess their osteoporosis risk.