EULAR recommendations for women's health and the management of family planning, assisted reproduction, pregnancy and menopause in patients with systemic lupus erythematosus and/or antiphospholipid syndrome.

OBJECTIVES: Develop recommendations for women's health issues and family planning in systemic lupus erythematosus (SLE) and/or antiphospholipid syndrome (APS). METHODS: Systematic review of evidence followed by modified Delphi method to compile questions, elicit expert opinions and reach consensus. RESULTS: Family planning should be discussed as early as possible after diagnosis. Most women can have successful pregnancies and measures can be taken to reduce the risks of adverse maternal or fetal outcomes. Risk stratification includes disease activity, autoantibody profile, previous vascular and pregnancy morbidity, hypertension and the use of drugs (emphasis on benefits from hydroxychloroquine and antiplatelets/anticoagulants). Hormonal contraception and menopause replacement therapy can be used in patients with stable/inactive disease and low risk of thrombosis. Fertility preservation with gonadotropin-releasing hormone analogues should be considered prior to the use of alkylating agents. Assisted reproduction techniques can be safely used in patients with stable/inactive disease; patients with positive antiphospholipid antibodies/APS should receive anticoagulation and/or low-dose aspirin. Assessment of disease activity, renal function and serological markers is important for diagnosing disease flares and monitoring for obstetrical adverse outcomes. Fetal monitoring includes Doppler ultrasonography and fetal biometry, particularly in the third trimester, to screen for placental insufficiency and small for gestational age fetuses. Screening for gynaecological malignancies is similar to the general population, with increased vigilance for cervical premalignant lesions if exposed to immunosuppressive drugs. Human papillomavirus immunisation can be used in women with stable/inactive disease. CONCLUSIONS: Recommendations for women's health issues in SLE and/or APS were developed using an evidence-based approach followed by expert consensus.

Pregnancy induces numerical and functional changes of CD4+CD25 high regulatory T cells in patients with rheumatoid arthritis.

OBJECTIVE: In a prospective study we investigated whether numerical and functional changes of CD4+CD25(high) regulatory T cells (Treg) were associated with changes of disease activity observed during pregnancy and post partum in patients with rheumatoid arthritis (RA). METHODS: The frequency of CD4+CD25(high) T cells was determined by flow cytometry in 12 patients with RA and 14 healthy women during and after pregnancy. Fluorescence-activated cell sorting (FACS) was used to sort CD4+CD25(high) T cells and CD4+CD25- T cells were stimulated with anti-CD3 and anti-CD28 monoclonal antibodies alone or in co-culture to investigate proliferation and cytokine secretion. RESULTS: Frequencies of CD4+CD25(high) Treg were significantly higher in the third trimester compared to 8 weeks post partum in patients and controls. Numbers of CD4+CD25(high) Treg inversely correlated with disease activity in the third trimester and post partum. In co-culture experiments significantly higher amounts of IL10 and lowered levels of tumour necrosis factor (TNF)alpha and interferon (IFN)gamma were found in supernatants of the third trimester compared to postpartum samples. These findings were independent from health or disease in pregnancy, however postpartum TNFalpha and IFN gamma levels were higher in patients with disease flares. CONCLUSION: The amelioration of disease activity in the third trimester corresponded to the increased number of Treg that induced a pronounced anti-inflammatory cytokine milieu. The pregnancy related quantitative and qualitative changes of Treg suggest a beneficial effect of Treg on disease activity.

Symmetry in biology: from genetic code to stochastic gene regulation.

Mathematical models, as instruments for understanding the workings of nature, are a traditional tool of physics, but they also play an ever increasing role in biology--in the description of fundamental processes as well as that of complex systems. In this review, the authors discuss two examples of the application of group theoretical methods, which constitute the mathematical discipline for a quantitative description of the idea of symmetry, to genetics. The first one appears, in the form of a pseudo-orthogonal (Lorentz like) symmetry, in the stochastic modelling of what may be regarded as the simplest possible example of a genetic network and, hopefully, a building block for more complicated ones: a single self-interacting or externally regulated gene with only two possible states: 'on' and 'off'. The second is the algebraic approach to the evolution of the genetic code, according to which the current code results from a dynamical symmetry breaking process, starting out from an initial state of complete symmetry and ending in the presently observed final state of low symmetry. In both cases, symmetry plays a decisive role: in the first, it is a characteristic feature of the dynamics of the gene switch and its decay to equilibrium, whereas in the second, it provides the guidelines for the evolution of the coding rules.

Impact of pregnancy on health related quality of life evaluated prospectively in pregnant women with rheumatic diseases by the SF-36 health survey.

OBJECTIVE: To gain insight into patient experience of the disease course and health related quality of life during and after pregnancy in women with rheumatoid arthritis and ankylosing spondylitis. METHODS: 10 patients with rheumatoid arthritis, 10 patients with ankylosing spondylitis, and 29 age matched healthy pregnant controls were evaluated by the medical outcomes study short form 36 (SF-36) health survey once at each trimester and at 6, 12, and 24 weeks postpartum. A group of non-pregnant age matched female patients (40 rheumatoid arthritis, 16 ankylosing spondylitis) was studied for comparison. RESULTS: Impaired physical dimensions as well as increased bodily pain was observed in healthy women in late pregnancy. Patients with rheumatoid arthritis showed improved physical functioning scores in the second trimester and reduced pain in the third trimester. Among pregnant patients, those with ankylosing spondylitis suffered the greatest impairment of health related quality of life during pregnancy. In all patient groups the physical impairment in the third trimester was less pronounced than in healthy controls. Mental health scores remained stable even with persisting active disease during pregnancy, or with a postpartum flare. CONCLUSIONS: Pregnancy reduced physical functioning in healthy women and patients, but had no impact on mental and emotional health, even at times of disease aggravation. The pregnancy experience documented in our patients may be helpful when counselling patients contemplating pregnancy.

Activation markers of peripheral blood mononuclear cells in late pregnancy and after delivery: a pilot study.

OBJECTIVE: To study the putative shift of a Th1 to a Th2 immune response in pregnancy and its reversal post partum in healthy women and patients with rheumatoid arthritis (RA). METHODS: Peripheral blood mononuclear cells (PBMC) were examined by FACS analysis for the expression of activation markers CD25 and HLA-DR and chemokine receptors CXCR3 and CCR4 on CD4+ and CD8+ T cells in four healthy women and four patients with RA. Samples were analysed once in the third trimester and six and 12 weeks post partum. Eight healthy non-pregnant women served as controls. RESULTS: No reduction of CD25 and HLA-DR+ T cells occurred in the third trimester, but a significant increase was observed post partum in healthy women and an even greater increase in patients. Proportions of T cells expressing the CXCR3 or CCR4 marker were similar in patients and controls during pregnancy, whereas a significant increase occurred post partum. The ratio of CXCR3+ to CCR4+ cells remained unchanged during the observation period and did not differ significantly from that in non-pregnant controls. CONCLUSION: A shift from a Th1 to a Th2 immune response was not detected in the circulation of healthy pregnant women or pregnant patients. The significant increase of T cell activation after pregnancy warrants further investigation into the mechanisms of adjustment of the immune system post partum and its clinical correlates in rheumatic patients.

Pregnancy in patients with rheumatic disease: anti-inflammatory cytokines increase in pregnancy and decrease post partum.

OBJECTIVE: To investigate changes in the levels of circulating cytokines with a focus on the Th1/Th2 balance during and after pregnancy in patients with rheumatoid arthritis (RA), juvenile idiopathic arthritis (JIA), and ankylosing spondylitis (AS). METHODS: Plasma and serum samples of 34 pregnant patients, 19 with RA, 6 with JIA, and 9 with AS, and of 30 healthy pregnant women, 20 non-pregnant patients, and 10 non-pregnant healthy women were analysed for levels of interferon gamma (IFNgamma), interleukin (IL) 1beta, IL10, IL1 receptor antagonist (IL1Ra), soluble tumour necrosis factor receptor (sTNFR), and soluble CD30 (sCD30) by ELISA. Clinical assessment and blood sampling in pregnant women was done once in each trimester and 6, 12, and 24 weeks post partum. Disease activity in the patients was evaluated by validated clinical instruments and correlated with circulating levels of cytokines. RESULTS: Low levels of IL10 were found sporadically, whereas IFNgamma and IL1beta were below detection level in the samples tested. Significantly higher concentrations of sTNFR and IL1Ra were measured in pregnant than in non-pregnant subjects. An increase of IL1Ra from the second to the third trimester correlated with improvement of disease activity in patients with RA and AS. Compared with non-pregnant patients and the other pregnant women, patients with RA showed markedly raised levels of sCD30 during pregnancy. CONCLUSIONS: IFNgamma and IL10, markers of a Th1 and Th2 response, respectively, were either low or undetectable in the cohorts analysed. The increase of cytokine inhibitors IL1Ra and sTNFR was related to pregnancy and was independent of an underlying disease. These anti-inflammatory mediators seem to affect disease activity.

Clinical significance of anti-dsDNA antibody isotypes: IgG/IgM ratio of anti-dsDNA antibodies as a prognostic marker for lupus nephritis.

The objective of this paper is to investigate the association between patterns of anti-dsDNA antibody isotypes and specific clinical manifestations (categorized in renal, musculoskeletal, cutaneous, hematological, pulmonary, neurological and cardiac). Sera of 202 systemic lupus erythematosus (SLE) patients, 33 patients suffering from other autoimmune diseases and 115 healthy blood donors were analysed for anti-dsDNA antibodies by IgG-, IgA- and IgM-specific ELISA, Farr-assay and CLIF. A subset of 24 SLE patients was investigated in a longitudinal study over a period of one to six years. Disease activity of 105 SLE patients was measured according to the ECLAM score. In the cohort of SLE patients 63% were positive for the IgG class, 40% for the IgA and 57% for the IgM class specific anti-dsDNA ELISA. Sensitivity (79%) and specificity (99%) for the diagnosis of SLE appeared to be highest for the ELISA measuring all isotypes of anti-dsDNA antibodies. The concentrations of anti-dsDNA isotypes showed a strong correlation with disease activity. Analysing the relationship between IgG, IgA and IgM anti-dsDNA antibody isotypes and clinical manifestation, we found a significant association of the IgM isotype with cutaneous involvement and of the IgG isotype with lupus nephritis. The IgG/IgM ratio of anti-dsDNA antibodies represented a significant parameter to distinguish patients with lupus nephritis from those without renal involvement. In the longitudinal study, a continuous ratio under 0.8 was associated with absence of renal involvement throughout the investigated period. In conclusion, the evaluation of anti-dsDNA isotypes provides a diagnostic tool to define subsets within SLE patients with different clinical manifestations. In particular, the IgG/IgM ratio of anti-dsDNA antibodies could be used as a prognostic marker for lupus nephritis during the course of the disease.

Diagnostic and clinical value of anti-cyclic citrullinated peptide antibodies compared with rheumatoid factor isotypes in rheumatoid arthritis.

OBJECTIVE: To assess the additional diagnostic and clinical value of the second test generation of anti-cyclic citrullinated peptide antibodies (CCP2) compared with rheumatoid factor isotypes (IgG-RF, IgA-RF, IgM-RF) in patients with rheumatoid arthritis. METHODS: This was a prospective study on 715 patients: rheumatoid arthritis (n = 295), degenerative or other inflammatory joint disease (n = 163), connective tissue disease or vasculitis (n = 103), and healthy controls (n = 154). Sera from each subject were tested for CCP2 and RF isotypes by enzyme linked immunosorbent assay (ELISA). Agreement with clinical indices such as disease activity, joint destruction, disease duration, and other laboratory tests was assessed. Sensitivity and specificity of the tests were evaluated taking the clinical diagnosis as the gold standard. RESULTS: Highest sensitivity was found for IgM-RF (66.4%) and CCP (64.4%). Highest specificity was achieved by CCP (97.1%) and IgG-RF (91.0%). In rheumatoid patients with high disease activity or severe joint damage, CCP was more often present (81.4% and 83.6%) than all RF isotypes. Of special diagnostic value was the detection of positive CCP in 34.5% of all patients with rheumatoid arthritis when all measured RF isotypes (IgG-RF, IgA-RF, and IgM-RF) were negative. CONCLUSIONS: As a screening method for rheumatoid arthritis the IgM-RF and the CCP assays are superior to other RF isotypes. Positivity in the highly specific CCP ELISA supports the diagnosis of rheumatoid arthritis. CCP proved to be a powerful diagnostic tool, especially in ambiguous cases or RF negative patients with rheumatoid arthritis.