A Young Disease: A Holistic Approach to the Treatment of Antiphospholipid Syndrome

EULAR 2022 (VIRTUAL)—Described only about 40 years ago, antiphospholipid syndrome (APS) is a relatively young disease. It wasn’t until 2019 that the European Alliance of Associations for Rheumatology (EULAR) published evidence-based recommendations for the management of APS in adults, and the ACR has not yet released clinical practice guidelines.¹ Although progress is being made, we still have a lot of questions to answer regarding best management practices.

At the EULAR 2022, Ricard Cervera, MD, PhD, senior consultant and head, Department of Autoimmune Diseases, Hospital Clinic of Barcelona, Spain, described a holistic approach to the treatment of APS.

Clot Risk

The incidence of first thrombosis depends on multiple factors, such as the antiphospholipid antibody (aPL) profile, which is defined by the aPL type, multiple vs. single aPL positivity, apL titers and the persistence of aPL positivity on repeated measurements.¹ A high-risk aPL profile is defined as the presence—on two or more occasions at least 12 weeks apart—of a lupus anticoagulant, double or triple aPL positivity, or the presence of persistently high aPL titers.

The aPL profile helps determine the risk of thrombotic and obstetric events and informs the aggressiveness of treatment. Example: The incidence of events is less than one per 100 patient-years in aPL asymptomatic carriers, but rises to seven per 100 patient-years in patients with systemic lupus erythematosus (SLE) with obstetric APS.² The EULAR recommendations for the management of APS in a patient vary based on aPL profile, history of thrombosis or obstetric complication, coexistence of other systemic autoimmune diseases and the presence of traditional cardiovascular risk factors.¹

Primary Thromboprophylaxis

Is there anything we can do to prevent clots from occurring in the first place? A 2007 randomized controlled trial—the APLASA study—showed no protective benefit of aspirin for primary thromboprophylaxis in asymptomatic aPL-positive individuals. However, a 2014 meta-analysis of 11 studies found asymptomatic aPL-positive patients treated with long-term, low-dose aspirin (75–100 mg daily) had a 50% risk reduction for occurrence of first clot.³ This finding held true for patients with SLE and obstetrical APS.

EULAR recommends low-dose aspirin for primary thromboprophylaxis in patients who have a high-risk aPL profile, SLE or obstetrical APS. Low-dose aspirin may also be considered for those with lower risk aPL profiles.¹

Would anticoagulation added to aspirin also help prevent primary thrombosis? In 2014, the ALIWAPAS trial examined low-dose aspirin vs. low-dose aspirin plus low-intensity warfarin (i.e., international normalized ratio [INR] goal of 1.5) for primary thromboprophylaxis in aPL-positive individuals with SLE or obstetric morbidity (i.e., higher risk patients).⁴

“Results were not as expected,” Dr. Cervera said. No significant difference was found in the number of thromboses between groups, but patients on combination therapy had more episodes of bleeding.

“At this time, I recommend low-dose aspirin for primary thromboprophylaxis,” Dr. Cervera said. “Should a patient have an aspirin allergy, low molecular weight heparin [LMWH] should be considered for high-risk individuals. Smoking and sedentarism should be avoided, and hypertension and hyperlipidemia effectively controlled. Hydroxychloroquine should also be used for clot prevention in SLE [because] studies show a protective benefit.”⁵

The EULAR recommendations for the management of APS vary based on the patient’s aPL profile, history of thrombosis or obstetric complication, coexistence of other systemic autoimmune diseases & the presence of traditional cardiovascular risk factors.

Secondary Thromboprophylaxis

In 1995, a landmark trial demonstrated the benefit of warfarin with a goal INR of 3 to 4 for secondary prevention of venous clots in APS.⁶ Thereafter, similar benefit was confirmed for the currently recommended INR target of 2 to 3, though a higher target may be appropriate for certain patients.⁷

When it comes to arterial clots, the situation may be different. The Euro-Phospholipid Project followed 1,000 patients with APS over 10 years. With the implementation of warfarin, the incidence of venous thrombosis declined over time, but there was still an excess of arterial thrombosis at the 10-year mark.⁸

“This means the therapy we’re prescribing to our patients is still not good enough to prevent arterial thrombosis. An INR of 3 to 4 and/or the addition of low-dose aspirin may be the right thing to do in these cases,” he said

Direct Oral Anticoagulants in APS

Warfarin is the cornerstone of secondary thromboprophylaxis in APS, but INR monitoring is taxing on patients and providers alike. What about direct oral anticoagulants?

“We suspected that these may be a good solution, especially for refractory patients,” Dr. Cervera said. “Initial mechanistic studies showed promise, but the TRAPS study—the randomized controlled trial comparing rivaroxaban to warfarin in patients with APS—was discontinued early due to an excess of thrombosis in those receiving rivaroxaban.”⁹

The results of the TRAPS study led to warnings from international agencies to avoid the use of direct oral anticoagulants in patients with APS. But the patients studied were high-risk with triple positive aPLs. Dr. Cervera said, “There’s some new information and longer follow-up data that suggest it’s probably not necessary to avoid [direct oral anticoagulants] in all APS patients. Patients with venous thrombosis only, or only single or double aPL positivity may do okay on these drugs. We are revisiting this question.”

CAPS

Catastrophic antiphospholipid syndrome (CAPS) is a highly lethal variant of APS, causing multi-organ failure due to microcirculation thrombosis. The good news is that it’s relatively uncommon. According to data from the European Forum on aPL CAPS Registry, only 1% of patients with APS develop CAPS.¹⁰ The CAPS Registry was created in the year 2000 and now includes about 1,000 patients worldwide.

“Initially, the mortality rate from CAPS was 50%,” Dr. Cervera said. “So the 50% who recovered—what therapies did they receive? If they received the combination of anticoagulation, steroids and plasma exchange [PLEX] or intravenous immunoglobulin [IVIG], the survival rate was as high as 70%.”  This finding was a statistically significant difference compared with other treatment combinations.¹¹

These data ultimately led to the proposal of triple therapy for CAPS, which includes anticoagulation, high-dose intravenous glucocorticoids and PLEX with or without IVIG.^12,13 Glucocorticoids are included to treat the cytokine storm and systemic inflammatory response that occur in CAPS.  PLEX and IVIG help remove the aPL and cytokines from the body as quickly as possible.

“We are very proud to share that with the use of triple therapy, the mortality rate from CAPS has decreased from 75% (if no drugs are used) to 26%. In other words, the risk of death is nearly 10 times higher if you don’t use triple therapy. The importance of this cannot be stressed enough,” Dr. Cervera said.¹⁴

Despite the success of triple therapy, some patients with CAPS relapse or don’t respond to triple therapy. In these cases, adding rituximab is an option.¹⁵ Because complement is involved in APS pathogenesis, adding eculizumab, a monoclonal antibody targeted against complement C5, may be another option.¹⁶ 

We are very proud to share that with the use of triple therapy, the mortality rate from CAPS has decreased from 75% (if no drugs are used) to 26%. —Dr. Cervera

Ask the Expert

Dr. Cervera was kind enough to field questions from the audience at the end of his talk.

Question: What about the risk of thrombosis with IVIG? 

Dr. Cervera: Be aware that [thrombosis] is a potential risk, but it’s a small risk as compared with the benefits in this very fatal condition [CAPS].

Question: What about heparin-induced thrombocytopenia?

Dr. Cervera: In this case, use fondaparinux.

Question: Do you discuss the risk of CAPS with all of your patients with APS?

Dr. Cervera: Patients with triple aPL positivity are at higher risk of developing CAPS, but there are single aPL-positive patients who can get it too. The most important thing is to avoid triggers, such as infection, surgical procedures and lupus flares. Even a simple upper respiratory infection or minor procedure, such as a dental extraction or renal biopsy, can trigger CAPS. Pregnancy can, too. So discuss potential triggers with your patients, and try to prevent those that you can.

Question: What do you recommend for patients with APS and low platelets?

Dr. Cervera: Fortunately, thrombocytopenia isn’t an issue when treating typical APS because platelets are rarely less than 70,000/mL. But in CAPS, platelet levels can be life-threateningly low. In those cases, first try to increase the platelets with glucocorticoids and IVIG. As soon as platelets are above 10,000–15,000, you can start low-dose heparin prophylaxis. When they reach 40,000 to 50,000, you can start full-dose anticoagulation.

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Samantha C. Shapiro, MD, is an academic rheumatologist and an affiliate faculty member of the Dell Medical School at the University of Texas at Austin. She is also a member of the ACR Insurance Subcommittee.

References

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