Mechanisms determining the amelioration of rheumatoid arthritis in pregnancy: A systematic review

The phenomenon of pregnancy-induced remission of rheumatoid arthritis (RA) was first reported by Philip Hench in 1938. Despite extensive efforts, the underlying scientific basis has remained elusive. A number of different potential mechanisms have been investigated. We have undertaken a systematic review of the available peer-reviewed articles involving pregnant patients with RA in order to establish the depth of current scientific understanding of this important topic.

This review was conducted according to guidelines of preferred reporting items for systematic reviews and meta-analyses. Studies were identified by a thorough search of multiple databases including Medline, PubMed and EMBASE. Search terms used were different combinations of the keywords: rheumatoid arthritis, inflammatory arthritis, pregnancy, mechanisms, disease activity, relapse and remission. Non-English language articles and studies that were not directly relevant were excluded. Two independent reviewers (CR and KA) screened the retrieved articles by reading the title and abstract to identify studies that addressed potential mechanisms determining RA activity in pregnancy. Articles were further refined after reading the full text. A data extraction sheet was developed for the purpose of this review and used by the independent reviewers.

After exclusion of irrelevant, duplicate and foreign language articles, a final total of 37 original articles were identified. The largest body of literature concerned glycosylation of immunoglobulins, with 9 published articles. There is evidence of an association between increasing levels of galactosylation of immunoglobulins and reduced RA disease activity in pregnancy. Other identified articles comprised 5 on cytokine changes in pregnancy, 5 on human leucocyte antigen (HLA) incompatibility, 5 on changes in peripheral blood mononuclear cell (PBMC) gene expression; 4 on changes in corticosteroids; 3 on pregnancy associated α2-glycoprotein; 2 on changes in rheumatoid factor (RF)/anti-citrullinated protein antibody (ACPA); and 1 each on microchimerism, gamma delta T cells, regulatory T cells, and mannose-binding lectin. The results of these studies were heterogenous and occasionally conflicting. Selected studies varied greatly in terms of population size, methodology and use of controls and disease activity assessments.

This systematic review has found that the cause of the pregnancy-induced amelioration of RA remains to be determined, despite extensive efforts. It is unclear which of the various transitory changes in pregnancy may be responsible for initiating downstream anti-inflammatory immunological mechanisms. We discuss limitations of the current literature and suggest areas for future study.