Lupus nephritis (LN) is one of the most serious complications of systemic lupus erythematosus (SLE) and is a major predictor of poor prognosis.1 Mortality is greater in patients with LN than in those without renal damage.2 Among those patients with LN, up to 70% develop renal insufficiency in some series.1 2 In most cases, LN appears early during the course of SLE.1^–3 However, in some instances it may be a late complication of the disease. Therefore, it is important to assess which patients with SLE are more prone to develop delayed LN (DLN) and might benefit from an accurate diagnosis and earlier treatment. The initial goal of this study was to provide further insight into the extent to which the clinical and autoimmune response profiles of DLN differ from those of early-onset LN (ELN). We next sought to identify the clinical and histopathological characteristics of renal involvement in DLN.

PATIENTS AND METHODS

Patients

This was a cross-sectional study of subjects selected from a cohort of patients with SLE followed up at the Clinical Immunology and Rheumatology Unit at the Clínica Universitaria Bolivariana-Corporación para Investigaciones Biológicas (CIB) in Medellín, Colombia; the Department of Autoimmune Diseases at the Hospital Clinic in Barcelona, Catalonia, Spain and the Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA between 2003 and 2007. All patients fulfilled four or more of the American College of Rheumatology criteria for classification of SLE.4 Patients who developed renal disease ⩾5 years after the first manifestation(s) of the disease were classified as DLN. The patients in the control groups were divided into two sets: the ELN group included patients who developed renal involvement within 5 years or less after SLE onset; the no LN (NLN) group included patients with longstanding SLE (⩾10 years) who did not meet criteria for renal involvement. The institutional review boards at each centre approved the study design.

Clinical variables

Information on patient demographics and cumulative clinical and laboratory manifestations over the course of the disease were obtained by chart review, and were collected by a standard procedure. The clinical and laboratory variables associated with SLE, including each feature of the revised American College of Rheumatology criteria,4 were evaluated, and defined as follows: (a) arthritis: non-erosive arthritis affecting two or more peripheral joints and characterised by tenderness, swelling or effusion. Jaccoud’s arthropathy was defined as a progressive deforming, non-erosive arthropathy of the hands and feet5; (b) malar rash; (c) photosensitivity; (d) alopecia; (e) discoid lupus; (f) Raynaud’s phenomenon; (g) renal involvement included the presence of active urinary sediment, proteinuria >500 mg/24 h, creatinine clearance <60 ml/min per/1.73 m² or a renal biopsy result demonstrating World Health Organization (WHO) class II–V histopathology.2 3 6 Nephrotic syndrome was defined as >3.5 g/day proteinuria, hypoalbuminaemia (<28 g/l), hyperlipidaemia and oedema. A value for nephrotic syndrome of >3 g/day was considered in the Michigan cohort. Nephritic syndrome was defined by the presence of proteinuria >500 mg/24 h, haematuria with or without hypertension. LN was defined as present or absent based on the abnormalities of the previous tests. (h) Neurological involvement, as shown by seizures without any other definable cause, or psychosis lacking any other definable cause, or other conditions such as peripheral neuropathy, stroke, transverse myelitis, chorea, or other central nervous system lesions directly attributable to SLE in the absence of other causes; (i) pleuritis: pleural rub and/or effusion and/or typical pleuritic pain; (j) pericarditis: documented by electrocardiogram, rub, or evidence of pericardial effusion; (k) parenchymal lung involvement attributed directly to SLE (interstitial fibrosis and pulmonary vasculitis); (l) autoimmune haemolytic anaemia, with a haematocrit <35%, a reticulocyte count >4%, and a positive Coombs’ test; (m) leucopenia, white cells <4×10⁹/l; (n) thrombocytopenia, platelets <100×10⁹/l; (o) arterial or venous thrombosis diagnosed on clinical grounds and confirmed by appropriate tests.

The presence of other autoimmune diseases was also evaluated, including Sjögren’s syndrome (SS),7 antiphospholipid syndrome (APS)8 and hypothyroidism (thyroid-stimulating hormone levels above 5 mU/l or the use of thyroid supplement, taken as a surrogate marker of hypothyroidism).

Autoantibodies

Antinuclear antibodies were determined by indirect immunofluorescence assay using HEp-2 cells as substrate, and anti-dsDNA antibodies were determined by immunofluorescence assay with Crithidia luciliae as substrate, by enzyme-linked immunosorbent assay (ELISA) or by the Farr radioimmunoassay. Precipitating antibodies to extractable nuclear antigens, including Sm, U1-RNP, Ro/SSA, La/SSB, as well as anticardiolipin antibodies were detected by ELISA using commercial kits (QUANTA-Lite, INOVA, San Diego, California, USA or REAADS semiquantitative, Corgenix, Broomfield, Colorado, USA). The presence of lupus anticoagulant was either suspected because of a prolonged partial thromboplastin time, and confirmed by either dilute or modified Russell viper venom screen, a hexagonal (II) phase phospholipid assay (Staclot-LA test) or kaolin clotting time, or screened by using the dRVVT method (University of Michigan).

Statistical analysis

Data were managed and stored using the SPSS program (version 15 for Windows, Chicago, Illinois, USA). Comparisons between means were made by the Student t test or analysis of variance, and those between percentages by the χ² or Fisher exact tests, as appropriate. Odds ratios (ORs) were calculated with 95% confidence intervals (CIs). A p value <0.05 was considered significant.

RESULTS

Three hundred and ninety-nine patients included in the study, of whom 48 had DLN, 187 had ELN and 164 had NLN (table 1). No significant differences in the proportions of men and women were noted between groups. There were no significant differences in the musculoskeletal manifestations; with the exception of Jaccoud’s arthropathy, which was a protective factor against nephritis (OR = 0.16, 95% CI 0.04 to 0.58, p = 0.002). The mucocutaneous manifestations, such as malar rash, photosensitivity, oral/nasal ulcers, subacute cutaneous lupus, cutaneous vasculitis and discoid rash, as well as the prevalence of pleurisy/pericarditis and cytopenias were not statistically different for any of the three groups. The presence of SS was significantly higher in the group of patients with DLN than in the other two groups, and the presence of interstitial lung involvement (OR = 2.3, 95% CI 1.11 to 4.71, p = 0.03) and APS (OR = 2.6, 95% CI 1.22 to 5.73, p = 0.02) was higher in patients with DLN than in the ELN group. A family history of SLE was not a differentiating factor between the three groups.

As expected, the frequency of anti-dsDNA, anti-Sm and anti-RNP antibodies was higher in both groups of nephritis than in the NLN group, as was the frequency of low complement levels (table 1).

Table 2 compares the renal characteristics of patients with DLN and ELN. The prevalence of nephritic or nephrotic syndrome was similar in both the groups. The most common WHO histological patterns were class II–III with no differences between the groups.

DISCUSSION

In this study, we described and analysed the characteristics of DLN for the first time, and found that it is positively associated with SS, interstitial lung involvement and APS.

Coexistent SS and SLE is associated with the possibility that 5 years after the onset of SLE, renal disease will appear regardless of the age of the patient. The prevalence of SS among patients with SLE varies considerably in the published studies from 8% to 30%.9 10 Classically, patients with SLE and SS constitute a subgroup of patients characterised by milder lupus and distinctive clinical, serological, pathological and immunogenetic features.9 11 This subgroup characteristically has a late-onset presentation of SLE.9 It is noteworthy, in our study, that the mean (SD) age at onset of SLE in those patients who developed DLN was 26.5 (10.0) years. Therefore, DLN must be differentiated from the nephritis in late-onset SLE (ie, those patients who developed SLE in their sixth decade of life or later).12 It is also well known that patients with an autoimmune disease such as SLE have an increased risk of developing a second autoimmune disease, and the probability of the second autoimmune disease appearing is inversely correlated with age at onset of the first autoimmune disease.13 In addition, when SS is associated with other autoimmune diseases, it may appear at younger ages, and even before these diseases, such as in the case of SLE.9 Therefore, the presence of SS in patients with DLN is not unexpected in these patients owing to the considerations mentioned above and to the persistent immune activation that might favour the appearance of a second autoimmune condition.13

We observed a higher than expected prevalence of parenchymal lung involvement among patients with DLN (31.3%). This complication is reported to be in the range of 3–8%.14 We systematically check for this complication in our research, thus the rates previously reported might be underestimated since patients with longstanding SLE (ie, the NLN group) disclosed a similar prevalence of this complication. In our series not one patient had pulmonary-renal syndrome. It has been suggested that antiphospholipid antibodies predict LN.15 However, other studies have observed a lack of association between these antibodies and histological activity, chronicity or proteinuria.16 In our study, APS was associated with DLN. Finally, Jaccoud’s arthropathy was inversely associated with the development of nephritis as observed in the past.5

In conclusion, DLN is not uncommon in patients with SLE. Although cross-sectional and hypothesis-generating, this study highlights the importance of continuing follow-up and surveillance of patients with apparently mild SLE and, in particular, those who have an early-onset of disease and other autoimmune disease such as SS, APS or interstitial lung disease.