Rituximab and its therapeutic potential in catastrophic antiphospolipid syndrome

Abstract

The catastrophic antiphospholipid syndrome (CAPS) is characterized by thrombosis in more than three organs or systems developing over a short period of time. Despite conventional treatment with a combination of anticoagulation plus corticosteroids plus plasma exchange, and/or intravenous immunoglobulin, mortality remains high and some patients suffer from recurrent CAPS episodes. In selected patients, new therapies such as rituximab may be a treatment option. In this review, the rationale for using rituximab in CAPS is discussed.

Introduction

Catastrophic antiphospholipid syndrome (CAPS) is a variant of antiphospholipid syndrome (APS) described by Asherson [Asherson, 1992], and is characterized by thrombosis in multiple organs developing over a short period of time in patients with antiphospholipid antibodies (aPL) [Erkan et al. 2010].

Due to a lack of studies on the pathophysiological mechanisms of CAPS, knowledge of the pathogenic mechanisms of this intriguing entity is scarce. In fact, it has been hypothesized that the excessive cytokine release from injured tissues leading to the development of systemic inflammatory response syndrome (SIRS) is the key point of CAPS [Espinosa et al. 2007].

From the clinical point of view, one of the main characteristic features of CAPS is the identification of a precipitating factor in up to 50% of patients [Cervera et al. 2009]. Among them, the most frequent factors were infections (present in 22% of cases), surgical procedures (10%), anticoagulation withdrawal or low international normalized ratio (8%), medications (7%), obstetric complications (7%), neoplasia (5%), and lupus flares (3%) [Cervera et al. 2009].

In 2003, the Catastrophic APS Registry Project Group published the preliminary classification criteria for CAPS (Table 1) and the treatment algorithm [Asherson et al. 2003]. The first step in therapy for this potential devastating complication is the identification and treatment of a precipitating factor. In addition, first-line therapies include the combination of anticoagulation against thrombosis plus glucocorticoids plus plasma exchange, and/or intravenous immunoglobulins against both aPL (antiphospholipids) and SIRS [Asherson et al. 2003]. Glucocorticoids have an anti-inflammatory profile and this medication can reduce the manifestations of SIRS. Notably, the combined treatment of anticoagulation plus glucocorticoids plus plasma exchange followed by anticoagulation plus glucocorticoids plus plasma exchange, and/or intravenous immunoglobulins achieved the higher recovery rate [Bucciarelli et al. 2006].

Table 1.

Diagnostic criteria for catastrophic antiphospholipid syndrome.

1. Evidence of involvement of three organs, systems, and/or tissues.

2. Development of manifestations simultaneously or in less than 1 week.

3. Laboratory confirmation of the presence of antiphospholipid antibodies (aPL) (lupus anticoagulant antibodies and/or anticardiolipin antibodies, and/or anti-2-glycoprotein I antibodies) in titers higher than 40 UI/L.

4. Exclude other diagnosis.

Definite catastrophic antiphospholipid syndrome (CAPS):

• all four criteria

Probable CAPS:

• all four criteria, except for involvement of only two organs, system, and/or tissues

• all four criteria, except for the absence of laboratory confirmation at least 12 weeks apart associable to the early death of a patient never tested for aPL before onset of CAPS

• 1, 2, and 4

• 1, 3, and 4, and the development of a third event in less than 1 week but more than 1 month, despite anticoagulation treatment

This treatment algorithm is based on two potential underlying pathophysiologic events, thrombosis and SIRS, that have been involved in the development of CAPS. However, it is important to note that no firm evidence on the high levels of cytokines exists in these patients. Despite the empirical basis of the proposed treatment of CAPS, mortality decreased from 53% in patients diagnosed before 2001 to 33% in those diagnosed between 2001 and February 2005 [Bucciarelli et al. 2006].

Data from the web-based, international CAPS Registry that collects the clinical, laboratory, and therapeutic data of all reported cases of CAPS, has allowed us to identify refractory patients who died despite first-line treatment or those suffering from recurrent episodes of CAPS. Due to the existence of these refractory cases, other medications such as rituximab may have a potential role together with conventional combined therapy in the treatment of CAPS.

Rituximab is a chimeric monoclonal antibody against CD20, a surface antigen expressed by B cells. Currently, rituximab is approved for relapsed or refractory CD20+, B-cell non-Hodgkin lymphoma, and rheumatoid arthritis [Buch et al. 2011]. In the field of systemic lupus erythematosus (SLE), two randomized controlled trials failed to demonstrate its effectiveness as an add-on therapy [Merrill et al. 2010; Rovin et al. 2012]. However, global analysis of the observational studies [Mosca and van Vollenhoven, 2013], and a meta-analysis [Duxbury et al. 2013], support the off-label use of rituximab in severe, refractory SLE cases, whereas its use as a first-line therapy or in patients with a predominantly mild form of the disease is not advised. Conversely, two randomized controlled trials have demonstrated that rituximab was not inferior to daily cyclophosphamide treatment for induction of remission in severe antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis and may be superior in relapsing disease [Stone et al. 2010; Jones et al. 2010].

Regarding APS, evidence of the effectiveness of rituximab is scarce and comes from a recent open-label phase II trial that has shown the safety of rituximab use in patients with APS and some benefit controlling noncriteria manifestations such as thrombocytopenia, skin ulcers, nephropathy, and cognitive dysfunction [Erkan et al. 2013]. Considering CAPS, the results from a recent review from our group demonstrated that rituximab could have a role in the treatment of patients with refractory CAPS because, regardless of its potential side effects seen in other settings, rituximab was shown to be safe in patients with CAPS with few major side effects [Berman et al. 2013].

Rational basis for the use of rituximab in CAPS

Rituximab induces B-cell death through its binding to the CD20 surface marker. However, the mechanisms of this cell death are not fully understood and three mechanisms have been described: (a) complement-dependent cytotoxicity, which involves the complement system protein C1q; (b) antibody-dependent cellular cytotoxicity, which acts through recruitment of macrophages, natural killer cells, and cytotoxic T cells; (c) apoptosis, induced directly through the binding of rituximab to CD20 [Golay et al. 2000].

The main advantage and rationale for the use of rituximab in systemic autoimmune diseases is that CD20 is expressed throughout the maturation process of B cells, but not on stem cells or fully mature plasma cells. Therefore, the protective immunologic memory derived from plasma cells should be preserved following depletion of CD20-positive B cells [Silverman and Weisman, 2003].

Notably, the effect of rituximab was closely associated with a reduction in anti-dsDNA and antinucleosome antibody levels in SLE patients [Cambridge et al. 2008], and ANCA in ANCA-associated vasculitis [Stone et al. 2010]. Given the evidence for the role of B lymphocytes in aPL generation [Youinou and Renaudineau, 2004], rituximab could decrease the titers of aPL and, therefore, decrease the thrombotic risk of patients with APS. Despite this experimental evidence, the effect of rituximab on aPL generation is contradictory in the clinical studies. On the one hand, Ioannou and colleagues observed the negativization of the immunoglobulin G isotype of anticardiolipin (aCL) antibody titers in seven SLE patients who had received treatment with rituximab and cyclophosphamide [Ioannou et al. 2008]. Moreover, 8 out of 12 APS patients treated with rituximab due to recurrent thrombosis or refractory thrombocytopenia showed normalization or a reduction in aPL titers [Erre et al. 2008]. On the other hand, in a recent uncontrolled and nonrandomized prospective pilot study rituximab was effective in controlling some noncriteria aPL manifestations, such as thrombocytopenia and skin ulcers despite any substantial change in aPL profiles after 12 months of follow up [Erkan et al. 2013]. The authors suggested that improvement might be due to the blockade of B-cell effector functions independently of antibody production. Finally, it is important to highlight that a young female with refractory lupus nephritis developed a stroke 2 weeks after the last dose of rituximab. Of note, she had several previous negative determinations of aPL and lupus anticoagulant (LAC) antibodies was confirmed in two determinations 2 months after rituximab administration [Faillace and De Carvalho, 2012]. The potential generation of aPL by rituximab needs to be analyzed in the future.

Given all this evidence, rituximab may appear an attractive alternative in the treatment of CAPS. Reducing the number of B cells, rituximab may decrease both the aPL titer and also the production of ferritin and cytokines such as tumor necrosis factor-alpha, interleukin (IL)-1, IL-2, and IL-6, that may be responsible for some of the clinical features of CAPS. In other words, the combination of rituximab with the conventional immunosuppressive treatment may work synergistically to achieve, through the depletion of CD20+ precursors of B cells, the decrease in aPL titers and modulation of the inflammatory response.

Clinical evidence of the effectiveness and safety of the use of rituximab in CAPS

The evidence for the use of rituximab in patients with CAPS comes from the recent review performed by our group [Berman et al. 2013]. In this review, we identified 20 out of 441 (4.6%) patients included in the CAPS Registry as of May 2013 who were treated with rituximab.

Regarding therapy, anticoagulation was the most frequent treatment, being used in all patients, followed by glucocorticoids in 17 (85%) patients, intravenous immunoglobulins in 16 (80%), plasma exchange in 13 (65%), and cyclophosphamide in 4 (20%). Overall, 16 (80%) patients were initially treated with the complete combination of anticoagulation plus glucocorticoids plus plasma exchange, and/or intravenous immunoglobulins.

Rituximab was the first-line treatment associated with the combined therapy in eight (40%) patients; in six patients, the reason was the initial severity of clinical picture and, in the remaining two, rituximab was administered as a treatment for lymphoma. In 12 (60%) patients with poor response to the initial treatment or recurrent episodes of CAPS, worsening of thrombocytopenia, or development of new thrombosis, rituximab was the second-line therapy. Rituximab was used in different regimens; the most frequent was two fortnightly doses of 1000 mg (eight patients), followed by four weekly doses of 375 mg/m² (six patients).

Considering the outcome, 16 (80%) patients recovered from the acute CAPS episode and 4 (20%) died at the time of the event. Two of the patients who died had received rituximab as a first-line therapy. The median follow-up time was 9.5 months (interquartile range 17.25; range, 1–36 months). A recurrent episode of thrombocytopenia 24 months after the episode of CAPS developed in a patient requiring an increase of prednisone dosing and a second course of rituximab. Another patient presented with cutaneous necrosis 9 months after a CAPS event and required a high dose of intravenous methylprednisolone and a second 4-week course of rituximab (375 mg/m²/week) with complete resolution. Interestingly, no further episodes of thrombosis developed in the remaining patients.

Regarding the effect of rituximab in an aPL profile, data were available in only eight patients. Overall, half of the patients remained with persistent aPL in the follow up with positive LAC at 11 weeks and LAC plus aCL at 2, 3, and 5 months of follow up, respectively. In the remaining four patients (50%), aPL became negative. Briefly, in one patient, LAC became negative 7 months after the infusion without information on the aCL and anti-β2-glycoprotein I antibodies (aβ2GPI) status after and before rituximab administration. In the second patient, LAC became negative several weeks later following discharge from the hospital. Unfortunately, no information about aCL and aβ2GPI status after rituximab was available. In the third patient, triple aPL negativity was described after 1 month of follow up. Finally, the fourth patient became negative for aβ2GPI. Information on LAC and aCL was not available.

Despite the scientific value of this review, it has several limitations such as the low number of patients with CAPS treated with rituximab, and the difficulty of analyzing the isolated effect of rituximab given that all these patients received a combined therapy including anticoagulation, glucocorticoids, plasma exchange, and/or intravenous immunoglobulins.

Conclusion

Despite the several limitations of the present review, rituximab could have a role in the treatment of patients with refractory CAPS. Given the low prevalence of CAPS, a randomized study to evaluate the effectiveness of any treatment in this setting is very difficult. Information from the CAPS Registry should be valuable in the future to support the use of rituximab in these patients and to attempt to answer questions such as the optimal dose of rituximab, the role of immunosuppressant agents administered together with rituximab, and the usefulness of this biologic drug as a first- or second-line of treatment for CAPS.