16th International Congress on Antiphospholipid Antibodies Task Force Report on Catastrophic Antiphospholipid Syndrome

Abstract

The Task Force on Catastrophic Antiphospholipid Syndrome (CAPS) met again on occasion of the 16th International Congress on Antiphospholipid Antibodies (aPL) that was held in Manchester, England, in September 2019. Its aims were to assess the up-to-date knowledge on pathogenesis, clinical and laboratory features, diagnosis and classification, precipitating factors, and treatment of CAPS. This article summarizes the main aspects that were presented during the Task Force meeting at that Congress.

Keywords

Anticardiolipin antibodies antiphospholipid syndrome catastrophic antiphospholipid syndrome

Introduction

Catastrophic antiphospholipid syndrome registry update

Most of our knowledge about CAPS is based on the “CAPS Registry”, a web-based database created in order to increase awareness of this disease.¹ It aims to assemble all CAPS cases published or reported to the registry. The “CAPS Registry” is available online at https://ontocrf.grupocostaisa.com/en/web/caps/home. The number of publications and case reports on this life-threatening situation included in MEDLINE is increasing every year since its description in 1992 by Ronald Asherson, thus reflecting the increased awareness of this syndrome within the scientific community. Up to September 2019, 335 papers with “catastrophic antiphospholipid syndrome” in the title were available in PubMed, from whom 193 have the label of “case report”.

Up to September 2019, the CAPS registry included 547 patients corresponding to 571 episodes of CAPS. Overall, 70% are females, with a mean age of 39 years (SD = 17) (range, 0 to 85 years). Half of these cases developed the catastrophic event as their first clinical manifestation of antiphospholipid syndrome (APS). Twenty-eight percent presented in association with systemic lupus erythematosus (SLE), 3% with a SLE-like (clinical and/or laboratory features of SLE not fulfilling SLE criteria), and the remaining cases were associated with other autoimmune diseases such as rheumatoid arthritis. Overall, 60 (11%) presented in childhood, and 47 (9.3%) patients were over 65 years of age. The association between CAPS and SLE was rare in the elderly patients with CAPS (5%).²

CAPS was usually related to a precipitating factor.³ A trigger was found in 68% of episodes, of which the most frequent were infections (29%), followed by surgeries (9%) and malignancies (9%). Other precipitants less often described were estrogen use (4%), pregnancy or puerperium (3%), drugs (3%) and SLE flares (2%). Infections were more often described in the pediatric age group, while malignancies were more often reported in elderly patients and in males.³

Regarding the clinical manifestations, the kidneys were the organ system more often affected (74%), followed by the lungs (55%), the brain (56%), the heart (53%), and the skin (45%). Other organs less often affected were the skin (47%), liver (34%), peripheral vessels (37%), and the gastrointestinal tract (12%).

All patients with renal involvement had renal failure, often with proteinuria (97%) with a mean protein loss of 3.7 g in 24 h, and almost half in the nephrotic range (47%). More than three quarters of patients with renal involvement had hematuria (79%). Most patients with renal involvement were females (66%), often with fever (62%) and hypertension (68%). Two thirds of those with renal involvement had laboratory features of hemolysis and 40% fulfilled criteria for thrombotic thrombocytopenic purpura (TTP). Only a few patients had a kidney biopsy undertaken but those showed pathologic features of thrombotic microangiopathy (85%) and some showed features of proliferative glomerulonephritis (35%).

Among laboratory investigations, thrombocytopenia was frequent, detected in 60% of cases, while 15% showed features of microangiopathic hemolytic anemia. Lupus anticoagulant (LA) was present in 83% of episodes, IgG isotype of anticardiolipin antibodies (aCL) was positive in 81%, with IgM aCL positivity in 51%. Anti-β₂-glycoprotein-I antibodies (aβ₂GPI) were reported in 75%, while IgM aβ₂GPI was reported in 44% of cases. However, there was heterogeneity in reporting of these data.

Overall, mortality was 36%. The so-called triple therapy with anticoagulation, glucocorticoids, plasma exchange, and/or intravenous immunoglobulin was used in 45% of the cases who survived.⁴ In refractory cases, novel therapies such as rituximab or eculizumab are emerging as a rescue therapy, although there are only a small number of cases reported to date.⁵,⁶

Although the potential biases inherent in reported cases can bias the findings on the CAPS Registry analysis, the number of patients included in the CAPS Registry gives robustness to the results of this effort - it is currently the most comprehensive source of information on this rare disease for use by clinicians and researchers.

To summarize, CAPS seems to involve mostly young patients in their 4^th decade of life, although cases in both genders and all ranges of age have been reported. It is usually associated with a trigger, and among them infections and malignancies are the most frequent. CAPS involves all organs and body systems but kidney, lung, and central nervous system are the most frequent organs affected. Although most patients with CAPS appear to show “triple positivity” for LA, aCL, and aβ₂GPI, these data need to be further explored. Triple therapy is considered the first-line treatment of CAPS, given its association with survival. However, although the use of triple therapy appears to have improved the survival of patients with CAPS, a third of patients still died due to the catastrophic event.

Summary of the “McMaster RARE-Bestpractices clinical practice guideline on catastrophic antiphospholipid syndrome”

The “McMaster RARE-Bestpractices Clinical Practice Guideline on CAPS” was funded by the European Commission Seventh Framework program.⁷ The RARE-Bestpractices group identified CAPS as a rare disease of interest in which a guideline could be created, both for the purposes of assisting in clinical decision-making, as well as to test the hypothesis that guidelines can be developed for rare diseases using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach.⁸ The steering committee and methodology work were based at McMaster University, and a panel of experts from Canada, the European Union, the United Kingdom, and the United States was convened as guideline developers. The panel consisted of clinical and laboratory experts in CAPS/APS, and experts in GRADE methodology. The guideline developers utilized the Guidelines International Network-McMaster Guideline Development checklist and GRADE methodology as the process for guideline development.⁸,⁹ Conflicts of interest were declared using the World Health Organization Conflict of Interest Guidelines and Procedures and were managed by abstention.¹⁰

The panel progressed through the GRADE development steps guided by the steering committee. Panel members were provided with training on GRADE methodology and guideline development process using a web-based tutorial and webinar. A preliminary question list was developed using the GradePRO online platform, and the question list then underwent a prioritization exercise by the panel members. The 10 questions deemed of highest priority were retained for use for formulation of guideline recommendations (Table 1). Outcomes were similarly generated and prioritized, and the ultimate list included the seven outcomes of death, permanent organ dysfunction, permanent neurologic deficit, complete recovery, major bleeding, amputation, and thrombotic event. Systematic reviews of the evidence were undertaken for each question, and Evidence Profiles, and Summary of Findings tables were created. Further searches were undertaken for values and preferences and economic analyses pertaining to each question, and Evidence to Decision tables were created.¹¹,¹² These were available to the panel members for review prior to the meeting and formed the main basis for guideline recommendations.

Table 1.

Prioritized questions for CAPS clinical practice guideline.

Diagnosis Questions

1. Should the Preliminary Criteria for Classification of catastrophic antiphospholipid syndrome (CAPS) be used to diagnose CAPS in patients with features suggest of CAPS?

2. Should biopsy be used to diagnose CAPS in patients with suspected CAPS?

3. Should criteria with detection of antiphospholipid antibodies be used to diagnose CAPS in patients with suspected CAPS?

Therapy Questions

4. Should combination therapy with glucocorticoids, unfractionated heparin, and plasmapheresis and/or IVIG be used as first-line therapy for CAPS?

5. Should anticoagulation be used as first-line therapy for CAPS?

6. Should plasmapheresis be used as first-line therapy for CAPS?

7. Should IVIG be used as first-line therapy for CAPS?

8. Should antiplatelets be used as first-line therapy for CAPS?

9. Should rituximab be used as first-line therapy for CAPS?

10. Should glucocorticoids be used as first-line therapy for CAPS?

While the systematic reviews forms the main basis for panel decision-making on guideline recommendations, the methodologists and panel explored two novel means for gathering evidence to address issues unique to rare diseases. Firstly, concern was raised that given the low certainty of evidence common in studies of rare diseases, the decisions resulting from a panel discussion might become influenced predominantly by expert opinion and experiences, rather than relying on the more rigorous and transparent process of analysis of the data at hand. This could allow for a biased discussion and decision-making process based on anecdotal recollections. To mitigate this potential bias, as well as to quantify the collective expertise at the table, systematic collection of prior experience and opinion was sought in advance using Systematic Observation Forms developed by the methodologists. These forms asked the investigators to describe the number of CAPS patients, their outcomes, and perceived efficacy and safety of key interventions. This data was then tabulated and presented to the panel for each question. Any discussion that arose regarding an individual’s personal perceptions of efficacy or safety was then highlighted and compared against the collective experience to minimize the effect of anecdote on any guideline recommendation.

The second method for gathering evidence involved direct interrogation of the CAPS Registry to obtain data for each respective question rather than relying purely on the published evidence. This was accomplished by a database expert from McMaster University who was available on-site during the panel meetings to generate information to assist the decision-making process. The rationale for this method was that the published data on the most recent complete registry cohort was nearly seven years out of date, and close to 200 additional cases had been collected at the time of the panel meeting. It was felt that use of all available data was preferable in a rare disease with a relative paucity of available data such as CAPS.

The panel met in person in Barcelona, Catalonia, on April 27, 2016, and online on June 3, 2016 to complete discussions. Final voting on all guideline questions was completed online in July 2016. The panel was able to come to a consensus recommendation using this process for all questions (Table 2). Each guideline recommendation is accompanied by the certainty of evidence and strength of recommendation. In addition, the full guideline describes a summary of the evidence used for each recommendation, and explanations and special considerations regarding each recommendation.⁷ The Evidence Profiles and Evidence to Decision tables, along with the data from the Systematic Observation Forms, are also available as supplements to the guideline.

Table 2.

Guideline recommendations, certainty of evidence and strength of recommendation.

Recommendation	Strength of recommendation, certainty of evidence
Diagnosis
1. For patients suspected of having CAPS, the panel suggests using the Preliminary Criteria for Classification of the Catastrophic Antiphospholipid Syndrome for diagnosis of CAPS	conditional recommendation,very low certainty of evidence
2. For patients suspected of having CAPS, the panel suggests either using or not using biopsy to diagnose CAPS	conditional recommendation,very low certainty of evidence
3. For patients suspected of having CAPS, the panel suggests using antiphospholipid antibodies to diagnose CAPS	conditional recommendation, very low certainty of evidence
Therapy
4. For first-line treatment of patients with CAPS, the panel suggests combination therapy with glucocorticoid, heparin, and plasmapheresis or IVIG over single agents or other combinations of therapies	conditional recommendation, very low certainty of evidence
5. For first-line treatment of patients with CAPS, the panel recommends using therapeutic dose anticoagulation	strong recommendation, very low certainty of evidence
6. For first-line treatment of patients with CAPS, the panel suggests using plasmapheresis	conditional recommendation, very low certainty of evidence
7. For first-line treatment of patients with CAPS, the panel suggests using intravenous immune globulin	conditional recommendation, very low certainty of evidence
8. For first-line treatment of patients with CAPS, the panel suggests using antiplatelet agents as add-on therapy. In patients for whom anticoagulation is contraindicated for reasons other than bleeding, the CAPS guideline panel recommends using antiplatelet agents as an alternative	for add-on therapy: conditional recommendation, very low certainty of evidencefor alternative therapy to anticoagulation: strong recommendation, very low certainty of evidence
9. For first-line treatment of patients with CAPS, the panel suggests not using rituximab.	conditional recommendation, very low certainty of evidence
10. For first-line treatment of patients with CAPS, the panel suggests not using glucocorticoids.	conditional recommendation, very low certainty of evidence

The guideline recommendations were presented initially at the European League against Rheumatism European Rheumatology Congress in June 2017, and the guideline methodology was presented at the American College of Rheumatology annual meeting in November 2017.¹³,¹⁴ The complete guideline was published in the Journal of Thrombosis and Haemostasis in 2018.⁷

Therefore, the “McMaster RARE-Bestpractices Clinical Practice Guideline on CAPS” achieved its objective of developing guideline recommendations in a rare disease using the GRADE methodology. We expect that the guideline will be useful for clinicians caring for CAPS patients.

Unmet needs on the diagnosis and management of catastrophic antiphospholipid syndrome

The presentation of CAPS, mainly (micro)thrombosis and hematologic manifestations, i.e., thrombocytopenia and anaemia, may evolve gradually, commonly overlapping with other thrombotic microangiopathy (TMA) conditions. Thus, the diagnosis and management of CAPS, which also requires a high index of clinical suspicion, can be challenging.

Unmet needs on the diagnosis

The challenges of CAPS diagnosis in general, and diagnostic algorithms to guide clinicians, are discussed elsewhere.¹⁵ The task force concluded the major diagnostic unmet need is the lack of specific tests to better subgroup catastrophic APS patients, as well as to differentiate them from those with other TMA conditions.

Based on the CAPS classification criteria,¹⁶ definite CAPS is defined as thromboses in three or more organs developing in less than a week, microvascular thrombosis in at least one organ, and persistent aPL positivity. However, when only three out of four requirements are met, the patient is classified as probable CAPS. Furthermore, aPL-positive patients exist with solely microvascular involvement, e.g., diffuse pulmonary hemorrhage (DAH), that do not fulfill the definite or probable CAPS criteria (“microvascular APS”).

Microvascular involvement with/without thrombocytopenia or anemia is not specific for CAPS. “TMA” describes microvascular disease with ischemia due to fibrin formation and/or platelet aggregation resulting in occlusion of arterioles and capillaries. This endothelial injury-related thrombosis in arterioles and capillaries is commonly associated with thrombocytopenia, microangiopathic haemolytic anaemia, and organ failure (usually kidney); usually referred as “TMA syndrome”, which is an umbrella term for several conditions (e.g., TTP, hemolytic-uremic syndrome [HUS], atypical HUS, Hemolysis -Elevated Liver Enzymes - Low Platelet [HELLP] syndrome, sepsis, or heparin-induced thrombocytopenia [HIT]).

Thrombotic thrombocytopenic purpura, which can be hereditary (ADAMTS13 mutations) or acquired (antibodies against ADAMTS13), can present with a wide spectrum of manifestations including microangiopathic haemolytic anaemia, thrombocytopenia, neurologic manifestations, gastrointestinal symptoms, purpura, and/or renal disease. Hereditary (mutations of the complement regulatory proteins) or primary acquired (antibodies against factor H) complement-mediated TMA (CM-TMA) develops secondary to the uncontrolled activation of the alternative complement pathway. Of note, these CM-TMA patients were previously classified as atypical HUS, clinically defined as: a) thrombocytopenia; b) microangiopathic haemolysis (normal or near-normal ADAMTS13 activity and negative testing for Shiga-toxin); and c) neurological, renal, or gastrointestinal involvement.¹⁷

CAPS patients with thrombocytopenia, when compared with those without thrombocytopenia, are more likely to develop haemolysis, schistocytes, disseminated intravascular coagulation, and high fibrin degradation products.¹⁸ Thus, a subgroup of CAPS patients exists with predominant haematologic manifestations, sometimes overlapping with other TMA conditions. Unfortunately, the true prevalence of aPL in these TMA conditions is unknown and, without comparison studies between CAPS and other TMA conditions, it is difficult to know whether aPL are bystanders or truly pathogenic when these conditions coexist together.

Given that aPL can trigger complement system, which eventually activates endothelial cells, neutrophils, monocytes, and tissue factor expression^19–21 there have been recent studies of SLE and/or APS patients presenting with CM-TMA. Two recent case series investigated the role of complement inhibition in the management of these patients.²²,²³ In one of these studies,²³ complement-related protein mutations were detected in six of 10 patients. In another report, a rare heterozygous mutation in exon 13 of the C3 gene (c.1677C>T; p.C559C) was detected in a CAPS patient presenting with biopsy-proven renal TMA, myocardial ischemia, DAH, thrombocytopenia, and haemolytic anaemia.²⁴ More recently, Chatuvedi et al. prospectively demonstrated the complement activation via cell surface deposition of C5b-9 and complement-dependent cell killing (the modified Ham assay) in thrombotic APS patients; the investigators also performed targeted sequencing to demonstrate that CAPS is associated with rare germline variants in complement regulatory genes.²⁵

For CAPS diagnosis, although clinical presentation, traditional blood tests (e.g., aPL profile, platelet count, anti-platelet factor-4/heparin antibodies, schistocystes, or lactic acid dehydrogenase, ADAMTS13, or fibrinogen levels), or non-traditional tests (e.g., complement-mediated aHUS/TMA gene panel, aHUS complement panel, anti-complement Factor H antibody, or complement deposition in tissue biopsies), may help determine the most likely etiology to guide the management, it is usually challenging to determine which of the TMA conditions discussed above (including CAPS) is the major driving force behind the clinical presentation of these acutely ill and rapidly progressing patients. Furthermore, these non-traditional tests are not widely available and, when available, results are only partially helpful to subgroup or differentiate CAPS patients, or to predict the treatment response.

Unmet needs on the management

The management of CAPS, which is usually complicated due to the high risk of bleeding, is discussed above and more information can be found elsewhere.⁶,²⁶ The task force concluded that, besides the lack of controlled clinical trials, a major management unmet need is to better understand the role of immunosuppressive approach²⁷ in the management of microvascular and CAPS patients.

There have been reports of CD 20 specific B-cell inhibition, terminal (C5) complement inhibition, mechanistic target of rapamycin inhibition, vascular endothelial cell modulation, statins, and traditional immune-mediated disease–modifying agents (hydroxychloroquine, mycophenolate mofetil, azathioprine, and cyclophosphamide) use in the management of microvascular APS and/or CAPS patients.²⁷ However, we hope that in parallel to: a) our increased understanding of aPL-mediated mechanisms, additional immunosuppressive pathways will be investigated in CAPS, and b) the improvement in diagnostic tools, CAPS patients will be better subgrouped for more targeted medication choices.

Concluding remarks

Thirty years after the introduction of the term CAPS to define this severe subset of APS patients, many advances in our understanding have been made, and patient outcomes have clearly improved. However, the unmet needs depicted in this article are still waiting solutions, and the CAPS Task Force will continue pursuing this objective.

Footnotes

Acknowledgements

The authors want to thank Dr. Mark Crowther for his critical review of this manuscript.

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

ORCID iDs

Ricard Cervera

Kim Legault

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