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Med Clin (Barc). 2015;144(3):115–117
www.elsevier.es/medicinaclinica
Editorial article
Rituximab in antiphospholipid syndrome: Always, never,
sometimes?夽
Rituximab en el síndrome antifosfolípido: ¿siempre, nunca o a veces?
Amaia Ugarte, Guillermo Ruiz Irastorza ∗
Unidad de Investigación de Enfermedades Autoinmunes, Servicio de Medicina Interna, BioCruces Health Research Institute, Hospital Universitario Cruces, Universidad del País
Vasco/Euskal Herriko Unibertsitatea, Barakaldo, Bizkaia, Spain
Antiphospholipid syndrome (APS) is an autoimmune disorder that has been classically characterised by the presence of
thrombotic episodes and/or obstetric morbidity along with the
maintained existence of antiphospholipid antibodies (APAs)1 .
Patients who experience this clinical-analytical spectrum fulfil Sydney’s 2006 classification criteria for APS2 . However, it should not
be forgotten that there is a wide spectrum of clinical manifestations that, without being included in the classification criteria
(livedo reticularis, thrombocytopenia, haemolytic anaemia, valvulopathy, nephropathy associated to APA, skin ulcers or cognitive
dysfunction), can be symptomatic of APS3 . Finally, there is an entity
known as catastrophic APS, defined by the presence of thrombosis
in multiple locations in a short period of time, with the subsequent
development of multiple organ failure4 .
Based on its prothrombotic nature, the standard treatment
for APS is marked by the administration of anticoagulants (vitamin K antagonists or low molecular weight heparin) and/or
antiaggregation5 . Other treatments that can contribute with an
additional effect are hydroxychloroquine, the use of which in
patients with systemic lupus erythematosus (SLE) with APA has
been associated with a decrease in the thrombosis rate5 , and
statins, based on their anti-inflammatory, immunomodulatory and
antithrombotic properties6 .
However, based on the key role of APAs, and by extension, B
lymphocytes in this entity, there is increasing interest in observing
the effects that the treatments targeted against them can have on
APS7 . Animal models have been developed to study the effect of
modulatory treatments on the antibodies producing cells, specifically, through an inhibition of co-stimulation with CTLA4-Ig and
through BAFF antagonists, with positive effects in both cases8,9 .
DOI of original article: http://dx.doi.org/10.1016/j.medcle.2015.05.012
夽 Please cite this article as: Ugarte A, Irastorza GR. Rituximab en el síndrome
antifosfolípido: ¿siempre, nunca o a veces? Med Clin (Barc). 2015;144:115–117.
∗ Corresponding author.
E-mail address: [email protected] (G. Ruiz Irastorza).
2387-0206/© 2014 Elsevier España, S.L.U. All rights reserved.
The available data on the use of this type of treatment in humans
is basically restricted to rituximab (RTX), a chimeric monoclonal
antibody used against the antigen CD20 of B cells, the use of which
is approved for B cell lymphoma, rheumatoid arthritis, granulomatosis with polyangiitis and micropolyangiitis. Two clinical trials
on the use of RTX in SLE (EXPLORER and LUNAR) did not show
superiority over the baseline treatment, but their results are questionable due to the high doses of glucocorticosteroids used to treat
the patients in the “placebo” group10,11 . In fact, it is still currently
used in severe or refractory cases, although the indication is not
included on the technical data sheet.
In relation to APS, its possible efficacy was initially shown in
clinical cases, case series and registries of patients with catastrophic
APS, such as the CAPS Registry12–15 . In most cases, it was administered as a treatment for clinical manifestations that are not included
in Sydney’s criteria, such as thrombocytopenia or autoimmune
haemolytic anaemia. It is worth mentioning that in almost all the
published cases, RTX was not used in isolation but, rather, concomitantly with glucocorticosteroids and other immunosuppressants,
clearly limiting any assessment of its efficacy. Concurrently, some
authors have demonstrated a maintained decrease in APA levels
after treatment with RTX12–14 but this has not been confirmed in
other cases16 .
If we consider the data published in the CAPS Registry15 , in a
total of 20 patients treated with RTX, we observe that 40% received
this as first line treatment, while it was used as a second therapeutic
step in the remaining 60%. Mortality was 20% (4 patients, including 2 initially treated with RTX). Of the remaining 16 patients, 12
achieved complete remission and 2 required further RTX administration due to skin necrosis and recurrent thrombocytopenia,
respectively. The scarce number of patients makes it difficult to
assess the findings obtained, although they could guide us towards
a potential role for RTX in patients with catastrophic APS.
In 2013, Erkan et al. published a prospective pilot study on the
administration of RTX in 19 patients with primary APS with clinical
manifestations outside Sydney’s16 criteria, in particular valvulopathy, thrombocytopenia, cognitive dysfunction and skin ulcers. This
study confirmed an acceptable safety profile for the drug in this
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A. Ugarte, G. Ruiz Irastorza / Med Clin (Barc). 2015;144(3):115–117
group of patients (with 26% of pro-infusional reactions, none of
which required hospitalisation, and a severe infection rate of 16.9
per 100 patients/year) without confirming the diminishing effects
on the levels of APA that have been observed by other authors in
isolated cases. In terms of efficacy, except in the case of skin ulcers
(which showed greater uniformity in terms of good results), the
response was somewhat irregular regarding the remaining clinical manifestations but, once again, the scarce number of patients
included limits this data16 .
The study in question, published in this edition of Medicina
Clínica17 , includes a review of the articles published up to 2013
in which cases of patients with primary APS treated with RTX
are analysed, excluding those with catastrophic APS. The main
indications for RTX treatment were thrombocytopenia and skin
involvement, followed by neurological and valvular involvement,
autoimmune haemolytic anaemia and alveolar haemorrhage. Thus,
the patients enrolled have manifestations that are mostly not
included in Sydney’s criteria. However, it is interesting that the
treatment indications in 2 of the 24 patients were thrombotic
manifestations: one patient with cerebral venous thrombosis concomitantly with thrombocytopenia, and another with recurrent
transient ischaemic attack (TIA) despite the administration of anticoagulant and antiaggregant treatment. It is worth mentioning that
among those cases where RTX was used as the primary line of
treatment (a total of 7: one cerebral venous thrombosis, one with
symptoms of recurrent TIA, 2 cases of valvulopathy, 2 cases of skin
involvement and one case of cognitive dysfunction), 5 achieved
complete remission, among them, the 2 patients with thrombotic symptoms. However, except in the case of cerebral venous
thrombosis, in which RTX (along with glucocorticosteroids iv and
acetazolamide) was the only treatment administered, for the rest
of the patients it was administered simultaneously with anticoagulation and/or antiaggregation treatments, and in some cases,
hydroxychloroquine.
Overall, the response varied and slightly more than half of
the patients achieved the complete clinical response as defined
according to the specific criteria of the different authors. There
was a lack of response in 16.6% of patients and the rest showed
partial improvement. In terms of specific manifestations, it is surprising that the 8 patients with skin manifestations, ulcers and
livedoid vasculopathy, which are in general very difficult to manage, responded to the treatment completely (62.5%) or partially
(27.5%). A high frequency of complete response was also observed
in patients with thrombosis (100%) and valvulopathy (66.7%), even
if in this instance the number of cases was lower (2 and 3, respectively). The effects were more irregular in patients with other
manifestations, such as thrombocytopenia, haemolytic anaemia
and cognitive deterioration.
On the other hand, this review confirms the good safety profile
of the drug. It should be noted that RTX efficacy is not invariably associated with a decrease in or elimination of APAs, as in
different situations the cases of complete or partial remission do
not show significant modifications in their levels. However, only 9
patients had sufficient data to analyse the evolution of APA titres
after treatment, so the significance of this observation is also limited.
What is the practical value of the review by Pons et al.? Overall, we consider it highly premature to infer a potential use of
RTX as the first therapeutic option for patients with APS. Our caution is based on the scarce number and heterogeneity of patients,
the difficulty in accessing part of the clinical information for
many of them, the additional effect of the other drugs administered and, particularly, the difficulty in establishing objective
response criteria, in particular, in the cases of cardiac valvular condition and thrombosis. However, the results of this study
invite us to consider the early administration of RTX in patients
with severe dermatological manifestations of APS, in particular
ulcers and skin necrosis, which are generally chronic and very
difficult to manage at a therapeutic level with the customary
means.
At the opposite end of the scale we find thrombotic manifestations, for which there is a generally efficient therapeutic option5 . In
cases when progress is deficient, instead of the standard anticoagulant treatment, it seems more reasonable to use more conventional
drugs such as hydroxychloroquine or statins and, particularly, to
insist on maintaining adequate control of vascular risk factors. In
other cases with APS manifestations not included in Sydney’s classification criteria, RTX can be considered an option when an added
immunosuppressant treatment is required and the clinical manifestations are resistant to that treatment.
Finally, we have yet to determine the attitude we should adopt
in the case of patients who, as a result of RTX treatment, continue
to neutralise APAs. Even if the possibility of discontinuing the anticoagulant treatment is included in the cases in which antibodies
spontaneously disappear5 , this decision should always be personalised, taking into consideration together with the patient the risks
and consequences of new thrombosis in the face of the possibility of haemorrhage and the discomfort of chronic anticoagulant
treatment.
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