Pregnancy in granulomatous vasculitis.

OBJECTIVE--To study the fetal and maternal outcome of pregnancy in patients with granulomatous vasculitis. METHODS--Four pregnancies in two patients with Wegener's granulomatosis (WG) and one patient with Churg-Strauss syndrome (CSS) were identified and followed in our specialised clinic for pregnancy and connective tissue diseases. RESULTS--Three pregnancies ended with live babies and one with intrauterine death at 25 weeks of gestation. One WG patient remained in remission throughout pregnancy and the other experienced severe activity at 12 weeks. The CSS patient was in remission during her first pregnancy, but the disease flared severely in the second. CONCLUSIONS--Pregnancy in patients with granulomatous vasculitis requires preconceptual planning, careful clinical management, and vigorous treatment of active disease.     

Liver disease in pregnancy

Development of liver diseases during pregnancy is not uncommon. They are caused by either a disorder that is unique to pregnancy or an acute or chronic liver disease that already exists or coincidentally develops as a comorbidity of pregnancy. Liver diseases unique to pregnancy include hyperemesis gravidarum; hypertensive disorders of pregnancy, such as pre‐eclampsia/eclampsia; hemolysis, elevated liver enzymes, and low platelet count syndrome; intrahepatic cholestasis of pregnancy; and acute fatty liver of pregnancy. Chronic liver diseases that affect pregnancy, or are affected by pregnancy, mainly include autoimmune liver diseases and non‐alcoholic fatty liver disease. Prompt diagnosis and management of liver diseases in pregnancy, while very challenging, is extremely important, as they might cause adverse maternal and fetal outcomes. Therefore, a multidisciplinary, collaborative approach involving both hepatologists and obstetricians is required. In this review article, the up‐to‐date epidemiology, etiology, clinical features, and outcomes of liver diseases in pregnancy are discussed, to promote a deeper understanding among physicians, and subsequently improved outcomes.     

Immune Components of Liver Damage Associated with Connective Tissue Diseases

Autoimmune connective tissue diseases are associated with liver abnormalities and often have overlapping pathological and clinical manifestations. As a result, they can present great clinical challenges and evoke questions about diagnostic criteria for liver diseases. Moreover, discriminating between liver involvement as a manifestation of connective tissue disease and primary liver disease can be challenging since they share a similar immunological mechanism. Most patients with connective tissue diseases exhibit liver test abnormalities that likely result from coexisting, primary liver diseases, such as fatty liver disease, viral hepatitis, primary biliary cirrhosis, autoimmune hepatitis, and drug-related liver toxicity. Liver damage can be progressive, leading to cirrhosis, complications of portal hypertension, and liver-related death, and, therefore, must be accurately identified. In this review, we highlight the challenges facing the diagnosis of liver damage associated with connective tissue disease and identify immune mechanisms involved in liver damage associated with connective tissue diseases.     

Esophageal manometric findings in autoimmune rheumatic diseases: is scleroderma esophagus a specific entity?

Summary In order to assess whether distal esophageal hypomotility in scleroderma is unique to this disease or not, we studied 25 normal volunteers and 109 patients with autoimmune rheumatic diseases (27 with primary Sjögren's syndrome, 25 with idiopathic Raynaud's phenomenon, 25 with rheumatoid arthritis, 19 with scleroderma, 5 with undifferentiated connective tissue disease, 3 with systemic lupus erythematosus, 2 with mixed connective tissue disease, 2 with sclerodermatomyositis, and one with morphea). Esophageal dysfunction typical of scleroderma was present in 17 patients (15.6%), of whom 13 had scleroderma (68%) and one each primary Sjögren's syndrome, rheumatoid arthritis, undifferentiated connective tissue disease, and mixed connective tissue disease. Twenty-two percent of all patients had nonspecific esophageal motility changes, clustered among primary Sjögren's syndrome, idiopathic Raynaud's phenomenon, and rheumatoid arthritis. We conclude that lower esophageal hypomotility, although most frequent in scleroderma, is not unique to this disease and can be encountered in several other autoimmune rheumatic diseases.     

Pregnancy outcome in patients with undifferentiated connective tissue disease: a preliminary study on 25 pregnancies

Undifferentiated connective tissue disease (UCTD) is a group of systemic autoimmune conditions not fulfilling the classification criteria for a definite connective tissue disease (CTD). While an average of 20% of UCTD patients develop a defined CTD during follow-up, the remaining patients maintain an undefined disease. Since pregnancy is considered to be an important factor that may alter the course of autoimmune diseases, we examined 25 pregnancies in 20 UCTD patients being followed at our unit in order to evaluate: (i) the pregnancy outcome; (ii) whether pregnancy is associated with flares of disease activity; and (iii) whether pregnancy may be a trigger for the development of a defined CTD. Twenty-two pregnancies (88%) were successfully brought to term, while the remaining three (12%) ended in an abortion in the first trimester. Obstetric complications were observed in six out of the 22 successful pregnancies (27%). Six patients (24%) experienced a disease flare during pregnancy or puerperium, one of whom presented a major flare and developed systemic lupus erythematosus. In the other five patients the manifestations at flare were mild and included arthritis, fever and skin rash. The incidence of flares in a control population of non-pregnant UCTD patients over a period of 1 year was 7%. Although UCTD is a mild condition, the risk of flares during pregnancy appears increased and therefore careful monitoring is as necessary as in other CTD patients. Further prospective studies will be necessary to confirm these preliminary observations.     

Autoimmune rheumatische Erkrankungen in der Schwangerschaft

Pregnancy is an exceptional state of natural immunomodulation which protects the fetus against the immunological attack by the maternal immune system. The mechanisms of pregnancy-related tolerance may have a positive or negative effect on autoimmune rheumatic diseases. The majority of patients with rheumatoid arthritis experience an improvement in the disease during pregnancy whereas in most ankylosing spondylitis patients the inflammatory back pain remains unchanged. Connective tissue diseases or vasculitis pose a threat to the well-being of both mother and fetus particularly when the activity of the disease is high. In general, pregnancy in patients with rheumatic diseases should be planned in a phase of quiescent disease. Medication compatible with pregnancy should be tailored for the individual patients according to disease activity. A close interdisciplinary observation of these patients is the key for successful pregnancy outcome.     

Pregnancy and autoimmune diseases

Until about 15 years ago, the general advice to women with autoimmune rheumatic diseases, especially systemic lupus erythematosus, systemic sclerosis and vasculitic syndromes, was to avoid pregnancy as there was a high risk of maternal and fetal morbidity and mortality. However, it is now clear that these risks can be reduced in general by avoiding pregnancy when the diseases are active and continuing appropriate medication to reduce the chances of disease flare during pregnancy. This article will review the evidence for this advice and will also consider other issues that should be discussed with women before they attempt to become pregnant. This will include the influence of pregnancy on the individual autoimmune diseases, as well as the potential impact of the diseases and drug therapy on fertility and pregnancy outcomes. Anti-phospholipid antibody syndrome has emerged as a major cause of fetal loss, pre-eclampsia and premature birth. The clinical and laboratory diagnosis of this condition will not be covered, but the reader is referred to an excellent recent review. Much of the data on pregnancy and autoimmune rheumatic diseases come from retrospective analyses, but some prospective studies have been reported over the past 10 years. There have been very few meta-analyses or randomized clinical trials.     

Pregnancy and rheumatic disorders

Autoimmune rheumatic diseases commonly affect young women with child-bearing potential. It is important to know the impact of these diseases on pregnancy, and conversely the effect of pregnancy on these diseases, which may have important implications for mothers and neonates. Majority of studies suggest that pregnancy aggravates systemic lupus erythematosus (SLE) disease activity while ameliorating the symptoms of rheumatoid arthritis (RA). This contrasting finding between RA and SLE in pregnancy is postulated to be due to the differences in autoimmune response. There is a raised Th2 type response during pregnancy in comparison to the non-pregnant state, leading to the over expression of Th2 cytokines, such as IL-4 and IL-10. These cytokines are believed to increase the autoantibody response in SLE but to be immunosuppressive in RA. Studies suggest that patients of systemic sclerosis and mixed connective tissue disorder (MCTD) also have worsening of their underlying disorder while paucity of data precludes any solid conclusion regarding disease activity in patients of Sjogren's syndrome. Pregnancies in SLE, RA, systemic sclerosis (SSc) and MCTD patients are associated with a greater risk of relatively poor foetal outcome than in the general population, especially with increased disease activity before conception and early in pregnancy. This review provides an update regarding the effect of pregnancy on autoimmune rheumatic disorders and vice-versa.     

Risks to the children born to mothers with autoimmune diseases

This article reviews current information regarding the development and long-term effects on children born to women with connective tissue diseases. There are few data on specific effects attributed to the underlying maternal disease, but fetal growth restriction and preterm birth are relatively common. Antenatal use of prednisone as treatment for these disorders appears to be safe, and most children have developed normally. However, there is growing concern that prolonged fetal exposure to other glucocorticoids such as dexamethasone or betamethasone may lead to decreased growth and abnormal neuronal development. Low birth weight is reportedly associated with long-term medical complications such as adult-onset hypertension. Evidence also suggests that immunosuppressive agents taken during pregnancy might predispose the progeny to autoimmune disorders, malignancies and reproductive problems. Further research is warranted to determine that there are no unrecognized long-term risks to the offspring of these women.     

Connective tissue diseases and the liver

Connective tissue diseases such as systemic lupus erythematosus (SLE), rheumatoid arthritis, Sj?gren's syndrome, and scleroderma are systemic disorders that may have an autoimmune basis. The system manifestations vary, and there is frequent overlap among the syndromes. Liver involvement in patients with connective tissue diseases has been well documented but is generally considered rare. Although advanced liver disease with cirrhosis and liver failure is rare in patients with connective tissue diseases, clinical and biochemical evidence of associated liver abnormalities is common. Previous treatment with potentially hepatotoxic drugs or coincident viral hepatitis has usually been implicated as the main causes of liver disease in patients with connective tissue diseases. However, even after careful exclusion of these etiologies, the question remains whether to classify the patient as having a primary liver disease with associated autoimmune, clinical, and laboratory features or as having liver disease as a manifestation of generalized connective tissue disease. The main example of this pathogenetic dilemma is autoimmune hepatitis and SLE-associated hepatitis, which have been regarded as two different entities, although they have features in common of autoimmune syndromes. Several clinical and histopathologic features have been used to discriminate autoimmune hepatitis from SLE, a relevant diagnostic exercise because complications and therapy are quite different. Although hepatic steatosis and abnormal results on biochemical liver function tests are the most common hepatic abnormalities associated with connective tissue diseases, other less frequent abnormalities have been noted, such as nodular regenerative hyperplasia, portal vein obliteration and portal hypertension, features of primary biliary cirrhosis, and rarely portal fibrosis with abnormal lobular architecture. Vascular disorders of the liver also have been described, such as Budd-Chiari syndrome. Histologic assessment may reveal a variety of subclinical liver diseases. The aim of this contribution is to review the current published data regarding liver involvement in connective tissue diseases.     

Estimating the incidence of connective tissue diseases and vasculitides in a defined population in Northern Savo area in 2010

Objective of the study was to evaluate the annual incidence and distribution of autoimmune connective tissue diseases and vasculitides during 2010. All units practicing rheumatology in the Northern Savo area, Finland, participated in the study by collecting data on newly diagnosed adult patients with autoimmune connective tissue disease or vasculitis over 1-year period. Seventy-two cases with autoimmune connective tissue disease were identified. The annual incidence rates were as follows: systemic lupus erythematosus 3.4/100,000 (95 % CI 1.4–7.0), idiopathic inflammatory myopathies 1.9 (0.5–5.0), systemic sclerosis 4.4 (2.0–8.3), mixed connective tissue disease 1.0 (0.1–3.5), Sjögren’s syndrome 10.7 (6.7–16.1) and undifferentiated connective tissue disease 13.6 (9.0–19.6). The annual incidence rates among vasculitis category were as follows: antineutrophil cytoplasmic antibody-associated vasculitis 1.5/100,000 (95 % CI 0.3–4.3), central nervous system vasculitis 0.5 (0–2.7) and Henoch-Schönlein purpura 1.5 (0.3–4.3). The annual incidence of giant cell arteritis in the age group of 50 years or older was 7.5/100,000 (95 % CI 3.2–14.8). The longest delay from symptom onset to diagnosis occurred in systemic sclerosis. The incidences of autoimmune connective tissue diseases and vasculitides were comparable with those in published literature. The present study showed female predominance in all connective tissue diseases, excluding idiopathic inflammatory muscle diseases and mean age at onset of disease around 50 years of age. Despite improved diagnostic tools, diagnostic delay is long especially among patients with systemic sclerosis.     

Clinical Review 160: Postpartum autoimmune thyroid disease: the potential role of fetal microchimerism

Fetal microchimerism is defined as the presence of fetal cells in maternal tissues established during pregnancy. Immune suppression of maternal immunity during pregnancy by the placenta may play an important role in allowing the establishment of such fetal microchimerism. However, peripheral blood fetal microchimerism that persists in the postpartum period is considered a natural event and implies the induction of tolerance during pregnancy. Identification of fetal cells that persist preferentially in maternal tissues subject to autoimmunity, such as skin and thyroid, has also suggested the possible immune modulation of the autoimmune response at the target tissue by fetal cells. Accumulating evidence suggests that fetal immune cells may be reactive to maternal antigens and, therefore, have the capacity to trigger graft vs. host reactions. This would provide a mechanism for the initiation and/or exacerbation of autoimmune disease. The course and severity of autoimmune thyroid disease have long been known to be profoundly influenced by pregnancy, with disease suppression prepartum and exacerbation postpartum. However, the precise mechanisms involved have not been fully understood. Here we have reviewed recent information on the possible role of fetal microchimerism in autoimmune thyroid disease, focusing on the immunological consequences of intrathyroidal fetal cells and their contribution to postpartum exacerbations.     

Obstetric complications due to autoantibodies

Autoimmune diseases are most common and most active in young women; it is therefore not uncommon for obstetricians and physicians to encounter pregnant women with these conditions, and knowledge of the potential maternal, foetal and neonatal complications is essential for good clinical management. The most common maternal autoimmune endocrine conditions in pregnancy are insulin-dependent diabetes mellitus and thyroid disease. Other relatively common non-endocrine autoimmune conditions include systemic lupus erythematosus and anti-phospholipid syndrome. Much rarer autoimmune conditions include autoimmune thrombocytopenia, rheumatoid arthritis, myasthenia gravis and Addison's disease. In this chapter, we discuss autoimmune endocrine conditions and briefly mention some non-endocrine conditions of particular importance.     

Autoantibodies in connective tissue disease

Autoimmune connective tissue diseases are heterogeneous rheumatic diseases with the potential to affect multiple body systems. Autoantibodies are a characteristic feature of these diseases and are typically highly disease specific. In addition to aiding diagnosis, many autoantibodies have established associations with clinically important disease complications including internal organ involvement. In this chapter, we review the autoantibodies relevant to autoimmune connective tissue diseases, excluding systemic lupus erythematosus, with particular reference to the associated clinical features and how identification of such an autoantibody may inform prognosis and clinical management. We also discuss the practicalities of testing for autoantibodies along with potential difficulties and pitfalls.     

The influence of fetal loss on the presence of fetal cell microchimerism: a systematic review

OBJECTIVE: Fetal cells enter the maternal circulation during most pregnancies. Their persistence for years occurs in only some women and has been associated with several autoimmune diseases such as systemic sclerosis. The objective of this study was to determine whether pregnancy history influences the persistence of fetal microchimeric cells. METHODS: We reviewed all reports of studies on fetal cell microchimerism, defined as male DNA in maternal tissue, that describe individual pregnancy histories, disease diagnoses, and microchimerism status. The total numbers of pregnancies, births, and sons, the history of fetal loss (spontaneous abortion and elective termination), and the presence of a maternal autoimmune disease were tested as factors potentially associated with persistent microchimerism. RESULTS: One hundred twenty-four subjects from 11 studies met the inclusion criteria. Only fetal loss was significantly associated with the presence of microchimerism (odds ratio 2.4, 95% confidence interval 1.2-6.0). CONCLUSION: These results suggest that fetomaternal cell trafficking following fetal loss may be important for the engraftment of microchimeric cells in maternal tissue. This may be due to an increased amount of fetomaternal transfusion or to transfer of a cell type that is more likely to engraft. We recommend that investigators in future studies on microchimerism report detailed pregnancy information, since these data are critical for the understanding of factors that influence the development of fetal cell microchimerism.     

Management of pregnancy and lactation

Management of pregnancy in patients with rheumatic and musculoskeletal disorders is both challenging and rewarding. Most patients with rheumatic disease can have a successful pregnancy. Pregnancy outcome is improved when maternal autoimmune disease is stable or quiescent. Prepregnancy evaluation and counseling is important to identify risk factors for adverse maternal and pregnancy outcomes and to guide therapy and monitoring. Severe disease-related damage, disease activity, and the presence of antiphospholipid and anti-Ro/SS-A and La/SS-B antibodies may all impact prognosis. Knowledge of the safety of certain medications during pregnancy and lactation is still incomplete, but an increasing number of effective rheumatic disease medications can be used during these periods with low risk to maintain stable disease and to improve outcomes for mother and child.     

Two cases of reactive hemophagocytic syndrome: a patient with adult-onset Still's disease and a patient with herpes zoster and autoimmune abnormalities

We report two cases of bone marrow hemophagocytosis. One patient had adult-onset Still's disease, and the other had herpes zoster associated with potential autoimmune abnormalities. Our findings suggested a pos-sible role of cytokines and/or antibodies in the induction of hemophagocytosis in patients with connective tissue diseases and/or immune abnormalities. Received: November 28, 2000 / Accepted: March 12, 2001     

Pregnancy and liver disease

Liver disease has an impact on women's health during pregnancy because of the complex interactions between the physiologic changes induced by pregnancy and the pathophysiologic changes of liver disease. In particular, liver diseases that predominantly afflict females, such as primary biliary cirrhosis and autoimmune hepatitis, pose a special problem for conception and management of pregnancy. Pregnancy, moreover, specifically is associated with several potentially life-threatening liver diseases. This article reviews comprehensively the impact of liver diseases on pregnancy and of pregnancy on liver function and liver disease.     

Rheumatic diseases and pregnancy: a perspective

The interaction between certain rheumatic diseases, sex hormones and their wide fluctuation during pregnancy and postpartum may be responsible for the variable course of rheumatic diseases during pregnancy. Important issues include effects on the mother and fetus by the disease, pregnancy and maternal drug therapy.     

Drug exposure, pregnancy outcome and fetal and childhood development occurring in the offspring of mothers with systemic lupus erythematosus and other chronic autoimmune diseases

Most autoimmune diseases occur more commonly in females and many of these young women wish to become mothers. For pregnancy to proceed successfully immunomodulation and physiological changes preparing the reproductive system need to occur. Pregnancy occurring in a chronically ill mother who requires medications in order to maintain her own health and who may have already incurred significant organ pathology gives rise to several problems and so four questions arise: 1) What will be the effect of the pregnancy on the underlying disease? 2) What will be the effect of the disease on the outcome of pregnancy? 3) How to manage the disease, just prior to, throughout and immediately after the pregnancy? 4) The long term fetal and childhood effects of maternal disease and its management. This paper reviews the current literature pertaining to these questions in patients with systemic lupus erythematosus (SLE) and other chronic rheumatic and autoimmune diseases.