Non-criteria manifestations of pediatric APS common yet ‘under-recognized’

Peer-reviewed papers on pediatric antiphospholipid syndrome do not appear very often.

However, when they do, they can be incredibly useful for rheumatologists who find themselves trying to diagnose and manage a patient with this rare and complicated condition, which can present in myriad ways.

Jason S. Kniught

Jacqueline A. Madison

Jason S. Knight, MD, of the department of internal medicine in the division of rheumatology, and Jacqueline A. Madison, MD, of the departments of internal medicine and pediatrics in the divisions of rheumatology and pediatric rheumatology, both at the University of Michigan, in Ann Arbor, recently published a retrospective case series of APS patients aged 18 years or younger.

Together with colleagues, Knight and Madison reviewed medical records from 2000 through 2019, including patients with primary or secondary APS. The results demonstrated that secondary APS occurred in 11 cases, while primary APS was reported in 10 patients. Secondary disease was most commonly diagnosed in patients with systemic lupus erythematosus.

The data also revealed that as many as two-thirds of the cohort demonstrated APS manifestations that did not meet standard criteria for the condition. Such manifestations included thrombocytopenia, autoimmune hemolytic anemia and livedo reticularis/racemosa, according to the findings.

Recurrent thrombosis was reported in 43% of the cohort.

In addition, both primary- and secondary-disease groups showed chronic APS burden as assessed by Damage Index in Patients with Thrombotic APS (DIAPS) scores.

Healio sat down with Knight and Madison to discuss treatments and outcomes in pediatric APS, and the need for diagnostic criteria specific to younger patients.

Healio: There were 11 patients with secondary APS and 10 patients with primary APS. Could you discuss some differences between the two, and the significance of this finding?

Madison: The two groups were actually fairly similar. Among the patients with secondary APS, nine of 11 also had a diagnosis of lupus, which accounts for more positivity for [antinuclear antibodies (ANA)], anti-double-stranded-DNA, and anti-chromatin in the secondary APS group. This was the main difference we found.

Knight: The lack of positivity for these antibodies in primary APS highlights the importance of testing specifically for antiphospholipid antibodies when there is a suspicion for APS. An ANA cannot be used as a screening tool for APS as we sometimes see happen in pediatric clinics.

Madison: We will get to this later, but some features that doctors may typically associate with lupus, such as thrombocytopenia and hemolytic anemia, were also quite common in the primary APS patients, hence there was no difference between primary and secondary APS.

Healio: What about outcomes such as organ damage accrual and thrombosis in this cohort, and in pediatric APS in general?

Madison: We used the DIAPS scoring system as a way of quantifying the degree to which patients accrued organ damage. This was adapted by researchers in Mexico — Mary–Carmen Amigo, MD, FACP, and colleagues — from a lupus damage index and has had some validation over the years in adults. Three patients in our cohort scored high enough to indicate severe damage from their APS. To our knowledge, this is the first application of the DIAPS to pediatric APS.

Knight: An important finding was the frequency of recurrent thrombotic events, which were found in about half of patients. Some of these patients with recurrence even had multiple recurrent events. Recurrences occurred almost entirely when patients were off full-dose anticoagulation, whether on purpose — as when their doctor only prescribed a prophylactic therapy such as aspirin — or by accident — the medication dose was found to be subtherapeutic by blood testing.

This underlines the importance of, and difficulties with, anticoagulation therapy in this pediatric age group. It is worth noting that most of the group were teenagers.

Madison: Another notable finding from this group with recurrence was that although the initial event may have been one type of thrombotic event, the recurrent event could be a different type of thrombotic event. For example, one patient initially had deep vein thrombosis (DVT), but later had an arterial stroke. Also, recurrence sometimes occurred even though antiphospholipid levels had decreased. This disease can be unpredictable.

Healio: What did you learn about the clinical characteristics of pediatric APS?

Knight: In our cohort, we largely had patients with thrombotic events, and venous events were by far the most common, occurring in 62% of patients. There were arterial events in 29% of patients, and small vessel or microscopic events in 24% of patients. We had no confirmed cases of catastrophic APS (CAPS), though in one patient it was suspected. We often think of pediatric patients as too young for pregnancy, but one patient included in this cohort did have obstetric APS.

Healio: What treatment information did you take from this series?

Madison: Although our study was too small to come to conclusions about treatment in pediatric APS, we did note which treatment types had been employed. In both primary and secondary APS, a wide variety of anticoagulation agents were used, but the most common was low-molecular-weight heparin, followed closely by warfarin.

Knight: Two patients had used direct oral anticoagulants, which have a shorter-lived effect in the blood as compared with warfarin, and both had breakthrough thrombotic events. This raises the question of optimal anticoagulant half-life in the pediatric or adolescent age group. Is it safer to use a medication with a more sustained effect in a patient with less-than-optimal adherence to anticoagulation?

Madison: In considering medications besides anticoagulation, immunomodulatory agents and hydroxychloroquine were used more often in patients with secondary APS, likely due to the predominance of lupus diagnoses in this group, but there were also primary APS patients put on these therapies. Overall, although we cannot draw many conclusions, we hope that the information we gathered on treatment may introduce new ideas needing further study in pediatric APS.

Healio: Many of the patients demonstrated non-criteria clinical manifestations of APS. Is this common? Why do you think this happened?

Madison: We think that non-criteria — meaning not included in the strict classification criteria for APS — clinical manifestations of APS are actually probably quite common, but nevertheless under-recognized. Patients were especially likely to have thrombocytopenia or hemolytic anemia. Manifestations like this have been reported in basically every case series of pediatric APS, but the message may still not be out to the doctors working on the ground. We hope that a better understanding of these clinical manifestations may help to identify the disease sooner, especially if included in future pediatric-specific classification criteria.

Healio: What might these findings add to future diagnostic or classification criteria for pediatric APS?

Knight: We really appreciate what Healio is doing to highlight this topic as pediatric-specific criteria are definitely needed. We hope that these findings may add more data to better inform those future diagnostic or classification criteria for pediatric APS, especially in characterizing the non-criteria manifestations.

Madison: We also described two patients with positive anti-phosphatidylserine/prothrombin (PS/PT) antibodies. These antibodies are not currently part of the classification criteria for APS, and with more study, they could be considered when developing future criteria.

Healio: Classification criteria for clinical trials and diagnostic criteria for individual patients can differ or be applied differently. Is this the case in pediatric APS?

Madison: Yes, classification criteria have been developed for APS, but there are no diagnostic criteria and no pediatric-specific classification criteria. Meeting the classification criteria can give a physician more confidence in making a diagnosis, but some patients who may have the diagnosis do not fulfill the current classification criteria. Ultimately, it is up to a physician’s discretion when making a diagnosis and developing a treatment plan.

Healio: In your conclusion, you mention the need for pediatric-specific classification criteria. Could you discuss what this might include, specifically in the context of criteria for clinical trials vs. individual diagnoses?

Madison: We suspect that when pediatric-specific classification criteria are developed, they are likely to include some of these other non-criteria clinical manifestations, such as thrombocytopenia, hemolytic anemia, and livedoid skin rashes. They could also include some non-criteria lab tests, such as the anti-PS/PT antibodies.

Knight: Such an effort is very much necessary to enable clinical trials. At the same time, the attention afforded to classification criteria does seem to make doctors in the clinic smarter when they are attempting to make a diagnosis.

Madison: Ultimately, our goal would be for pediatric APS to be able to be diagnosed sooner before a potentially devastating thrombotic event occurs. There is a good chance that pediatric APS is underdiagnosed, but we will not know that for sure until the knowledge is disseminated, and testing is more widely implemented.

Reference:

Madison JA, et al. Pediatr Rheumatol. 2022;doi:10.1186/s12969-022-00677-8.