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OBJECTIVE: To determine whether key features of systemic lupus erythematosus (SLE), namely, production of non-nuclear antibodies (anti-C1q and anticardiolipin antibodies [aCL]) and depletion of complement components C3 and C4, aggregate in families. In addition, we examined relationships between anti-C1q and C3 and C4 levels. METHODS: The study cohort comprised 1,037 predominantly white (82%) nuclear families in which at least 1 member had SLE. Associations of antibody measurements between probands and their unaffected siblings were examined using parametric and nonparametric analyses, along with associations between unaffected siblings and their parents. The heritability of anti-C1q, C3, and C4 was estimated, and interdependencies between these factors were examined in a regression model accounting for the family structure of the data set. RESULTS: We demonstrated associations between siblings for anti-C1q (odds ratio [OR] 3.74, 95% confidence interval [95% CI] 2.65, 5.28) and IgG and IgM aCL (OR 4.08, 95% CI 1.83, 5.13 and OR 2.06, 95% CI 1.46, 2.91, respectively) and, for anti-C1q, association between unaffected parents and their unaffected offspring (OR 4.34, 95% CI 2.16, 8.72). We also demonstrated significant heritability of anti-C1q, C3, and C4 (approximately 45%). Anti-C1q was negatively associated with C3 and C4 in SLE probands but not in their healthy relatives. CONCLUSION: Non-nuclear antibodies and C3 and C4 cluster within the families of SLE probands, suggesting that specific autoantibody formation is partly genetically determined, even if the total genetic effect in unaffected relatives is insufficient to cause disease. Anti-C1q antibodies accelerate C3 and C4 depletion in patients with SLE but have no effect in the absence of disease. [ABSTRACT FROM AUTHOR]

To formulate a ‘logic’ for how a single immunoglobulin variable region gene generates antibodies with different antigen specificity and polyreactivity, we analysed chimeric antibodies produced in transgenic mice carrying the germ-line human V3–23 gene, multiple diversity (D) and joining (J) gene segments. Hybridomas producing antibodies encoded by the V3–23 gene in combination with different mouse Vκ genes were obtained by fusion of splenocytes from transgenic mice. All antibodies had human μ-chains and mouse light chains, were multimeric in structure and expressed the human V3–23 gene. Nucleotide sequence analyses of genes encoding the heavy and light chains of 12 antibodies in relation to antigen specificity highlighted the importance of heavy chain variable region CDR3 in determining reactivity with different antigens. However, the results also suggest that non-CDR3 sequences intrinsic to the V3–23 gene itself may be involved in, or determine, the binding of the chimeric antibodies to some of the antigens tested in the current study. [ABSTRACT FROM AUTHOR]

Ziad Farah, Sabreen Ali, Fiona Price-Kuehne, Charles G Mackworth-Young Department of Rheumatology, Charing Cross Hospital, London, UKObjectives: To evaluate the long-term efficacy and safety of tocilizumab (TCZ) in clinical patients with rheumatoid arthritis (RA) refractory to synthetic disease-modifying antirheumatic drugs, anti-tumor necrosis factor agents, and B-cell depletion therapy with rituximab (RTX).Methods: We conducted a single-center retrospective study of 22 patients with RA treated with TCZ. We collected data including demographics and medication histories. We recorded clinical parameters including tender joint counts and swollen joint counts, and laboratory parameters including inflammatory makers and lipid profiles over regular intervals of TCZ treatment.Results: In all, 22 patients with RA were included, 20 of whom were female. The median age at the first dose of TCZ was 62 years (range: 35–75 years). The mean duration of the disease from diagnosis with RA to May 2015 was 15.7 years (range: 6–30 years). A total of 15 out of 22 patients remained on TCZ at the end of the study, and in all, there was an improvement in markers of disease activity following initiating TCZ. The effect was sustained for a mean of 35 months (SD ±15.5 months, range: 9–72 months). Of the 17 patients who failed to respond to RTX previously, 12 patients remained on TCZ. In all, eight out of 22 patients developed adverse events, five of whom discontinued TCZ. In contrast to previously documented short-term data, TCZ did not result in a statistically significant (P

The public idiotype Id-16/6 and the public idiotope Id-LLa were originally defined on the same human monoclonal anti-DNA antibody, but they are also known to occur separately on other anti-DNA antibodies. We sought the presence of these immunoglobulin variable region markers in purified immunoglobulins from the serum of nine patients with systemic lupus erythematosus (SLE) and 33 healthy donors. Sera from five patients were positive for Id-16/6. and five were positive for Id- LLa. The immunoglobulin preparations were passed over a Sepharose-Id-16/6 column in order to recover auto-anti-idiotypes. An eluate of that column was obtained from the immunoglobulin preparation of one patient whose serum was Id-16/6+and Id-LLa-. This eluate was shown by competition assay to bind to IdLLa. This is the first demonstration of spontaneously arising human auto-anti-idiotypes against a specific idiotypic system in SLE. The results suggest that antibodies against the Id-LLa idiotope may play a role in immunoregulation. [ABSTRACT FROM AUTHOR]

Raised levels of serum antiphospholipid antibodies have most commonly been reported in patients with systemic lupus erythematosus (SLE). There remains, however, a group of patients with raised antiphospholipid antibody levels who do not have any other well defined disease, but do have clinical features associated with these raised antibodies. The clinical, haematological, and serological features of 20 such patients are reported. Antiphospholipid antibody levels were measured by a solid phase assay for anticardiolipin activity. Fourteen patients had raised IgG antiphospholipid antibodies, 12 had raised IgM, and six had both. Nine out of 19 had raised antinuclear antibody levels; however, non fulfilled criteria for the diagnosis of SLE. Seven patients had a history of venous thrombosis and five of definite or presumed arterial thrombosis-for example, stroke. Of the 15 female patients who underwent pregnancy, 12 experienced fetal loss with up to eight abortions each (mean 3.6). Six individuals had thrombocytopenia and four others had migraines. Other clinical features included livedo reticularis, cardiac and neuropsychiatric disorders, arthralgias, and Raynaud's phenomenon. These findings confirm that the clinical features of individuals with what may be called the 'primary antiphospholipid syndrome' are similar to those in patients with other diagnoses who have raised antiphospholipid antibodies. They indicate that the antiphospholipid syndrome may be related to SLE and other autoimmune diseases, but that, although it frequently overlaps with these disorders, it also exists as a distinct entity. [ABSTRACT FROM PUBLISHER]

A double blind, placebo controlled trial was performed in 25 patients to study the use of intravenous methylprednisolone (IVMP) in the treatment of active systemic lupus erythematosus (SLE). The trial examined the additive effect of IVMP on a background of conventional oral steroid treatment. Patients were followed up for six months. The results showed a trend towards more consistent overall improvement in the first two weeks after IVMP administration compared with placebo, but this difference was not maintained at one month or subsequently. They also suggested a quicker resolution of hypocomplementaemia in the treatment group. Other parameters of disease activity showed no difference. Side effects were generally mild and were similar in incidence between the two groups. Thus it is concluded that IVMP may improve initial suppression of active lupus in some patients when added to conventional oral steroid treatment, but that this additional benefit is not maintained; IVMP is, however, a relatively safe treatment when used in this way. [ABSTRACT FROM PUBLISHER]

The genetic background of systemic lupus erythematosus (SLE) has been reexamined in a study of the serum of 31 lupus patients and 80 asymptomatic first degree relatives by measuring a common, cross reacting anti-DNA antibody idiotype designated 134, antibodies to poly(ADP-ribose), serum C3, circulating immune complexes, and antinuclear antibodies (ANA). Over 30% of the relatives had raised 134 and anti-poly(ADP-ribose) levels, and 9% had ANA titres greater than 1/20. In contrast, only one relative had a low serum C3 level. These results confirm that immunogenetic abnormalities associated with the production of autoantibodies and particular idiotypes must exist amongst lupus relatives as well as the patients. The production of autoantibodies, however, is not necessarily matched to the clinical expression of SLE. [ABSTRACT FROM PUBLISHER]

We have developed a sensitive, solid phase radioimmunoassay (RIA) to quantify the amount of complement (C') fixation by anti-double-stranded DNA (anti-dsDNA) antibodies and have studied sera from 48 patients with systemic lupus erythematosus (SLE). 46% of the patients were positive in this assay. There was no correlation with serum C' levels, and only weak correlation with anti-dsDNA activity as measured by a solid phase RIA. An association was shown between positive values for C' fixation by anti-dsDNA antibodies and the presence of active lupus (p less than 0.01); there was a similar association with the presence of active renal disease in those patients with raised DNA binding (p less than 0.01). Our results suggest that quantitative measurement of C' fixation by anti-dsDNA antibodies may provide information about the pathogenicity of such antibodies in patients with SLE and be a better guide to potential end organ damage than the conventional measurement of DNA binding. [ABSTRACT FROM PUBLISHER]

Two elderly patients with systemic lupus erythematosus (SLE) are presented. Both developed an acute polyradiculoneuropathy which is an unusual complication of this disease. Features of their presentation are discussed. [ABSTRACT FROM PUBLISHER]

Autoantibodies against cyclophilin, a cyclosporin A binding protein, were detected in sera of 29 of 46 (63%) patients with systemic lupus erythematosus and 14 of 41) (35%) Lyme disease patients. The antibodies arc directed against the denatured form of both the major and minor isoform of cyclophilin and can be demonstrated in Western blots. Some first-degree relatives of tupus patients also express these antibodies. They are specific for cyclophilin and are not the consequence of hypergammaglobulinaemia. Four monoclonal IgM antibodies (ruin a patient with lepromatous leprosy also hound to cyclophilin. The generation of these antibodies may be of special interest because the are against a protein involved in the control of the immune system not known to he directly associated with DNA or RNA. [ABSTRACT FROM AUTHOR]

Susceptibility to systemic lupus erythematosus (SLE) is known to be governed by genes in the HLA region of the 6th chromosome. From previous studies it has not been possible to distinguish between the effects of null genes for the complement component C4 and HLA- DR3, because of the marked linkage disequilibrium between DR3 and a null allele of C4A (C4A*QO) in caucasoid populations. We report here an immunogenetic study of 44 cases of SLE, selected because they were DR3 negative. Eighteen of the 30 Caucasoid cases (60%) had extended HLA haplotypes with a C4 null allele, compared with 22 of 60(37%) of a control panel of 60 DR3 negative normal Caucasoid subjects. This difference is significant (χ²= 44l; 0.05 > P> 0.01). Of 14 non-caucasoid patients analysed, 10 had a C4 null allele. It is concluded that the null alleles of the C4 A and B genes are themselves directly responsible for conferring susceptibility to SLE. [ABSTRACT FROM AUTHOR]

It has been claimed that patients with systemic lupus erythematosus (SLL) have an inherited deficiency of erythrocyte complement receptor type I (CR1, with ligand binding specificity for C3b. iC3b and C4b). CR1 functions as the only cofactor for factor I-mediated cleavage of iC3b to C3c and C3dg. The activity of this receptor on red cells may be an important mechanism for handling immune complexes which have bound C3b or iC3b. Radioligand binding studies were performed using a monoclonal antibody to CR3, E11, to enumerate these receptors accurately. The results confirmed that patients with SLE have a reduced number of CR1 molecules per red cell, but showed no reduction in CR1 levels amongst their consanguineous relatives, Study of 13 normal families suggested the presence of heritable factors controlling the numbers of erythrocyte CR1 molecules: in particular there was a correlation between mean parental CR1 numbers and CR1 numbers in their children. However, amongst 17 families of 19 patients with SLE. four families were identified in which genotypically 'high CR1' SLE patients had persistently low phenotypes. This is not compatible with the hypothesis that the reduction in erythrocyte CR1 numbers in these patients is inherited. [ABSTRACT FROM AUTHOR]