Rituximab treatment in lupus nephritis--where do we stand?

Renal involvement in systemic lupus erythematosus (SLE) is a severe disease manifestation in which novel therapeutic strategies are needed, especially in non-responding patients or patients who relapse after conventional treatment. Rituximab has been used as off-label treatment for lupus nephritis (LN) during the last decade, and to date reports on the clinical effects on more than 400 patients, including the randomized controlled LUNAR study population, have been published. Despite promising results obtained from observational studies and registries, with complete or partial renal response after 6-12 months in 67-77% of patients, the LUNAR trial failed to attain the primary endpoint and rituximab is today unlikely to be approved as treatment for LN. Rituximab has mainly been used as induction therapy in combination with standard of care but the optimal treatment protocol is still to be determined. From observational studies, rituximab has been shown to be efficient in both proliferative and membranous LN, and histopathological studies have demonstrated improvement in renal activity. Adverse events mainly include infusion reactions and infections. Although not approved for the treatment of LN, the currently available data support that rituximab may be used in severe, refractory cases of LN.

Autoantibodies associated with RNA are more enriched than anti-dsDNA antibodies in circulating immune complexes in SLE.

To what extent different autoantibodies accumulate in systemic lupus erythematosus (SLE) immune complexes (ICs), and whether such accumulation is associated with disease activity has been investigated. ICs were isolated from SLE sera by both polyethylene glycol (PEG) precipitation and C1q-binding. Autoantibody specificities were determined using a lineblot assay quantified by densitometry. To compare the relative levels of autoantibodies, levels were normalized to the total levels of IgG measured by ELISA in sera and parallel ICs. Samples were investigated both in a cross-sectional design as well as in a paired design with samples obtained during both active and inactive SLE. All investigated autoantibody specificities except anti-dsDNA were enriched in circulating ICs as compared with parallel sera. The group of antibodies against RNA-associated antigens (anti-RNP/Sm, anti-Sm, anti-SSA/Ro60, anti-SSA/Ro52, anti-SSB/La) all exhibited higher median enrichment than the DNA-associated (anti-dsDNA, anti-histones, anti-nucleosomes) or cytoplasmic (anti-ribosomal P) antigens. In particular autoantibodies against RNP/Sm and SSA/Ro52 had the highest degree of enrichment in SLE PEG precipitates. These findings were corroborated by analysis of autoantibody content in C1q-bound ICs. There was no difference in degree of IC accumulation of the investigated autoantibodies during active and inactive SLE. Our findings demonstrate a difference in enrichment between autoantibodies against RNA- and DNA-associated autoantigens in isolated SLE IC, suggesting that the RNA-associated autoantibodies are more prone to form circulating ICs in SLE, in contrast to antibodies against DNA-associated autoantigens such as dsDNA. These finding have implications in understanding mechanisms of differential autoantibody accumulation in target organs in SLE.

Treatment of refractory SLE with rituximab plus cyclophosphamide: clinical effects, serological changes, and predictors of response.

OBJECTIVE: To evaluate efficacy, serological responses, and predictors of response in patients with severe and refractory systemic lupus erythematosus (SLE) treated with rituximab plus cyclophosphamide. METHODS: 16 patients entered a treatment protocol using rituximab plus cyclophosphamide. Disease activity was assessed by the SLE disease activity index (SLEDAI) and by the British Isles Lupus Assessment Group (BILAG) index. RESULTS: At six months follow up, mean SLEDAI values decreased significantly from (mean (SD)) 12.1 (2.2) to 4.7 (1.1). Clinical improvement (50% reduction in SLEDAI) occurred in all but three patients. All but one patient responded according to BILAG. Remission defined as SLEDAI <3 was achieved in nine of 16 patients. Isotype analysis of anti-dsDNA antibodies revealed preferential decreases of IgG and IgA, but not IgM. Higher absolute numbers of CD19+ cells at baseline were correlated with shorter depletion time (r = -0.6). CONCLUSIONS: The majority of patients improved following rituximab plus cyclophosphamide. The differential downregulation of anti-DNA of the IgG and IgA but not the IgM isotypes supports the hypothesis that cells producing pathogenic autoantibodies are preferentially targeted by the treatment. The fact that greater absolute numbers of CD19+ cells at baseline predict a less impressive clinical and serological response suggests that more flexible dosing could be advantageous.

Treatment with tumour necrosis factor alpha antagonists in patients with rheumatoid arthritis induces anticardiolipin antibodies.

OBJECTIVE: To determine the frequency and clinical impact of anticardiolipin antibodies (aCL) in patients with rheumatoid arthritis treated with infliximab and etanercept. METHODS: 121 patients from the Stockholm tumour necrosis factor alpha (TNFalpha) follow up registry (STURE) treated with infliximab or etanercept were studied. RESULTS: At baseline 9/65 (14%) infliximab and 10/56 (18%) etanercept treated patients had positive aCL. After 3 months the frequencies of aCL positivity were 29% (p<0.05 compared with baseline) and 27%, respectively, and after 6 months 28% and 25%. Increases were seen for both IgG and IgM aCL. Increasing age, a higher number of prior DMARDs, and higher DAS28 were predictors for the development of aCL. In the infliximab treated patients, 26/30 (87%) aCL(-) but only 7/14 (50%) aCL(+) patients met the ACR20 criteria (p<0.05), and the frequency of treatment limiting infusion reactions in the aCL(+) patients was higher than expected (17%). aCL positivity in the etanercept treated patients did not show such a clinical correlate. Four patients had thromboembolic events, of whom two were aCL(+) and two aCL(-). CONCLUSION: Frequencies of both IgM and IgG aCL positivity increase in patients treated with these TNFalpha antagonists for 3 months or longer. Increasing age, a greater number of prior DMARDs and a greater disease activity at baseline are predictors for the development of aCL. The development of aCL during treatment with infliximab, but not etanercept, is associated with worse clinical results and more frequent serious infusion reactions. aCL are an important class of autoantibodies associated with TNFalpha blocking therapy.

A large Icelandic family with early osteoarthritis of the hip associated with a susceptibility locus on chromosome 16p.

OBJECTIVE: To describe a large kinship with inherited hip osteoarthritis (OA) and its associated susceptibility locus. METHODS: Four generations of a kinship with familial hip OA were identified and characterized by family history and by clinical, radiographic, and histopathologic examination. In the genome-wide search for a susceptibility locus, OA cases were defined as those who had undergone total hip replacement associated with a clinical and radiographic diagnosis of hip OA. A genome-wide scan was performed using a framework set of microsatellite markers with an average spacing of 10 cM. RESULTS: The hip OA of this family was indistinguishable from that of idiopathic, nonfamilial hip OA. There was no apparent evidence of spondyloepiphyseal dysplasia or other dysplasias usually associated with mutations in collagen genes. The genome-wide scan revealed a locus on chromosome 16p between 28 cM and 47 cM from the telomere, and this locus met the criteria for suggestive linkage (multipoint allele-sharing logarithm of odds [LOD] score 2.58, P = 1.6 x 10(-4)). Two additional regions with LOD scores of >1.5 were obtained. CONCLUSION: We have identified and described the largest kinship with familial hip OA reported to date. Evidence for linkage in this family suggests that a gene for susceptibility to hip OA exists on chromosome 16p. This represents an independent identification of a susceptibility locus previously reported for hip OA in this geographic region.

[Epidemiological study on cognitive abilities in the elderly in two separate rural areas in Iceland.].

OBJECTIVES: This study was undertaken to estimate the cognitive abilities in an elderly population in rural areas in Iceland and to get an idea of the prevalence of dementia. By examining inhabitants in two different areas it was further possible to detect any possible difference in these areas. MATERIAL AND METHODS: All persons aged 70 and over, living independently in the community and in institutions in two geographically separate areas were contacted. The areas were an agricultural (area A) and a fishing (area F) one. Four simple neuropsychological tests where used, the MMSE (Mini Mental State Examination), WAIS (Wechsler Adult Intelligence Scale)-Similarities, Trail making test A and Trail making test B. Two students in psychology and a teacher were trained in applying the tests but the results were scored and interpreted by the authors. RESULTS: In area A, 280 of 353 (79.3%) participated and in area F, 190 of 238 (79.8%). Participation was thus similar in both areas. There was a highly significant difference in all the tests with p<0.01 in Trail making test B but p<0.001 in the other three tests. In all the tests the results were better among the population in area A. The prevalence of dementia as estimated by the MMSE showed a prevalence of 14.4% in area A and 35.7% in area F. CONCLUSION: A significant difference in cognitive abilities was found between the elderly inhabitants of two separate rural areas in Iceland. There is substantial evidence to suggest that this difference is real but it is however not clear if the prevalence of dementia is higher in this study than in others. It is postulated that the difference found is due to cultural differences.

Auditory event-related potentials, auditory digit span, and clinical symptoms in chronic schizophrenic men on neuroleptic medication.

The aim of this study was to test predictions based on Grossberg's theories of overarousal in neural networks as related to schizophrenic symptomatology. We predicted that symptoms of blunted affect and volition would be associated with reduced P300 amplitude, while impaired attention and short-term memory and symptoms of disorganization would be associated with increased N200 and P300 latency. Event-related potentials, elicited by auditory stimuli, were recorded in 20 chronic schizophrenic men on neuroleptic medication and an age- and sex-matched control group of 20 normal volunteers. The amplitude and latency values of the N200 and P300 waves at the vertex (Cz) were compared with clinical ratings (the Scale for the Assessment of Positive Symptoms and the Scale for the Assessment of Negative Symptoms) and with neuropsychological test scores by means of Spearman rank correlation coefficient. The patients showed a reduced P300 amplitude and an increased N200 latency. No correlation was found between the P300 amplitude and the symptom scores. The N200 latency was negatively correlated with auditory digit span and positively correlated with high global scores for attentional impairment, alogia, and positive formal thought disorder. Our initial predictions are partly confirmed by the apparent association between increased N200 latency and symptoms of disorganization.

The in-vitro effect of temperature on MICs, bactericidal rates and postantibiotic effects in Staphylococcus aureus, Klebsiella pneumoniae and Pseudomonas aeruginosa.

Varying temperatures (35.5 degrees C, 38.5 degrees C, 41 degrees C) only minimally affected growth rates in vitro of Staphylococcus aureus, Klebsiella pneumoniae, and Pseudomonas aeruginosa, as well as bactericidal rates and postantibiotic effects of several antibiotics. However, MICs were reduced at least four-fold by increasing temperature in 25% of the drug-organism combinations tested.

A progression in the neuropsychological decline of Icelandic patients with probable or possible dementia of the Alzheimer's type: a longitudinal study.

To investigate the nature and rate of cognitive decline in dementia of the Alzheimer's type (DAT), 44 patients with probable or possible DAT (mean age 73.9, range 59-87 years) were given a comprehensive neuropsychological assessment. Twenty-five patients were retested 6 months later, and 11 were tested for the third time another 6 months later. Some tests of mental flexibility and double conceptual tracking ability were beyond the capabilities of the patients, and were left out of the statistical analysis because of floor effect. Poor initial performance on tests of attention, concentration, response speed, general cognitive ability, verbal memory, constructional skills, and perceptual closure ability resulted in nonsignificant changes over time (paired t tests). Tests of expressive speech, visuoperceptual functions and nonverbal memory, on the other hand, showed a significant deterioration over time. These findings indicate that when patients with DAT first receive medical attention, many neuropsychological functions are so severe impaired that there is little room for further decline. To describe the longitudinal course of cognitive decline in DAT, tests should be limited to those that assess the more resistant cerebral functions, and are more sensitive to progressive changes.