Frauke Förger

The EULAR points to consider for use of antirheumatic drugs before pregnancy, and during pregnancy and lactation

A European League Against Rheumatism (EULAR) task force was established to define points to consider on use of antirheumatic drugs before pregnancy, and during pregnancy and lactation. Based on a systematic literature review and pregnancy exposure data from several registries, statements on the compatibility of antirheumatic drugs during pregnancy and lactation were developed. The level of agreement among experts in regard to statements and propositions of use in clinical practice was established by Delphi voting. The task force defined 4 overarching principles and 11 points to consider for use of antirheumatic drugs during pregnancy and lactation. Compatibility with pregnancy and lactation was found for antimalarials, sulfasalazine, azathioprine, ciclosporin, tacrolimus, colchicine, intravenous immunoglobulin and glucocorticoids. Methotrexate, mycophenolate mofetil and cyclophosphamide require discontinuation before conception due to proven teratogenicity. Insufficient documentation in regard to fetal safety implies the discontinuation of leflunomide, tofacitinib as well as abatacept, rituximab, belimumab, tocilizumab, ustekinumab and anakinra before a planned pregnancy. Among biologics tumour necrosis factor inhibitors are best studied and appear reasonably safe with first and second trimester use. Restrictions in use apply for the few proven teratogenic drugs and the large proportion of medications for which insufficient safety data for the fetus/child are available. Effective drug treatment of active inflammatory rheumatic disease is possible with reasonable safety for the fetus/child during pregnancy and lactation. The dissemination of the data to health professionals and patients as well as their implementation into clinical practice may help to improve the management of pregnant and lactating patients with rheumatic disease.

Management of RA medications in pregnant patients

A desire for children or the presence of pregnancy limits the drug therapy options for a woman with rheumatoid arthritis. Combination therapies that include methotrexate or new drugs that have not been studied or used in pregnant patients must be excluded, even though they might be highly efficacious. With few exceptions, the reason for this exclusion is not the proven teratogenicity of the drugs, but the absence of proven safety for the fetus. Whereas methotrexate, leflunomide, abatacept and rituximab must be withdrawn before a planned pregnancy, tumor necrosis factor inhibitors and bisphosphonates can be continued until conception. Antimalarial agents, sulfasalazine, azathioprine and ciclosporin are compatible with pregnancy, and so can be administered until birth. Corticosteroids and analgesics such as paracetamol (acetaminophen) can also be used throughout pregnancy. NSAIDs can be safely administered until gestational week 32. The most important consideration when managing rheumatoid arthritis medications during pregnancy is that therapy must be tailored for the individual patient according to disease activity.

Effects of TNF antagonists on sperm characteristics in patients with spondyloarthritis

Objective To study the influence of tumour necrosis factor (TNF) antagonists on spermatogenesis in a cohort of patients with spondyloarthritis (SpA). Patients and methods Semen samples of 26 patients with SpA were analysed according to WHO 1999 guidelines with and without TNF blocking agents (infliximab, etanercept or adalimumab). Results were compared with semen samples of 102 healthy volunteers. Results Sperm abnormalities were found in 10/11 patients without anti-TNF therapy. The sperm of these 11 patients had significantly poorer motility (p=0.001) and vitality (p=0.001) than found in 15 patients tested during longstanding anti-TNF therapy, but sperm concentration and morphology were similar in the two groups. There was no significant difference of sperm quality between healthy controls and anti-TNF treated patients with SpA. Notably, sperm abnormalities were also found in 102 healthy controls. Conclusion Sperm abnormalities are a common finding in healthy men, they are more pronounced in patients with active SpA. The sperm quality of patients with SpA with inactive disease receiving long-term TNF inhibition is comparable to that in healthy controls. The data support continuation of anti-TNF treatment when fatherhood is planned.

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 womens 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 womens health issues in SLE and/or APS were developed using an evidence-based approach followed by expert consensus.

Pregnancy and reproduction in autoimmune rheumatic diseases

Despite evidence for the important role of oestrogens in the aetiology and pathophysiology of chronic immune/inflammatory diseases, the previous view of an unequivocal beneficial effect of oestrogens on RA compared with a detrimental effect on SLE has to be reconsidered. Likewise, the long-held belief that RA remits in the majority of pregnant patients has been challenged, and shows that only half of the patients experience significant improvement when objective disease activity measurements are applied. Pregnancies in patients with SLE are mostly successful when well planned and monitored interdisciplinarily, whereas a small proportion of women with APS still have adverse pregnancy outcomes in spite of the standard treatment. New prospective studies indicate better outcomes for pregnancies in women with rare diseases such as SSc and vasculitis. Fertility problems are not uncommon in patients with rheumatic disease and need to be considered in both genders. Necessary therapy, shortly before or during the pregnancy, demands taking into account the health of both mother and fetus. Long-term effects of drugs on offspring exposed in utero or during lactation is a new area under study as well as late effects of maternal rheumatic disease on children.

Interaction of pregnancy and autoimmune rheumatic disease

During pregnancy, the fetus represents a natural allograft that is not normally rejected. While the maternal immune system retains the ability to respond to foreign antigens, tolerance mechanisms are up-regulated to protect the fetus from immunologic attacks by the mother. The profound immunologic adaptations during and after pregnancy do influence maternal autoimmune rheumatic diseases in several ways. One is triggering the onset of a rheumatic disease in the post partum period, the other influencing disease activity of established rheumatic disease. The review will discuss the mechanisms of increased susceptibility of rheumatoid arthritis (RA) in the first year post partum with a specific emphasis on the role of fetal cells or antigens persisting in the maternal circulation (so called microchimerism). Furthermore, the different influences of pregnancy on established rheumatic diseases will be highlighted. A marked beneficial effect of pregnancy is observed on RA whereas several other rheumatic diseases as ankylosing spondylitis (AS) and systemic lupus erythematosus (SLE) show either no particular effect or an aggravation of symptoms during pregnancy. Differences emerging in regard to modulation of disease symptoms during pregnancy seem related to response to hormones, the type of cytokine profile and immune response prevailing as well as further downstream interactions of molecular pathways that are important in disease pathogenesis.

State of the art: reproduction and pregnancy in rheumatic diseases

Throughout the last decade, increasing awareness has been raised on issues related to reproduction in rheumatic diseases including basic research to clarify the important role of estrogens in the etiology and pathophysiology of immune/inflammatory diseases. Sub- or infertility is a heterogeneous condition that can be related to immunological mechanisms, to pregnancy loss, to disease burden, to therapy, and to choices in regard to family size. Progress in reproductive medicine has made it possible for more patients with rheumatic disease to have children. Active disease in women with rheumatoid arthritis (RA) affects their childrens birth weight and may have long-term effects on their future health status. Pregnancy complications as preeclampsia and intrauterine growth restriction are still increased in patients with systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS), however, biomarkers can monitor adverse events, and several new therapies may improve outcomes. Pregnancies in women with APS remain a challenge, and better therapies for the obstetric APS are needed. New prospective studies indicate improved outcomes for pregnancies in women with rare diseases like systemic sclerosis and vasculitis. TNF inhibitors hold promise for maintaining remission in rheumatological patients and may be continued at least in the first half of pregnancy. Pre-conceptional counseling and interdisciplinary management of pregnancies are essential for ensuring optimal pregnancy outcomes.

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.

Evaluation of Histologic, Serologic, and Clinical Changes in Response to Abatacept Treatment of Primary Sjögren's Syndrome: A Pilot Study

To prospectively evaluate histopathologic, blood cellular, serologic, and clinical changes in response to abatacept treatment in patients with primary Sjögrens syndrome (SS).

Pregnancy induces numerical and functional changes of CD4+CD25high regulatory T cells in patients with rheumatoid arthritis

Objective: In a prospective study we investigated whether numerical and functional changes of CD4+CD25high 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+CD25high 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+CD25high 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+CD25high Treg were significantly higher in the third trimester compared to 8 weeks post partum in patients and controls. Numbers of CD4+CD25high 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)α and interferon (IFN)γ were found in supernatants of the third trimester compared to postpartum samples. These findings were independent from health or disease in pregnancy, however postpartum TNFα and IFNγ 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.