Rheumatology Advance Access originally published online on July 25, 2008
Rheumatology 2008 47(9):1439-1440; doi:10.1093/rheumatology/ken297
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Comment on: Intravenous immunoglobulin therapy in pregnant patients affected with systemic lupus erythematosus and recurrent spontaneous abortion: reply
1Rheumatology, Department of Internal Medicine, University of Rome Tor Vergata, 2Department of Gynaecology and Obstetrics, S. Giacomo Hospital, ASL RMA, Rome, 3Rheumatology, Department of Internal Medicine, University of L'Aquila, L'Aquila and 4Internal Medicine, Department of Internal Medicine, University of Rome Tor Vergata, Rome, Italy
Correspondence to: R. Perricone, Rheumatology, Department of Internal Medicine, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy. E-mail: roberto.perricone{at}uniroma2.it
The Letter to the Editor from Buyukhatipoglu et al [1] raises several interesting concerns regarding the high-dose Intravenous Immunoglobulin (IVIg) treatment in pregnant patients affected with SLE. Indeed, we agree when they state that rheumatologists have limited therapeutic options in SLE pregnancy due to complications in SLE itself, to the occurrence of recurrent spontaneous abortion (RSA) and to the small proportion of drugs that can be said to be safe in pregnancy. Therefore, in these patients the reported evidence on the use of IVIg is relevant allowing a rescue treatment in selected cases [2].
On the contrary, the statement that the use of IVIg in patients affected with APS due to the presence of aPLs and RSA associated or not with SLE does not produce significant benefit in the percentage of live births [3], needs further insight and discussion.
Differently from what is reported in the letter from Buyukhatipoglu et al [1], Spinnato et al [4] demonstrated the efficacy and safety of IVIg on a small series of APS patients. In this article, IVIg did not show any major side-effect, and patients experiencing severe RSA could safely carry on successful deliveries. Furthermore, Triolo et al [5] stated that in women with APS, as thrombosis does not seem to be the only putative cause, simple anti-coagulation could not be completely satisfactory and certain patient subgroups might take advantage of IVIg therapy alone or in combination with heparin.
Second, lack of homogeneity in the selection of the patients among papers can be a major problem in meta-analyses, which consider papers often lacking of data concerning either thyroid autoimmunity or NK cells.
Indeed, studies from our group demonstrated the critical role of the presence of thyroid autoimmunity (even in the absence of any overt thyroid dysfunction) in these patients [6]. Thyroid autoimmunity in APS-RSA reduces fecundity and fertility, and in turn the efficacy of IVIg treatment. IVIg improved in ‘aPLs alone’ RSA patients the percentage of successful pregnancies up to >90%, while was almost ineffective (60%) in those patients with both aPLs and thyroid autoimmunity [6]. This means that the accurate selection of the patients, excluding from IVIg treatment those who have thyroid autoimmunity, is critical, and no data are reported under this point of view in [3, 4] as well as in many other papers, while in ours thyroid autoimmunity was an exclusion criteria.
Another key point is the presence of high NK-cell levels in APS-RSA patients, as was recently demonstrated by us [7]. As it is well known, natural immunity seems to play an important role in spontaneous abortion [8], not only from a pathogenic point of view but also in terms of the therapeutic response to IVIg in pregnant patients [9]. Therefore, it is possible that in APS-RSA patients not only aPLs but also high NK-cell levels may play a role. Since high NK cells have also been demonstrated in the majority of patients affected with idiopathic RSA [8], the study of NK cells is important and should be suggested in all RSA patients including those with SLE and/or aPLs. Finally, Spinnato et al [4] also showed the overall reduction of aPLs levels after IVIg infusion, another mechanism by which IVIg may act.
It is possible, for the aforementioned reasons, that IVIg may better work on selected groups of pregnant patients, such as those who have RSA associated with high levels of NK cells, without thyroid autoimmunity, rather than working preferably on SLE and/or APS pregnancy. Whether IVIg may act via different mechanisms in these diseases is of interest, as it is discerning the different pathophysiological conditions underlying RSA occurrence in these diseases. For these reasons not only the usage of IVIg as a short-term adjunctive treatment and a useful steroid-sparing agent in SLE patients during pregnancy but also as a rescue treatment in APS patients might be suggested. In future, the usage of fractionated IVIg specific for respective anti-DNA or anti-β2 glycoprotein-I (β2GP-I) anti-idiotypic antibodies that may show specific activity for SLE and reproductive failure or APS patients when compared with the whole IVIg compound would be of interest [10].
Finally, one further consideration that we are all used to consider the success of pregnancy in terms of spontaneous abortion—no abortion. However, we must consider the overall beneficial effects of IVIg in terms of maternal and fetal outcome. We showed this dramatic reduction in lupus activity index in pregnancy (LAI-P) score in these SLE patients and optimal biophysical fetal parameters in these pregnancies, in a previous paper and we have already demonstrated the biophysical fetal parameters to be dramatically improved by IVIg treatment in APS pregnancies [11].
In conclusion, for the aforementioned considerations, it is evident that the whole problem raised by Buyukhatipoglu et al in their letter [1] can still be a matter of debate and further studies designed for an optimal patients’ selection are warranted.
Disclosure statement: The authors have declared no conflicts of interest.
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- Buyukhatipoglu H, Pehlivan Y, Onat AM. Comment on: Intravenous immunoglobulin therapy in pregnant patients affected with systemic lupus erythematosus and recurrent spontaneous abortion. Rheumatology (2008) in press.
- Perricone R, De Carolis C, Krögler B, et al. Intravenous immunoglobulin therapy in pregnant patients affected with systemic lupus erythematosus and recurrent spontaneous abortion. Rheumatology (2008) 47:646–51.
[Abstract/Free Full Text] - Triolo G, Ferrante A, Ciccia F, et al. Randomized study of subcutaneous low molecular weight heparin plus aspirin versus intravenous immunoglobulin in the treatment of recurrent foetal loss associated with antiphospolipid antibodies. Arthritis Rheum (2003) 48:728–31.[CrossRef][Web of Science][Medline]
- Spinnato JA, Clark AL, Pierangeli SS, Harris EN. Intravenous immunoglobulin therapy for the antiphospolipid syndrome in pregnancy. Am J Obstet Gynecol (1995) 172:690–4.[CrossRef][Web of Science][Medline]
- Triolo G, Ferrante A, Accardo-Palumbo A, et al. IVIG in APS pregnancy. Lupus (2004) 13:731–5.
[Abstract/Free Full Text] - De Carolis C, Greco E, Guarino MD, et al. Anti-thyroid antibodies and antiphospholipid syndrome: evidence of reduced fecundity and of poor pregnancy outcome in recurrent spontaneous aborters. Am J Reprod Immunol (2004) 52:263–6.[CrossRef][Medline]
- Perricone C, De Carolis C, Giacomelli R, et al. High levels of NK cells in the peripheral blood of patients affected with anti-phospholipid syndrome and recurrent spontaneous abortion: a potential new hypothesis. Rheumatology (2007) 46:1574–8.
[Abstract/Free Full Text] - Perricone R, Di Muzio G, Perricone C, et al. High levels of peripheral blood NK cells in women suffering from recurrent spontaneous abortion are reverted from high-dose intravenous immunoglobulins. Am J Reprod Immunol (2006) 55:232–9.[Medline]
- Perricone R, Perricone C, De Carolis C, Shoenfeld Y. NK cells in autoimmunity: a two-edg'd weapon of the immune system. Autoimmun Rev (2008) 7:384–90.[CrossRef][Web of Science][Medline]
- Shoenfeld Y, Rauova L, Gilburd B, et al. Efficacy of IVIG affinity-purified anti-double-stranded DNA anti-idiotypic antibodies in the treatment of an experimental murine model of systemic lupus erythematosus. Int Immunol (2002) 14:1303–11.
[Abstract/Free Full Text] - Valensise H, Vaquero E, De Carolis C, et al. Normal foetal growth in women with antiphospholipid syndrome treated with high-dose intravenous immunoglobulin (IVIG). Prenat Diagn (1995) 15:509–17.[Web of Science][Medline]
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