Pre-disease pregnancy complications and systemic sclerosis: pathogenic or pre-clinical?

The fetal microchimerism theory for the pathogenesis of systemic sclerosis (SSc) has compelling biologic support, including the female predominance of the disease, the mean age of onset after childbearing years, similarities between diffuse cutaneous SSc and graft-versus-host disease, as well as the detection of microchimeric cells in peripheral blood and skin of SSc patients. The previous issue of Arthritis Research and Therapy presents findings of a positive association between pregnancy complications and future diagnosis of SSc in parous women. Before interpreting the results of this epidemiologic study as support for fetal microchimerism, however, other theories for the observed associations must be considered.

Akin to many autoimmune diseases with a strong female predominance, relationships between pre-disease pregnan cies and subsequent development of systemic sclerosis (SSc) have been the source of a great deal of study, often with confl icting results.
Fetal microchimerism -the bidirectional transfer of cells between mother and fetus during gestation and delivery, followed by perpetuation of small amounts of foreign cells or DNA in the host for years or decades, potentially leading to a graft-versus-host-like eff ect -has been implicated in the pathogenesis of SSc based upon epidemiologic and immunological studies. While the fetal micro chimerism theory of SSc carries compelling biologic plausibility given the clinical resemblance of diff use cutaneous SSc and graft-versus-host disease, as well as the increased presence of fetal cells in women with SSc, purely epidemiologic studies without translational, immuno logical, or cellular correlates cannot directly support a causal association. Th e current study by van Wyk and colleagues is an excellent example of a well-performed epidemiologic study identifying a positive association between pregnancy complications (hypertensive disorders of pregnancy (HTN) and intrauterine growth restriction (IUGR)) prior to diagnosis and the future development of SSc [1]. Th e authors conducted a case-control study of parous women with SSc compared with healthy women. Repro ductive history was obtained through questionnaires. Th e mean age at enrollment was 57 years, approximately 30 years after the fi rst pregnancy for both groups. Results showed a statistically signifi cant increase of HTN as well as IUGR among women who later developed SSc. Notably, the rates of HTN and IUGR among women in this study who were later diagnosed with SSc were not demonstrably diff erent from the rates reported for women with preexisting SSc (22.9% HTN [2] and 5 to 20% IUGR [2,3]).
Despite the merits of this study, it remains diffi cult to interpret the results as directly supportive of fetal microchimerism. Certainly, many pregnancy complica tions increase maternal-fetal cellular traffi cking. However, maternal-fetal cellular transfer is seen in almost all pregnancies, and is increased in other pregnancy disorders not reported in this study including preterm labor and pregnancy termination [4]. Other modes of microchimerism, including blood transfusions, are not assessed in the study. What perhaps may be more relevant to understanding the relationship between prior pregnancy complications and future diagnosis of SSc is to uncover whether fetal cells are perpetuated in maternal blood and tissues and to identify activation markers on fetal cells that may contribute to disease-related infl amma tion and fi brosis. Mere transfer of fetal cells is probably not enough; and mechanisms of perpetuation and activation of fetal cells in maternal tissue may be entirely independent of the amount of cellular transfer during pregnancy [5].
When thinking about the pathogenesis of SSc, it has becoming increasingly clear that combining both limited and diff use forms together may obscure important associations -the clinical manifestations, autoantibody profi le and natural history are quite diff erent between the two

Abstract
The fetal microchimerism theory for the pathogenesis of systemic sclerosis (SSc) has compelling biologic support, including the female predominance of the disease, the mean age of onset after childbearing years, similarities between diff use cutaneous SSc and graft-versus-host disease, as well as the detection of microchimeric cells in peripheral blood and skin of SSc patients. The previous issue of Arthritis Research and Therapy presents fi ndings of a positive association between pregnancy complications and future diagnosis of SSc in parous women. Before interpreting the results of this epidemiologic study as support for fetal microchimerism, however, other theories for the observed associations must be considered.
subtypes. Limited cutaneous SSc is characterized by a more prominent vasculopathy with less cutaneous fi brosis, is associated with anti-centromere antibodies, and generally has a prolonged clinical course prior to diagnosis. In contrast, diff use cutaneous SSc more closely resembles graft-versus-host disease, has more prominent cutaneous and organ fi brosis, is associated with antitopoisomerase I antibodies, and has a shorter period between symptom onset and diagnosis [6]. Fetal microchimerism may therefore not play the same role in the development of diff erent subsets of SSc. Indeed, a recent study of women with SSc found that male microchimeric cells were contained in diff erent maternal peripheral blood compartments in limited cutaneous SSc (whole blood) compared with diff use cutaneous SSc (peripheral blood mononuclear cells) [7]. Th is study also found associations between maternal-fetal HLA-DRB1 compatibility only in the limited cutaneous SSc subset compared with controls: no asso ciations were seen among women with diff use cutaneous SSc; and no signifi cant diff erences were seen when diff use cutaneous SSc patients and limited cutaneous SSc patients were combined [7]. van Wyk and colleagues' study did not separate women with limited and diff use cutaneous SSc, raising the potential that even stronger associations may be seen between prior pregnancy events and future development of disease in a particular subset that may either strengthen or diminish the possibility of fetal microchimerism as a potential etiologic factor.
Even purely epidemiologic studies of SSc have yielded confl icting data regarding associations between development of disease and previous pregnancies. Some studies fi nd an independent association between parity and later development of SSc [8], while others fi nd the greatest risk of SSc to be in nulliparous women [9]. Other studies have found that nulliparous women developed SSc approximately 10 years earlier than parous women (32 vs. 45.7 years) and were more likely to have diff use cutaneous disease with internal organ involvement [10].
Associations between previous pregnancies and future development of SSc thus remain puzzling. While fetal microchimerism may indeed play a role in the development of some cases of SSc, alternative biologic theories to explain the associations seen in van Wyk and colleagues' study must also be considered.
An entirely separate theory for these fi ndings posits that pregnancy complications, particularly vascular complications including hypertension and IUGR, may be a manifestation of very early, pre-clinical manifestations of SSc in otherwise healthy women. Th e data provided in this study showing a prolonged time between fi rst pregnancy and diagnosis of SSc of nearly 30 years may argue against this theory; however, the age of onset of Raynaud's phenomenon or the fi rst non-Raynaud's manifestation is not reported in the study, nor is the age of SSc diagnosis ascertained for 40% of respondents. Similarly, maternal age at last pregnancy is not reported, so the time from fi nal fetal-to-maternal traffi cking to onset of symptoms cannot be estimated. It is well known that, particularly for limited cutaneous SSc, diagnosis occurs years to decades after onset of Raynaud's phenomenon. Th e increased blood volume and other cardiopulmonary changes of pregnancy may possibly also lead to vascular compromise in pre-clinical phases of systemic vasculopathy that would otherwise remain asymptomatic for many years.