Intravenous immunoglobulins and antiphospholipid syndrome: How ...

AUTREV-01787; No of Pages 10 Autoimmunity Reviews xxx (2015) xxx–xxx

Contents lists available at ScienceDirect

Autoimmunity Reviews journal homepage: www.elsevier.com/locate/autrev

Review

Intravenous immunoglobulins and antiphospholipid syndrome: How, when and why? A review of the literature Sara Tenti, Sara Cheleschi, Giacomo Maria Guidelli, Mauro Galeazzi, Antonella Fioravanti ⁎ Rheumatology Unit, Policlinico “Le Scotte”, Department of Medicine, Surgery and Neurosciences, University of Siena, Italy

a r t i c l e

i n f o

a b s t r a c t

Article history: Received 3 November 2015 Accepted 19 November 2015 Available online xxxx

The antiphospholipid syndrome (APS) is defined by the occurrence of venous and arterial thromboses and recurrent fetal losses, frequently accompanied by a moderate thrombocytopenia, in the presence of antiphospholipid antibodies (aPL), namely lupus anticoagulant (LA), anticardiolipin antibodies (aCL), or anti-β2 glycoprotein-I (β2GPI) antibodies. The current mainstay of treatment for thrombotic APS is heparin followed by long-term anticoagulation, while in obstetric APS, the accepted first-line treatment consists in low-dose aspirin (LDA) plus prophylactic unfractionated or low-molecular-weight heparin (LMWH). Recently, new emerging treatment modalities, including intravenous immunoglobulins (IVIG), have been implemented to manage APS refractory to conventional therapy. The objective of this review is to summarize the currently available information on the IVIG therapy in APS, focusing on the use of IVIG in the obstetric form, CAPS and on primary or secondary thromboprophylaxis. We analyzed 35 studies, reporting the effects of IVIG in APS patients, and we discussed their results. IVIG in obstetric APS seem to be very useful in selected situations (patients not responsive to the conventional treatment, concomitant autoimmune manifestations or infections or patients in whom anticoagulation is contraindicated). IVIG treatment represents an important component of the combination therapy of CAPS and they could be useful, in addition to the standard therapy, to prevent recurrent thrombosis in APS patients refractory to conventional anticoagulant treatment. Anyway, in some cases we also found controversial results that claim the need of further well-designed studies to definitely state the efficacy and tolerability of IVIG in CAPS, obstetric and non-APS. © 2015 Elsevier B.V. All rights reserved.

Keywords: Intravenous immunoglobulin Antiphospholipid syndrome Obstetric antiphospholipid syndrome Catastrophic antiphospholipid syndrome Prevention of thromboses

Contents 1. Introduction . . . . . . . . . . . . . 2. Methods . . . . . . . . . . . . . . 3. Results . . . . . . . . . . . . . . . 4. IVIG in Obstetric APS . . . . . . . . . 5. IVIG in catastrophic APS . . . . . . . 6. IVIG in preventing recurrent thrombosis 7. Discussion . . . . . . . . . . . . . . 8. Conclusions . . . . . . . . . . . . . Competing interests . . . . . . . . . . . . Take-home messages . . . . . . . . . . . References . . . . . . . . . . . . . . . .

. . . . . . . . . . .

. . . . . . . . . . .

. . . . . . . . . . .

. . . . . . . . . . .

. . . . . . . . . . .

. . . . . . . . . . .

. . . . . . . . . . .

. . . . . . . . . . .

. . . . . . . . . . .

. . . . . . . . . . .

. . . . . . . . . . .

. . . . . . . . . . .

. . . . . . . . . . .

. . . . . . . . . . .

1. Introduction The antiphospholipid syndrome (APS) is defined by the occurrence of venous and arterial thromboses, often multiple, and recurrent fetal ⁎ Corresponding author at: Rheumatology Unit, Department of Medicine, Surgery and Neurosciences, Policlinico “Le Scotte”, Viale Bracci, 1, 53100 Siena, Italy. Tel.: +39 0577 233345; fax: +39 0577 40450. E-mail address: fi[email protected] (A. Fioravanti).

. . . . . . . . . . .

. . . . . . . . . . .

. . . . . . . . . . .

. . . . . . . . . . .

. . . . . . . . . . .

. . . . . . . . . . .

. . . . . . . . . . .

. . . . . . . . . . .

. . . . . . . . . . .

. . . . . . . . . . .

. . . . . . . . . . .

. . . . . . . . . . .

. . . . . . . . . . .

. . . . . . . . . . .

. . . . . . . . . . .

. . . . . . . . . . .

. . . . . . . . . . .

. . . . . . . . . . .

. . . . . . . . . . .

. . . . . . . . . . .

. . . . . . . . . . .

. . . . . . . . . . .

. . . . . . . . . . .

. . . . . . . . . . .

. . . . . . . . . . .

. . . . . . . . . . .

. . . . . . . . . . .

. . . . . . . . . . .

. . . . . . . . . . .

. . . . . . . . . . .

. . . . . . . . . . .

. . . . . . . . . . .

. . . . . . . . . . .

. . . . . . . . . . .

. . . . . . . . . . .

. . . . . . . . . . .

0 0 0 0 0 0 0 0 0 0 0

losses, frequently accompanied by a moderate thrombocytopenia, in the presence of antiphospholipid antibodies (aPL), namely lupus anticoagulant (LA), anticardiolipin antibodies (aCL), or anti-β2 glycoprotein-I (β2GPI) antibodies [1]. Preliminary classification criteria (Sapporo criteria) were developed in the 1999 international consensus meeting and updated in 2006 [2]. APS can occur either as a primary condition (primary APS) or in association with other autoimmune diseases, usually systemic lupus erythematosus (SLE) [3]. Also, a rare and severe subset

http://dx.doi.org/10.1016/j.autrev.2015.11.009 1568-9972/© 2015 Elsevier B.V. All rights reserved.

Please cite this article as: Tenti S, et al, Intravenous immunoglobulins and antiphospholipid syndrome: How, when and why? A review of the literature, Autoimmun Rev (2015), http://dx.doi.org/10.1016/j.autrev.2015.11.009

2

S. Tenti et al. / Autoimmunity Reviews xxx (2015) xxx–xxx

of APS, defined catastrophic APS (CAPS), has been described and it's characterized by multiorgan failure originated by widespread thrombotic disease, which usually affects small vessels over a short period of time and is associated with high mortality rates [4]. APS is recognized as the most common cause of acquired thrombophilia in the general population; some estimates indicate that the incidence of the APS is around 5 new cases per 100,000 persons per year and the prevalence around 40–50 cases per 100,000 persons [5]. There is a wide spectrum of clinical manifestations in APS that ranged from non-criteria aPL manifestations in persistent aPL-positive patients (livedo reticularis, thrombocytopenia, hemolytic anemia, skin ulcers, aPL-associated nephropathy, and heart valve disease), to APS with only pregnancy morbidity, APS with vascular events, and to life-threatening CAPS. Considering the heterogeneity of APS clinical manifestations, it's likely that more than one pathological process may play a role [6]. Despite the exact pathogenetic mechanisms have not been fully elucidated, aPL seem to promote the activation of the endothelial cells, monocytes and platelets, leading to a procoagulant state. Furthermore, aPL could act through anticoagulation factor inactivation and activation of the complement cascade [7]. The current mainstay of treatment for thrombotic APS is heparin followed by long-term anticoagulation with vitamin K antagonists, which is problematic because of numerous drug and food interactions that necessitate frequent monitoring; furthermore, anticoagulation is not effective for all aPL manifestations [8]. In obstetric APS, the accepted first-line treatment consists in low-dose aspirin (LDA) plus prophylactic unfractionated or low-molecular-weight heparin (LMWH). However, a sufficient control of the activity disease is actually not achieved in approximately 20% of pregnant APS patients [9]. Recent studies, based on newly understood mechanisms, suggest new treatments for aPL-positive patients that target new coagulation and immunomodulatory pathways. Furthermore, new emerging treatment modalities, such as hydroxychloroquine (HCQ), statins, rituximab, eculizumab and intravenous immunoglobulins (IVIG), have been implemented to manage APS refractory to conventional therapy [8]. IVIG are blood products prepared from the serum of a large number of donors and they are currently used to treat a wide variety of immune-driven diseases, such as immune thrombocytopenic purpura, Guillain–Barré syndrome, Kawasaki disease and polymyositis/dermatomyositis [10]. Data on the use of IVIG in patients with APS focused on the obstetric complications and on CAPS, while only few reports showed the efficacy of IVIG as an adjuvant to conventional therapy in primary and secondary APS [11]. The objective of this review is to summarize the currently available information on the IVIG therapy in APS, focusing on the use of IVIG in the obstetric form, CAPS and on primary or secondary thromboprophylaxis. We also discuss the protocols therapy adopted in the different studies, the tolerability and the possible mechanisms of action.

IVIG in preventing thrombosis relapses in APS patients. We applied no date restrictions, so the period examined was 1990 (year of the first publication in this field) — October 2015 (date of our search). Articles written in languages other than English were excluded. 3. Results In total, 235 potential studies were found; no additional papers were obtained by hand searching of references. Of these, 37 studies were excluded because they were written in a language other than English. Based on the title and the abstract content, 79 of these articles were not included in our review. The full texts of the remaining 119 studies were read, and a further 66 studies were excluded because review articles and 13 because not clinical trials (Fig. 1). We identified 35 assessable articles, 14 case reports, 9 case series and 12 clinical trials (9 open-label, 3 randomized controlled), reporting the effects of IVIG in APS patients, including a total number of patients of 802 (Tables 1, 2, 3, 4, 5). The 99% of the participants in the studies were women (795 women and 7 men). 4. IVIG in Obstetric APS Most of the reports about the use of IVIG in human APS focused on its obstetric complications, mainly recurrent pregnancy loss. The first description of a case of obstetric APS patient treated with IVIG was that by Carreras et al. in 1988 [12]. The authors presented the story of a pregnant 28-years-old woman who had had nine early spontaneous abortions, two intrauterine deaths and a perinatal death at 26 weeks.

2. Methods We conducted a review of the literature concerning clinical studies about IVIG therapy in APS in October 2015. First of all, the strategy to select the clinical studies consisted in a detailed search in scientific databases Pubmed, Scopus, Cochrane Library and EMBASE. The keywords were “intravenous immunoglobulin”, “intravenous immunoglobulin therapy” in combination with “antiphospholipid syndrome”, “antiphospholipid antibodies”, “recurrent miscarriage”, “recurrent pregnancy loss”, “catastrophic APS” and “thrombotic events”. Studies were considered eligible if they met the following criteria: (i) patients had a diagnosis of APS, according to the 2006 updated APS criteria [2]; (ii) original articles or case reports whose main objectives were to analyze the effect and tolerability of IVIG therapy in patients with obstetric APS; (iii) original articles or case reports that evaluated the effects of IVIG in CAPS; (iv) original articles or case reports about the efficacy of

Fig. 1. Study flow diagram.


References

Obstetric clinical reports

Autoantibodies profile

LA Carreras et al. 1988 [12] 28-year-old pt with 9 precedent early spontaneous abortions, 2 intrauterine deaths and 1 perinatal death at 26 weeks Scott et al. 1988 [13]

Parke et al. 1989 [14]

Wapner et al. 1989 [15]

Ron-El et al. 1993 [16]

Arnout et al. 1994 [17]

Somerset et al. 1998 [18]

Chang et al. 2006 [19]

aCL (IgG and IgM) 23-year-old pt with 9 previous fetal death (from 9 to 17 weeks of gestation) and 2 episodes of thrombophlebitis 29-year-old pt with 5 spontaneous abortions LA and aCL and a precedent pre-eclamptic gestation

Pt 1: 29-year-old with 4 previous pregnancy losses Pt 2: 35-year-old with 4 previous fetal losses and a gestation complicated with pre-eclampsia 31-year-old pt with 4 fetal pregnancy losses (after in vitro fertilization and embryo replacement treatment IVF-ET after 3 cycles) 38-year-old pt with 6 spontaneous abortions (from 12 to 23 weeks of gestation) and 2 episodes of deep venous thrombosis 31-year-old pt with 2 first and 2 second trimester miscarriages and a first trimester termination of pregnancy 35-year-old pts with 4 previous pregnancy losses

Pt 1: LA and aPL IgM Pt 2: positive for LA and aPL IgG and IgM

LA and aCL IgG

LA and aCL IgG

aCL and LA

aCL IgG

Stojanovich et al. 2007 [20]

34-year-old pts with 1 perinatal death (8-days old) after caesarian section, at 27

Mar et al. 2014 [21]

weeks of gestation, because of the progressive thrombocytopenia and fetal distress LA, aCL IgG, β2 GP1 36-year-old pts with right leg deep venous IgG thrombosis and a massive pulmonary embolism, fetal demise at first trimester after liver, pancreatic and ovarian infarctions

LA, aCL, aDNA, anti-RO/SSA, antiβ2 GP1

IVIG protocol

Concomitant therapy

Main findings

400 mg/kg/day for 5 days at week 17 followed by 2-day courses at 22 and 27

Bethametasone from week 31

At week 34 a healthy girl was delivered by caesarean section

weeks of gestation 400 mg/kg/day for 5 days at week 8 and 14

LDA (80 mg/day) and prednisone (60 mg/day) At week 30 a healthy male was delivered by caesarean section with no postpartum or neonatal complications s.c. heparin (5000 units twice/day) and LDA At week 36 a healthy male was delivered, (80 mg/day) but LA was again detected and the aCL levels remained elevated

−300 mg/kg/month for 6 months (before conception) -4-day induction of 400 mg/kg/day (after conception) continued at 600 mg/day/month Pts 1: 1 g/kg/month from week 9 to week 34 Pt 1: LDA (80 mg/day) and heparin every 12 h Pts 2: 1 g/kg/month from week 10 to 33 Pt 2: LDA (80 mg/day) and low-dose heparin

Pt 1: At week 40 a healthy female was delivered without complications Pt 2: At week 37 labor was induced and a healthy male was delivered

−400 mg/Kg/day for 4 days (prior to the embryo transfer) 400 mg/Kg/month (during the pregnancy) 400 mg/Kg for 5 days with a four-week interval (during the pregnancy for 6 months)

LDA (100 mg/day) and s.c. heparin (5000 units) twice/day from week 8

−1 g/Kg/month until week 19 1 g/Kg every 2 week from week 20 to week 22 1 g/Kg every week from week 23 to the end of the pregnancy 5 g/Kg/month for nine times during the pregnancy

Unfractioned heparin (5000 units/12 h until week 11; 7500 units/12 h from week 12 to week 18; 15000 units/12 h from week 19 to the end of pregnancy)

At week 32 a healthy female was delivered by caesarian section

LMWH (0,6 mg/day) and aspirin (100

At week 37 a healthy female was delivered by caesarian section

0,5 mg/Kg/month from week 8 (7 total doses)

s.c. enoxaparin, LDA and HCQ (400 mg/day)

At week 35 a healthy male was delivered without complications

LMWH (15000 units/day) and LDA (60 mg/day) At week 31 a healthy female, with bradycardia, was delivered by caesarian section because of a placental abruption 500 mg/Kg/day for 4 days at week 23 and 27 LDA (75 mg/day), folic acid and unfractioned At week 31 a healthy female was delivered s.c. heparin (7500 units twice daily) by caesarian section

mg/day). Dexamethasone (1,5–2,5 mg/day) from week 13 to week 36



Table 1 Different case reports that investigate the effect and tolerability of IVIG therapy in patients with obstetric APS.

At week a healthy male 37 was delivered by caesarian section without complications

Abbreviations: IVIG = intravenous immunoglobulins; pt = patient; LA = lupus anticoagulant; ANA = antinuclear antibodies; aCL = anticardiolipin antibodies; LDA = low-dose aspirin; IVF-ET = in vitro fertilization and embryo replacement treatment; LMWH = low-molecular-weight heparin; aDNA = anti-DNA; β2GP1 = beta-2 glycoprotein 1.

3

4

IVIG protocol

Autoantibodies profile Concomitant therapy

Main findings

1/3 3/3 (total no of events = 2) (total no of events = 10)

1 g/Kg/month

LA and aCL IgG

Case 1e 3: LDA (75 mg/day) Case 2: LDA (75 mg/day) and labetolol from week 25

5

0/5

400 mg/Kg/day for 3 days and repeated monthly up to week 34

aPL (not better specified)

ASA (80 mg/day), heparin (5000 units/day until week 34), prednisone (5 mg twice/day) (then increased to 10 mg) from 48 h after ovulation

Spinnato et al. 1995 [24]

5


400 mg/Kg/day for 5 days each month


4 patients received LDA (81 mg/day) and s.c. heparin (5000–7000 units/twice day) (1 patient was allergic)

Carp et al. 1996 [25]

12

Not reported

10/12 (total no of events = 68)

400 mg/Kg before pregnancy and when pregnancy was diagnosed


Not reported

Valensise et al. 1995 14 [26]

Not reported


500 mg/Kg/day for 2 days every month from week 5 to week 33

LA and aCL IgG and IgM Not reported

Clark et al. 1999 [27]

15


400 mg/Kg/day for 5 days or 1

LA and aCL IgG

LDA (81 mg/day, in 18 pregnancies), s.c. heparin (5000 to 10000 units/twice day in 15 pregnancies) and prednisone (6 pts)

Watanabe et al. 2014 [28]

3


400 mg/Kg/day for 5 days from week 6–7

LA, aCL and anti-β2GPI

Continuosunfractionated heparin injection (0,2 u/ml) from 4 gestation weeks, LDA and prednisone (10–20

Case 1 e 3: at week 36 a healthy child was delivered Case 2: at week 34 a female was delivered by caesarean section after diagnosis of pre-eclampsia 6 pregnancies were reported: 3 developed IUGR and 3 had complicated twin pregnancies. Suppression of the titer of IgG and IgM aPL was observed after each IVIG infusion 5 healthy infants were delivered at term without IUGR, except for 1 patient who was delivered at week 32 because of decreased fetal distress. Decreases of aCL were observed in 3 patients 10 patients conceived, 5 had subsequent live births. 2 infant were premature but their size was appropriate for gestational age, the other three delivered at term One patient developed gestational hypertension and abruptio placentae. No fetal or neonatal growth retardation were observed 16 of the 19 pregnancies resulted in a live birth. No cases of fetal growth restriction. Pre-eclampsia and fetal status were diagnosed in 25% of pregnancies. 75% of infants were delivered at week 34 of gestation or later. aCL IgG decreased in 7 pregnancies All patients achieved live births (case 2 ended in preterm delivery at week 32). No thrombotic or bleeding complications were observed

References

N° of pts

N° of pts with previous thrombotic events

Kaaja et al. 1993 [22]

3

Kwak et al. 1995 [23]

N° of pts with previous miscarriages


g/Kg/day for 2 days each month in first or early second trimester (13 pts), or started at week 21 (1 pt), or only 2 days courses (1 pt)

mg/day) (from diagnosis of pregnancy)

Abbreviations: pts = patients; IVIG = intravenous immunoglobulins; LA = lupus anticoagulant; aCL = anticardiolipin antibodies; LDA = low-dose aspirin; aPL = antiphospholipid antibodies; ASA = acetylsalicylic acid; IUGR = intrauterine growth retardation; β2GP1 = beta-2 glycoprotein 1.



Table 2 Different case series that investigate the effect and tolerability of IVIG therapy in patients with obstetric APS.

References

Trial design

N° of pts

N° of pts with previous miscarriages


Treatment during the course of pregnancy

Main findings

Marzusch et al. 1996 [29]

Pilot study

38


Not better specified

IVIG: 300 mg/Kg three-weekly intervals until week 16–17

Sher et al. 1998 [30]

Multicentercase-control study

121



Branch et al. 2000 [31]

Multicenter, randomized, double-blind placebo controlled pilot trial

16 Group I: 7 pts Group II: 9 pts


aCL IgG and LA

IVIG: 20 mg/Kg 7–10 days prior to embryo transfer + LDA (81 mg/day) and s.c. heparin (5000 units/twice day) starting on day 2 of controlled ovarian hyperstimulation Group I: LDA (81 mg/day) and unfractionated s.c. heparin (7500 units) every 12 h increased to 10000 units/12 h in the second trimester +

Pregnancy proceeded beyond the first trimester in 34 pts; 31 pts gave birth to healthy infants at 37 to 42 weeks' gestation In the patients with aPL directed specifically towards PS and PE, the addition of IVIG to the therapy with LDA and heparin improved the IVF birth rate All women delivered of live-born infants after 32 weeks' gestation. No reduction of obstetric/neonatal complications after IVIG therapy (only fewer cases of fetal growth restriction and neonatal intensive care)

Prospective 2-centers trial study


82/82

Vaquero et al. 2001 [32]

LA or aPL IgG and IgM or both

Diejomaoh et al. 2002 [33]

Prospective study

43

43/43

LA (9 pts) or aCL (23 pts) or both (11 pts)

Triolo et al. 2003 [34]

RCT


40/40

aCL (40 pts) and LA (27 pts)

Jeremic et al. 2005 [35]

Prospective observational study


40/40

aPL IgG and IgM (not better specified)

Dendrinos et al. 2009 [36]

Prospective multicenter trial


78/78

aCL IgG and/or IgM and LA

Heilmann et al. 2008 [37]

Retrospective study


119/121

aCL IgG and/or IgM or LA or aβ2GPI

Xiao et al. 2013 [38]

Clinical randomized comparative study


129/129

aCL IgG and/or IgM or LA or aβ2GPI

IVIG: 1 g/Kg/day for 2 days every month through 36 weeks of gestation Group II: LDA and heparin as above + placebo Group I: Prednisone (15–20 mg/day) until week 28; from week 32, prednisone (15–20 mg) + LDA (100 mg/day) Group II: IVIG: 500 mg/Kg/days for 2 days, once a month until week 32 All patients received LDA (100 mg/day) and s.c. heparin (5000 units every 12 h) until week 34 and 37 respectively and 7 of them also IVIG: 500 mg/kg/month from week 10 until week 34 Group I: IVIG (400 mg/kg/day) for 2 days followed by a single dose monthly until week 31 Group II: LMWH (5700 units/day) and LDA (75 mg/day) until week 37 and 34 respectively Group I: LDA (100 mg/day) + LMWH (0.3 units) at 12 h Group II: IVIG (10 g/Kg/month) until week 34 + LDA and LMWH as above Group I: LMWH (4500 units/day) and LDA (75 mg/day) until week 38 and 32 respectively Group II: IVIG (400 mg/Kg/month) until week 32 Group I: LMWH (3000–5000 units/day) and LDA (100 mg/day) Group II: LMWH and LDA as above + IVIG (200 mg/Kg/month) until week 30–32 Group I: Prednisone (5 mg/3 times day) and LDA (50 mg/day) Group II: prednisone and LDA as above + IVIG (10 g/Kg/day for 5 days in a month) followed by 2/3 other courses + LMWH (5000 units/day)

IVIG therapy improved pregnancy outcome (with significantly lower complication rates) if compared with prednisone + LDA therapy

IVIG added to the standard therapy resulted in 100% live births

Treatment with LMWH + LDA increased the rate of live births than the treatment with IVIG

No significant difference in pregnancy outcomes between the 2 groups.



Table 3 Several studies (observational and randomized trials) which described the IVIG therapy in patients with obstetric APS.

Treatment with LMWH + LDA increased the rate of live births than the treatment with IVIG Treatment with IVIG decreased pregnancy complications but no differences in the abortion rate Treatment with prednisone + LDA + LMWH + IVIG improved the live birth rate and reduced obstetric complications

Abbreviations: pts = patients; IVIG = intravenous immunoglobulins; LDA = low-dose aspirin; aPL = antiphospholipid antibodies; PS = phosphatidylserine; PE = phosphatidylethanolamine; IVF = in vitro fertilization; aCL = anticardiolipin antibodies; LA = lupus anticoagulant; LMWH = low-molecular-weight heparin; β2GP1 = beta-2 glycoprotein 1.

5

6


Table 4 Case reports/series that support the “triple therapy” in CAPS patients. Main findings

References

N° of pts


Precipitating events of CAPS

Treatment during the acute event

Koschmieder et al. 2003 [43]

1

aCL IgG and IgM, antiβ2GPI, LA

Despite full-dose of anticoagulation: –myocardial infarction –ARDS—purulent bronchitis –septic shock –thromboembolism of the right food and skin marmoration of her extremities Pt 1: Current pregnancy, fever, hypertension, renal involvement, livedo reticularis, seizures, Glasgow coma scale

The treatment determined a Anti-infective therapy, unfractionated i.v. decrease of aCL and antiβ2GPI and heparin, norepinephrine, plasmapheresis, IVIG (30 g/day for 3 days), methylprednisone the patient's condition improved i.v. (from 100 mg/day to 40 mg/day) and CYC (200 mg/day for 8 days)

Garcia-Carrasco et al. 2 2007 [44]

Pt 1: aCL IgG and LA Pt 2: not reported

Furmanczyk et al. 2009 [45]

1

LA, aCL IgG and IgM, antiβ2GPI IgG and IgM

Haskin et al. 2012 [46]

3a

Pt 3: aCL IgM, antiβ2GPI IgM, LA

= 5 with urine and blood cultures positive for Escherichia coli Pt 2: lupus flair after sun exposure, cutaneous vasculitis, kidney failure, fever, DVT and pulmonary embolism Rapidly progressive renal insufficiency, persistent lower leg ulcers, despite the long-term antithrombotic therapy Pt 3: extensive thrombosis of portal and superior mesenteric vein with severe abdominal pain, started after splenectomy

Pt 1 and 2: I.v. methylprednisolone, IVIG, LMWH, antibiotics

Pt 1: Cultures became negative, kidney function improved and the patient was discharged after 18 days Pt 2: the patient was discharged in good condition after 10 days of treatment

LMWH (120 mg/day), plasmapheresis, glucocorticoids (methylprednisolone 3 g followed by 80 mg/day of prednisone), IVIG (1 g/Kg in a single infusion) Pt 3: full heparinization treatment, pulse steroids (1 g/day for 3 days with gradual tapering down) and IVIG (2 g/kg)

Gradual clinical improvement was observed and renal function remained stable Pt 3: after the treatment the pain subsided and the patient was discharged.

Abbreviations: CAPS = catastrophic antiphospholipid syndrome; pts = patients; aCL = anticardiolipin antibodies; β2GP1 = beta-2 glycoprotein 1; LA = lupus anticoagulant; ARDS = acute respiratory distress syndrome; IVIG = intravenous immunoglobulins; CYS = cyclophosphamide; DVT = deep vein thrombosis; LMWH = low-molecular-weight heparin. a The data of patient 1 are not reported because of the inefficacy of “triple therapy”; the data about case 2 are not reported because the patient wasn't treated ith “triple therapy”.

During week 16 of her thirteenth pregnancy, the patient was positive for LA and she showed a prolonged activated partial thromboplastin test (APTT) and low platelet count. Treatment with IVIG at the standard dose of 400 mg/kg/day for 5 days was started at week 17 and followed by 2-day courses at 22 and 27 weeks of gestation. At week 34 a healthy girl was delivered by caesarean section. This report was followed by several other case reports of successful pregnancy outcome in APS patients with previous habitual abortions. However the literature showed heterogeneous data with respect to IVIG dosing, timing of administration and concomitant therapies used (heparin, aspirin, prednisone) [12–21] (Table 1). More consistent results derive from the publication of different case series (Table 2). Kaaja et al. [22] reported three APS patients with a history of pulmonary embolies related to pregnancy, 13 miscarriages and only one live-born after pre-eclamptic pregnancy. During the examined pregnancies the patients received aspirin 75 mg daily in combination with repetitive high-dose IVIG (1 g/kg). Three pregnancies ended in a delivery of healthy child after 36–38 weeks of gestation and one after 34 weeks (pre-term delivery). Progressive reduction of aCL IgG antibodies titer was observed after IVIG infusions, while the effect on LA was variable. A similar suppression of the titers of aPL was described by Kwak et al. [23] after each infusion of IVIG (400 mg/kg/day for 3 days and repeated monthly up to 34 weeks gestation) administered to 5 women with APS and one with antinuclear antibody, who were refractory to conventional treatment. The decrease of autoantibodies was transient and the aPL titers showed a definite rise again, before the next infusion; at the same time the development of intrauterine growth retardation and obstetrical complications were noticed. Encouraging results about the use of IVIG in pregnant APS patients were presented by Spinnato et al. [24]. Pregnancy outcomes were evaluated in five patients with 17 unsuccessful previous pregnancies, treated with IVIG 400 mg/kg for 5 days monthly beginning in the first or early second trimester. Four of them received concomitant heparin prophylaxis and 81 mg of aspirin daily. Short- and long-term decreases of aCL were observed in 3 patients. Four women were delivered of healthy infants at term, one at 32 weeks' gestation with a diagnosis of fetal distress. Neither preeclampsia nor fetal intrauterine growth retardation happened. Next year, Carp et al. [25] published the results of IVIG treatment (400 mg/kg in the follicular phase of last

cycle before pregnancy and when the pregnancy was diagnosed) in 12 APS patients. Ten of them conceived and 5 had subsequent live births. Valensise et al. [26] treated 14 APS women with a history of recurrent spontaneous abortions with IVIG at a dose of 0.5 g/kg for two consecutive days from the fifth week of pregnancy and repeated every 4 weeks until the 33rd week of gestation. One patient developed gestational hypertension and abruptio placentae; no other pregnancy complications were seen. Similarly, Clark et al. [27] reported the successful maternal and fetal outcomes in 15 APS women treated with monthly IVIG in association with LDA, sub-cutaneous heparin and steroid during pregnancy (19 pregnancies). The live-birth rate was 84%, no cases of fetal growth restriction happened and pre-eclampsia was diagnosed in the 25% of the pregnancies. Seventy-five percent of the babies were delivered at 34 weeks' gestation. Furthermore, the authors observed a significant decrease of aCL IgG throughout the course of therapy in 7 pregnancies. The benefit of IVIG therapy in APS pregnant patients was recently confirmed by Watanabe et al. [28]. The experience of three severe obstetric APS women treated with a combination therapy of continuous unfractionated heparin injection, LDA, prednisone and 5-day course of IVIG (400 mg/kg from 6–7 gestational weeks) was described. All 3 patients achieved live births and no thrombotic or bleeding complications were observed. Over the years, the promising data about the use of IVIG therapy in obstetric APS were confirmed by several studies, mostly observational, but by some randomized trials, too (Table 3). In 1996, a pilot-study, reporting the results of IVIG treatment given to 38 women with APS, was published [29]. They had a history of 3 or more consecutive spontaneous first trimester abortions associated with the presence of aPL. As soon as pregnancy had been confirmed, IVIG were administered at a dose of 300 mg/kg and repeated at 3 weekly intervals until the 16th–17th week of gestation. Pregnancy continued beyond the first trimester in 34 of the patients and 31 of them had an uncomplicated pregnancy terminating in delivery at 37 to 42 weeks. Four women aborted before the 17th week and 3 between the 19th and 22nd week as result of cervical incompetence. In 1998, Sher et al. [30] tested wheter aPL-positive infertile women undergoing in vitro fertilization (IVF) could have improved birthrates after IVIG administration. One hundred twenty-one aPL-positive women, who each, completed up to three consecutive IVF/embryo transfer cycles within a 12-month period,


Abbreviations: pts = patients; aCL = anticardiolipin antibodies; IVIG = intravenous immunoglobulins; MRA = magnetic resonance arteriography; β2GP1 = beta-2 glycoprotein 1; LA = lupus anticoagulant; HCQ = hydroxychloroquine; ASA =

Open-label prospective comparative Tenti et al. 2013

acetylsalicylic acid; VAS = visual analogue score; DVT = deep vein thrombosis.

Group I: no venous or arterial thrombosis years) + warfarin (3 pts), ASA (2 pts), warfarin occurred during the follow-up (2 years); at the end of the study, aCL and antiβ2GPI IgM + ASA (2 pts) Group II: warfarin (4 pts), warfarin + ASA (1 pt), acenocoumarol (2 pts) significantly decreased. Group II: 2 pts presented cerebral ischaemic attacks and one pt a DVT during the follow-up Group I and II: LA and aCL IgG (7 pts); aCL IgM (2 pts); antiβ2GPI IgG (6 pts); group I: antiβ2GPI IgM (4 pts) Group II: antiβ2GPI IgM (3 pts)

mg/kg/month for 9 months) + oral anticoagulant + HCQ. 3 pts also ASA Group I. 7 pts: IVIG (400 mg/kg/month for 2

In a long-term follow-up (N5 years) no further thrombosis occurred in all pts. VAS score improved after IVIG treatment All pts: IVIG (400 mg/kg for 3 days every month for 3 months, followed by 400 5 Open prospective Sciascia et al. 2012

Group I: 7/7 (total no of events = 9) 14 Group I: 7 pts Group II: 7/7 (total no of events = 8) Group II: 7 pts


N° of pts with previous thrombotic events 5/5 (total no of events = 9) Trial design References

N° of pts

aCL IgG 1 (cerebral thrombosis) Case report Arabshahi et al. 2007

1

aCL, antiβ2GPI and LA

aCL were no longer detectable within 6 months and continued to be negative. There was no clinical deterioration or further changes on MRA over 7 years Treatment to reduce recurrence of thrombosis Main findings

IgG and IgA aCL levels decreased after IVIG infusion and no further episodes of thrombosis occurred

mg/kg/month) + warfarin + aspirin (325 mg/day) IVIG (2 g/kg/month for 2 year and then every other month for 7 year) Contraindication to warfarin

IVIG (200 mg/kg over 5 days, then 40 aCL IgG and IgA 3 (2 of these under anticoagulation) Case report Hsiao et al. 2001

1

Autoantibodies profile N° of previous thrombotic events N° of pts Trial design References

Table 5 Original articles or case reports that report the efficacy of IVIG in preventing thrombosis relapses in APS patients.

Treatment to reduce recurrence of thrombosis Main findings


7

were treated with IVIG in combination with heparin and aspirin. The authors observed an improvement of birth rates when IVIG were added to the therapy with aspirin and heparin in patients who had aPL directed specifically towards to phosphatidyl-serine and phosphatidylethanolamine. Opposite results to the studies listed above were presented by Branch et al. [31] in a randomized, double-blind, placebo controlled pilot trial. Sixteen APS women were enrolled during a 2-year period; all patients were treated with LDA and unfractionated heparin by subcutaneous injection every 12 h as soon as the pregnancy was confirmed by ultrasonography. In addition, 7 of them received IVIG (1 g/kg) and 9 an identical-appearing placebo for 2 consecutive days each month until 36 weeks' gestation. Obstetric outcomes were excellent in both groups, with all women being delivered of live-born infants after 32 weeks' gestation. IVIG therapy didn't seem to reduce the rates of obstetric or neonatal complications, although a fewer cases of fetal growth restriction and neonatal intensive care unit admissions were reported in the IVIG group. Subsequently, Vaquero et al. [32] compared pregnancy outcomes and complication rates in patients with APS treated with IVIG versus prednisone and LDA. In this prospective, twocenters trial, 29 patients were treated with prednisone and LDA in one center, while 53 received IVIG in the other center with a dose of 0.5 g/kg for 2 consecutive days, once a month from the 5th to the 32nd week of pregnancy. Live-birth rates were equivalent between the two groups, whereas, gestational hypertension and gestational diabetes were found significantly more often in the prednisone-plus LDA treated patients than in the IVIG group. A favorable fetal outcome in APS women, after IVIG therapy, was also reported in a study conducted in 2002 [33]. In this trial, IVIG (at a dose of 500 mg/kg every month from 10th week until 34th week) were used in combination with LDA and heparin to treat 7 patients that are non-responders to the standard regimen. All seven pregnancies were significantly successful ending in live births with no maternal complications. Contrasting results were proposed in a randomized controlled study aimed to compare IVIG and an anticoagulation regimen (LDA and heparin), in aPL-positive women with recurrent pregnancy losses [34]. Forty women were randomly assigned to treatment with IVIG (400 mg/kg/day given for 2 consecutive days followed by a single dose each month) or LMWH plus LDA from the beginning of pregnancy. IVIG was stopped at the 31st week of gestation, aspirin at the 34th week, and heparin at the 37th week. Women treated with the anticoagulation regimen presented a significantly higher rate of live births compared to those treated with IVIG. Consistent with the above study, are the data published by Jeremic et al. [35] and Dendrinos et al. [36]. In the first study, a prospective observational trial, 20 APS women received LMWH and aspirin alone, while others 20 in combination with IVIG (10 g once a month from the beginning of pregnancy until 34 weeks of gestation). The authors failed to demonstrate any significant differences in pregnancy outcomes between the two groups of treatment. In the second one LMWH plus LDA resulted in a higher live birth rate than IVIG, at a dose of 400 mg/kg from the beginning of pregnancy, every 28 days until 32 weeks of gestation [36]. Conversely, the last two published papers presented again encouraging results about the helpful role of IVIG in obstetric APS. The first one [37] was a retrospective study on 121 APS pregnant patients who received two different treatments: 78 women received the standard therapy with LMWH and aspirin, and 43 0.2 g/kg of IVIG in addition to the standard therapy. The use of IVIG resulted in a decrease of pregnancy complications but no differences in the abortion rate. In the second paper, IVIG, at a dose of 10 g per day for five consecutive days in a month, followed by 2 or 3 other courses, were administered together with prednisone (5 mg three times per day), aspirin, LMWH (comprehensive treatment) in comparison to 15 mg of prednisone and aspirin alone (traditional treatment) in 129 APS women. This trial demonstrated that comprehensive treatment may be superior to the traditional method in improving the live birth rate and reducing obstetric complications [38].


8


5. IVIG in catastrophic APS Combination therapy with anticoagulants plus corticosteroids, plasma exchange (PE) and/or IVIG (“triple therapy”) was the most commonly used treatment for CAPS, in agreement with the international consensus guidelines [39]. IVIG are used in a dose of 0.4 g/d/kg for 5 days and should be administered after the last day of PE, when planned, to prevent their removal. IVIG are well tolerated, but they should be used with caution in case of thrombosis, particularly in those patients whom anticoagulation was discontinued because of bleeding. Avoiding products with high osmolality, reducing the rate of IVIG infusion, hydration, and using non-sucrose IVIG products (especially in patients with renal failure) are strategies that can reduce thrombosis risk [40]. Elderly patients with diabetes, hypertension or hypercholesterolemia should also be infused with care, with a reduced rate of IVIG infusion. IVIG are strongly recommended in CAPS patients with severe thrombocytopenia refractory to high dose steroid therapy or when a concomitant infection exists [41]. As there were no meta-analyses or randomized controlled trials, most of the scientific evidence derives from the online available “CAPS Registry” that includes the description of 342 cases of CAPS and their treatments. The analysis of this registry confirms that the “triple therapy” strategy improves the survival rate (around 70%) [41,42]. These data are also available in the literature in the form of case reports or series, as reported in the Table 4 [43–46]. 6. IVIG in preventing recurrent thrombosis The evidence about the efficacy and safety of IVIG therapy in nonpregnant APS patients is scarce, in particular the use of IVIG in the primary or secondary thromboprophylaxis was described only in two prospective open studies and in few case reports [47–50] (Table 5). In the first study 5 patients with primary APS were treated with IVIG therapy because of relapsing thrombotic events, despite anticoagulant conventional therapy. All patients had a high risk aPL profile, according to APS risk scale [51] and also received HCQ for mild arthralgia. Three consecutive daily infusions of IVIG were administered at a dose of 400 mg/kg/day every month for 3 months, followed by a monthly infusion of 400 mg/kg/day for 9 months. A long-term follow-up (N5 years) showed no further clinical or instrumental proven thrombosis and an improvement of Visual Analogue Score. Despite the good clinical outcome, no statistically significant differences were observed in the aPL profile before and after IVIG therapy measured at 6, 12 and 24 months [49]. More recently, Tenti et al. [50] assessed the long-term effects of IVIG in 7 patients with primary or secondary APS, in addition to conventional therapy (anticoagulants or antiplatelets) compared to a control group of 7 patients (following their regular conventional therapy). IVIG infusion was administered at a monthly dose of 400 mg/kg/day for two consecutive years; all patients were evaluated by clinical examination and biochemical analysis (including aPL profile) at baseline, after one and two years from the beginning of the study. During the follow-up period no further clinically or instrumentally confirmed thrombosis occurred in the group treated with IVIG in addition to standard therapy, while in the control group two patients presented cerebral ischaemic attacks and one patient developed deep vein thrombosis. Furthermore, the Authors observed a statistically significant decrease of aCL (IgG and IgM) and of IgM anti-β2GPI. LA measurement resulted positive in all patients at the beginning of the study and became negative in 3 patients of the group treated with IVIG in addition to standard therapy, at the end of follow-up, while no changes occurred in the control group [50]. 7. Discussion The aim of this review was to summarize the currently available information on the IVIG therapy in APS, focusing on the use of IVIG

in the obstetric form, CAPS and on the primary or secondary thromboprophylaxis. The strongest effects of aPL seem to occur in pregnancy and they have been associated with a pregnancy loss rate as high as 80–90% [52]. This is a challenging situation that requires careful management by the physician since no absolute evidence about the treatment of APS in pregnancy exists [52]. Obstetric APS should be treated by a multidisciplinary team of specialists with experience in this field. In this contest, secondary thromboprophylaxis with LDA and heparin is the mainstay of treatment and HCQ is usually added for patients suffering from SLE [53]. Although an optimal therapeutic target wasn't often reached, several new emerging therapies have been implemented in the last years. Among these IVIG showed a beneficial effect in some case reports/series and observational or randomized trials. The results derived from our literature analysis seem controversial; indeed, four of nine above-mentioned trials concluded that no benefits derived from the use of IVIG in association with LDA and LMWH compared to LDA and LMWH alone [31,34–36]. At the moment, IVIG therapy in obstetric APS seems to be reserved to selected situations, such as patients not responsive to the conventional treatment or in case of association of other autoimmune manifestations such as thrombocytopenia or when concomitant infections exist or in patients in whom anticoagulation is contraindicated. The optimal treatment regimen in CAPS is unknown. The management of this condition should be directed at two different points: the thrombotic events and the suppression of cytokine cascade. Anticoagulation with heparin is the mainstay of treatment in patients with CAPS, in addition, immunosuppressors and IVIG act mostly in the inflammation control. Current treatment guidelines suggest an early diagnosis and an aggressive therapy to avoid the potentially fatal outcome. At this regard, triple therapy (anticoagulants, glucocorticoids, PE and/or IVIG) is recommended for the management of CAPS patients [41]. The adequate strategy for the primary prophylaxis of thrombosis in patients with aPL is an important and controversial issue. The recommended primary thromboprophylaxis in SLE patients with positivity for LA or aCL at medium-high titers is with HCQ and LDA, whereas in non-SLE individuals with aPL and no previous thrombosis, only the prophylaxis with LDA is suggested. The secondary thromboprophylaxis in patients with definite APS and a first venous event, oral anticoagulants to a target INR 2–3 are recommended, while in patients with arterial thrombosis, an INR more than 3.0 or a combination with antiaggregants is requested. Recently, because of the not always satisfactory results of the conventional therapy, additive agents (such as LMWH, statins and IVIG) and advanced treatments targeting new coagulation and immunomodulatory pathways have been encouraged [54,55]. Our literature analysis showed that an additional therapy with IVIG could be useful to prevent recurrent thrombosis in APS patient refractory to conventional anticoagulant treatment, although the scientific evidence is confined by the lack of a consistent number of well designed trials. IVIG are blood products prepared from the serum of a large number of donors and their use has rapidly grown to treat a wide variety of autoimmune diseases. Actually, IVIG therapy has been shown to be effective in treating Kawasaki disease, idiopathic thrombocytopenic purpura, chronic inflammatory demyelinating polyneuropathy and Guillian– Barré syndrome and its use as second-line therapy is also supported in dermatomyositis/myositis and as a bridging therapy in some cases of ANCA-associated vasculitides [10,56]. The mechanisms in which IVIG exert their immunomodulatory and anti-inflammatory effects remain unclear, with many pathways in the innate and adaptive immune systems being potentially targeted. The many explanations for these actions include modulation of Fc receptor expression on leukocytes and endothelial cells, interaction with complement proteins, modulation of the synthesis and release of cytokines and chemokines,



modulation of cell proliferation and apoptosis, remyelinization, neutralization of circulating antibodies, selection of immune repertoires, interaction with other cell surface molecules expressed on lymphocytes and monocytes, modulation of dendritic cell maturation and restoration of idiotypic-anti-idiotypic networks [57,58]. Particularly, in APS IVIG have been shown to inhibit both the action of aPL and their production. Indeed, Caccavo et al. [59] reported that F (ab') 2 fragments from IVIG can neutralize the binding of aCL to cardiolipin in a dose dependent manner and Galli et al. [60] that the same fragment can also inhibit LA activity. The mechanisms responsible for the beneficial effects of IVIG in APS may be due to the presence of anti-idiotypic antibodies to aPL in IVIG or the inactivation of B-cell clones leading to subsequently decreased autoantibody production [11]. In addition, IVIG infusion was shown to prevent obstetric complications in APS animal models, possibly preventing the binding of aPL to trophoblast [61]. No current guidelines exist about the duration, frequency or optimal dose of IVIG. The doses used for autoimmune diseases are generally four to five times higher than those used in patients with immunodeficiency. A total amount of 2 g/Kg, administered over a period of 2–5 days once a month is often prescribed. On the other hand, some authors preferred low doses to decrease costs, adverse effects and to plan a long term therapy [50,14,16,21,25,29,62]. In general, IVIG therapy is well tolerated and the adverse reactions are usually mild and reversible. Immediate reactions occurring during or following IVIG administrations are the most common and of minor importance, too. These events consist mainly in headache, nausea, malaise, myalgia, arthralgia, fever, chills and chest discomfort. The majority of these reactions are associated with rapid infusions, so it is recommended to start the infusion with slow rate for the first 30 min and then increase gradually the flow [63]. Among the delayed adverse reactions, the occurrence of arterial and venous thrombosis has particular importance in patients affected by APS. The incidence of thrombotic events has been estimated to be 13–16.9% in autoimmune patients and seems to be related to the IVIG dosage, infusion rates, high concentrations of preparation (N5%) and presence of contaminants in IVIG products that can trigger the pro-coagulant cascade. Therefore, in patients with high risk of thrombotic events as APS patients, preventive measures, for example to reduce the osmolality by decreasing the concentration from 10 to 5%, avoid the viscous effect of IVIG, administering them in more-days course and at a slow rate infusion, should be adopted [63]. Furthermore, caution should be taken for patients with prior renal impairment or high risk for renal disease, because of the established relationship between kidney damage including acute renal failure, osmotic nephrosis and renal insufficiency, and IVIG stabilized with sucrose. So, for this kind of patients the use of a preparation containing a stabilizer other than sucrose is recommended, since the incidence of renal impairment is much lower for sucrose-free IVIG [63]. 8. Conclusions Our analysis of the literature revealed that IVIG therapy could be useful to manage obstetric APS, improving the live births rate and reducing pregnancy complications, to prevent recurrent thromboses in APS patients refractory to conventional therapy and it also represents an important component of the “triple therapy” of CAPS. Anyway, in some cases we also found controversial results that claim the need of further well-designed studies to definitely state the efficacy and tolerability of IVIG in CAPS, obstetric and non-APS. The evidence of our search is very limited by the difficulty to compare different studies, often not randomized and/or controlled, based on an heterogeneous series of patients, not considering the different severity of disease, the others cardiovascular or abortion-related risk factors. Furthermore, all examined studies didn't evaluate the aPL profile of the different patients and if the triple aPL positivity can influence the therapy outcome.

9

Another important question to investigate is the need to establish a standardized universally accepted IVIG protocol (IVIG dosage, the timing and duration of therapy). Finally, an important hurdle to overcome is the high cost of IVIG (one dose at 2 g/kg for a 70 kg patient = $8400) that may be partially justified by the reduction of pregnancy or thrombotic APS complications often requiring costly hospitalizations. Competing interests The authors declare that they have no competing interests. Take-home messages • IVIG in obstetric APS seem to be very useful in selected situations (patients not responsive to the conventional treatment, presence of other autoimmune manifestations or concomitant infections or patients in whom anticoagulation is contraindicated). • IVIG treatment represents an important component of the “triple therapy” of CAPS and they could be useful, in addition to the standard therapy, to prevent recurrent thrombosis in APS patients refractory to conventional anticoagulant treatment.

References [1] Gómez-Puerta JA, Cervera R. Diagnosis and classification of the antiphospholipid syndrome. J Autoimmun 2014;48–49:20–5. [2] Miyakis S, Lockshin MD, Atsumi T, Branch DW, Brey RL, Cervera R, et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost 2006;4:295–306. [3] Hughes G. Hughes Syndrome: the antiphospholipid syndrome—a clinical overview. Clin Rev Allergy Immunol 2007;32:3–12. [4] Cervera R, Bucciarelli S, Plasín MA, Gómez-Puerta JA, Plaza J, Pons-Estel G, et al. Catastrophic antiphospholipid syndrome (CAPS) registry project group (European Forum on Antiphospholipid Antibodies). Catastrophic antiphospholipid syndrome (CAPS): descriptive analysis of a series of 280 patients from the “CAPS Registry”. J Autoimmun 2009;32:240–5. [5] Mehrania T, Petri M. Epidemiology of the Antiphospholipid Syndrome. Amsterdam: Elsevier; 2009. [6] Comarmond C, Cacoub P. Antiphospholipid syndrome: from pathogenesis to novel immunomodulatory therapies. Autoimmun Rev 2013;12:752–7. [7] Giannakopoulos B, Krilis SA. The pathogenesis of the antiphospholipid syndrome. N Engl J Med 2013;368:1033–44. [8] Erkan D, Aguiar CL, Andrade D, Cohen H, Cuadrado MJ, Danowski A, et al. 14th International Congress on Antiphospholipid Antibodies: task force report on antiphospholipid syndrome treatment trends. Autoimmun Rev 2014;13:685–96. [9] Alijotas-Reig J, Garrido-Gimenez C. Current concepts and new trends in the diagnosis and management of recurrent miscarriage. Obstet Gynecol Surv 2013;68:445–66. [10] Mulhearn B, Bruce IN. Indications for IVIG in rheumatic diseases. Rheumatology (Oxford) 2015;54:383–91. [11] Sherer Y, Levy Y, Shoenfeld Y. Intravenous immunoglobulin therapy of antiphospholipid syndrome. Rheumatology (Oxford) 2000;39:421–6. [12] Carreras LD, Perez GN, Vega HR, Casavilla F. Lupus anticoagulant and recurrent fetal loss: successful treatment with gammaglobulin. Lancet 1988;2:393–4. [13] Scott JR, Branch DW, Kochenour NK, Ward K. Intravenous immunoglobulin 'treatment of pregnant patients with recurrent pregnancy loss caused by antiphospholipid antibodies and Rh immunization. Am J Obstet Gynecol 1988; 159:1055–6. [14] Parke A, Maier D, Wilson D, Andreoli J, Ballow M. Intravenous gamma-globulin, antiphospholipid antibodies, and pregnancy. Ann Intern Med 1989;110:495–6. [15] Wapner RJ, Cowchock FS, Shapiro SS. Successful treatment in two women with antiphospholipid antibodies and refractory pregnancy losses with intravenous immunoglobulin infusions. Am J Obstet Gynecol 1989;161:1271–2. [16] Ron-el R, Vinder A, Golan A, Herman A, Raziel A, Caspi E, et al. The use of intravenous gammaglobulin, heparin and aspirin in the maintenance of pregnancy of freeze thawed embryo in a patient with lupus-type anticoagulant. Eur J Obstet Gynecol Reprod Biol 1993;52:131–3. [17] Arnout J, Spitz B, Wittevrongel C, Vanrusselt M, Van Assche A, Vermylen J. High-dose intravenous immunoglobulin treatment of a pregnant patient with an antiphospholipid syndrome: immunological changes associated with a successful outcome. Thromb Haemost 1994;71:741–7. [18] Somerset DA, Raine-Fenning N, Gordon C, Weaver JB, Kilby MD. Intravenous immunoglobulin therapy in compromised pregnancies associated with antiphospholipid antibodies and systemic lupus erythematosus. Eur J Obstet Gynecol Reprod Biol 1998;79:227–9. [19] Chang P, Millar D, Tsang P, Lim K, Houlihan E, Stephenson M. Intravenous immunoglobulin in antiphospholipid syndrome and maternal floor infarction when standard treatment fails: a case report. Am J Perinatol 2006;23:125–9.


10


[20] Stojanovich L, Mikovic Z, Mandic V, Popovich-Kuzmanovich D. Treatment of antiphospholipid syndrome in pregnancy with low doses of intravenous immunoglobulin. Isr Med Assoc J 2007;9:555–6. [21] Mar N, Kosowicz R, Hook K. Recurrent thrombosis prevention with intravenous immunoglobulin and hydroxychloroquine during pregnancy in a patient with history of catastrophic antiphospholipid syndrome and pregnancy loss. J Thromb Thrombolysis 2014;38:196–200. [22] Kaaja R, Julkunen H, Ammälä P, Palosuo T, Kurki P. Intravenous immunoglobulin treatment of pregnant patients with recurrent pregnancy losses associated with antiphospholipid antibodies. Acta Obstet Gynecol Scand 1993;72:63–6. [23] Kwak JY, Quilty EA, Gilman-Sachs A, Beaman KD, Beer AE. Intravenous immunoglobulin infusion therapy in women with recurrent spontaneous abortions of immune etiologies. J Reprod Immunol 1995;28:175–88. [24] Spinnato JA, Clark AL, Pierangeli SS, Harris EN. Intravenous immunoglobulin therapy for the antiphospholipid syndrome in pregnancy. Am J Obstet Gynecol 1995;172: 690–4. [25] Carp HJ, Ahiron R, Mashiach S, Schonfeld Y, Gazit E, Toder V. Intravenous immunoglobulin in women with five or more abortions. Am J Reprod Immunol 1996;35: 360–2. [26] Valensise H, Vaquero E, De Carolis C, Stipa E, Perricone R, Arduini D, et al. Normal fetal growth in women with antiphospholipid syndrome treated with high-dose intravenous immunoglobulin (IVIG). Prenat Diagn 1995;15:509–17. [27] Clark AL, Branch DW, Silver RM, Harris EN, Pierangeli S, Spinnato JA. Pregnancy complicated by the antiphospholipid syndrome: outcomes with intravenous immunoglobulin therapy. Obstet Gynecol 1999;93:437–41. [28] Watanabe N, Yamaguchi K, Motomura K, Hisano M, Sago H, Murashima A. Combination therapy with anticoagulants, corticosteroids and intravenous immunoglobulin for women with severe obstetric antiphospholipid syndrome. Clin Exp Rheumatol 2014;32:299–300. [29] Marzusch K, Dietl J, Klein R, Hornung D, Neuer A, Berg PA. Recurrent first trimester spontaneous abortion associated with antiphospholipid antibodies: a pilot study of treatment with intravenous immunoglobulin. Acta Obstet Gynecol Scand 1996;75: 922–6. [30] Sher G, Matzner W, Feinman M, Maassarani G, Zouves C, Chong P, et al. The selective use of heparin/aspirin therapy, alone or in combination with intravenous immunoglobulin G, in the management of antiphospholipid antibody-positive women undergoing in vitro fertilization. Am J Reprod Immunol 1998;40:74–82. [31] Branch DW, Peaceman AM, Druzin M, Silver RK, El-Sayed Y, Silver RM, et al. A multicenter, placebo-controlled pilot study of intravenous immune globulin treatment of antiphospholipid syndrome during pregnancy. The Pregnancy Loss Study Group. Am J Obstet Gynecol 2000;182:122–7. [32] Vaquero E, Lazzarin N, Valensise H, Menghini S, Di Pierro G, Cesa F, et al. Pregnancy outcome in recurrent spontaneous abortion associated with antiphospholipid antibodies: a comparative study of intravenous immunoglobulin versus prednisone plus low-dose aspirin. Am J Reprod Immunol 2001;45:174–9. [33] Diejomaoh MF, Al-Azemi MM, Bandar A, Egbase PE, Jirous J, Al-Othman S, et al. A favorable outcome of pregnancies in women with primary and secondary recurrent pregnancy loss associated with antiphospholipid syndrome. Arch Gynecol Obstet 2002;266:61–6. [34] Triolo G, Ferrante A, Ciccia F, Accardo-Palumbo A, Perino A, Castelli A, et al. Randomized study of subcutaneous low molecular weight heparin plus aspirin versus intravenous immunoglobulin in the treatment of recurrent fetal loss associated with antiphospholipid antibodies. Arthritis Rheum 2003;48:728–31. [35] Jeremić K, Pervulov M, Gojnić M, Dukanac J, Ljubić A, Stojnić J. Comparison of two therapeutic protocols in patients with antiphospholipid antibodies and recurrent miscarriages. Vojnosanit Pregl 2005;62:435–9. [36] Dendrinos S, Sakkas E, Makrakis E. Low-molecular-weight heparin versus intravenous immunoglobulin for recurrent abortion associated with antiphospholipid antibody syndrome. Int J Gynaecol Obstet 2009;104:223–5. [37] Heilmann L, Schorch M, Hahn T, Adasz G, Schilberz K, Adiguzel C, et al. Pregnancy outcome in women with antiphospholipid antibodies: report on a retrospective study. Semin Thromb Hemost 2008;34:794–802. [38] Xiao J, Xiong J, Zhu F, He L. Effect of prednisone, aspirin, low molecular weight heparin and intravenous immunoglobulin on outcome of pregnancy in women with antiphospholipid syndrome. Exp Ther Med 2013;5:287–91. [39] Asherson RA, Cervera R, de Groot PG, Erkan D, Boffa MC, Piette JC, et al. Catastrophic Antiphospholipid Syndrome Registry Project Group. Catastrophic antiphospholipid syndrome: international consensus statement on classification criteria and treatment guidelines. Lupus 2003;12:530–4. [40] Cervera R. Update on the diagnosis, treatment, and prognosis of the catastrophic antiphospholipid syndrome. Curr Rheumatol Rep 2010;12:70–6.

[41] Cervera R, Rodríguez-Pintó I, Colafrancesco S, Conti F, Valesini G, Rosário C, et al. 14th International Congress on Antiphospholipid Antibodies Task Force Report on Catastrophic Antiphospholipid Syndrome. Autoimmun Rev 2014;13:699–707. [42] Bucciarelli S, Cervera R, Espinosa G, Gómez-Puerta JA, Ramos-Casals M, Font J. Mortality in the catastrophic antiphospholipid syndrome: causes of death and prognostic factors. Autoimmun Rev 2006;6:72–5. [43] Koschmieder S, Miesbach W, Fauth F, Bojunga J, Scharrer I, Brodt HR. Combined plasmapheresis and immunosuppression as rescue treatment of a patient with catastrophic antiphospholipid syndrome occurring despite anticoagulation: a case report. Blood Coagul Fibrinolysis 2003;14:395–9. [44] García-Carrasco M, Escárcega RO, Mendoza-Pinto C, Zamora-Ustaran A, EtchegarayMorales I, Rojas-Rodriguez J, et al. Preventing death in the catastrophic antiphospholipid (Asherson) syndrome. Isr Med Assoc J 2007;9:628–9. [45] Furmańczyk A, Komuda-Leszek E, Gadomska W, Windyga J, Durlik M. Catastrophic antiphospholipid syndrome. Pol Arch Med Wewn 2009;119:427–30. [46] Haskin O, Amir J, Schwarz M, Schonfeld T, Nahum E, Ling G, et al. Severe abdominal pain as a presenting symptom of probable catastrophic antiphospholipid syndrome. Pediatrics 2012;130:e230–5. [47] Hsiao GR, Wolf RE, Kimpel DL. Intravenous immunoglobulin to prevent recurrent thrombosis in the antiphospholipid syndrome. J Clin Rheumatol 2001;7:336–9. [48] Arabshahi B, Thompson ED, Smergel EM, Goldsmith DP. Long-term treatment of antiphospholipid syndrome-associated cerebral arterial thromboses with intravenous immunoglobulin: a case report. Clin Rheumatol 2007;26:251–3. [49] Sciascia S, Giachino O, Roccatello D. Prevention of thrombosis relapse in antiphospholipid syndrome patients refractory to conventional therapy using intravenous immunoglobulin. Clin Exp Rheumatol 2012;30:409–13. [50] Tenti S, Guidelli GM, Bellisai F, Galeazzi M, Fioravanti A. Long-term treatment of antiphospholipid syndrome with intravenous immunoglobulin in addition to conventional therapy. Clin Exp Rheumatol 2013;31:877–82. [51] Sciascia S, Cosseddu D, Montaruli B, Kuzenko A, Bertero MT. Risk Scale for the diagnosis of antiphospholipid syndrome. Ann Rheum Dis 2011;70:1517–8. [52] Carp HJ, Asherson RA, Shoenfeld Y. Intravenous immunoglobulin in pregnancies complicated by the antiphospholipid syndrome: what is its role? J Clin Rheumatol 2001;7:291–4. [53] Alijotas-Reig J. Treatment of refractory obstetric antiphospholipid syndrome: the state of the art and new trends in the therapeutic management. Lupus 2013;22: 6–17. [54] Ruiz-Irastorza G, Cuadrado MJ, Ruiz-Arruza I, Brey R, Crowther M, Derksen R, et al. Evidence-based recommendations for the prevention and long-term management of thrombosis in antiphospholipid antibody-positive patients: report of a task force at the 13th International Congress on antiphospholipid antibodies. Lupus 2011;20:206–18. [55] Erkan D, Aguiar CL, Andrade D, Cohen H, Cuadrado MJ, Danowski A, et al. 14th International Congress on Antiphospholipid Antibodies: task force report on antiphospholipid syndrome treatment trends. Autoimmun Rev 2014;13:685–96. [56] Crickx E, Machelart I, Lazaro E, Kahn JE, Cohen-Aubart F, Martin T, et al. French Vasculitis Study Group (FVSG). Intravenous immunoglobulin as immunomodulating agent in ANCA-associated vasculitides: a French nationwide study of 92 patients. Arthritis Rheum 2015 [Epub ahead of print]. [57] Gelfand EW. Intravenous immune globulin in autoimmune and inflammatory diseases. N Engl J Med 2012;367:2015–25. [58] Guidelli GM, Tenti S, Pascarelli NA, Galeazzi M, Fioravanti A. Granulomatosis with polyangiitis and intravenous immunoglobulins: a case series and review of the literature. Autoimmun Rev 2015;14:659–64. [59] Caccavo D, Vaccaro F, Ferri GM, Amoroso A, Bonomo L. Anti-idiotypes against antiphospholipid antibodies are present in normal polyspecific immunoglobulins for therapeutic use. J Autoimmun 1994;7:537–48. [60] Galli M, Cortelazzo S, Barbui T. In vivo efficacy of intravenous gammaglobulins in patients with lupus anticoagulant is not mediated by an anti-idiotypic mechanism. Am J Hematol 1991;38:184–8. [61] Bakimer R, Guilburd B, Zurgil N, Shoenfeld Y. The effect of intravenous gammaglobulin on the induction of experimental antiphospholipid syndrome. Clin Immunol Immunopathol 1993;69:97–102. [62] Francioni C, Galeazzi M, Fioravanti A, Gelli R, Megale F, Marcolongo R. Long-term I.V. IG treatment in systemic lupus erythematosus. Clin Exp Rheumatol 1994;12:163–8. [63] Cherin P, Marie I, Michallet M, Pelus E, Dantal J, Crave JC, et al. Management of adverse events in the treatment of patients with immunoglobulin therapy: A review of evidence. Autoimmun Rev 2015 [In press].
