PROF.

ALFONSO IORIO (Orcid ID : 0000-0002-3331-8766)

Accepted Article
Article type : Recommendations and Guidelines

Title: McMaster RARE-Bestpractices Clinical Practice Guideline on Diagnosis and

Management of the Catastrophic Antiphospholipid Syndrome

Running Head: Guideline on Catastrophic Antiphospholipid Syndrome

Authors: Kimberly Legault, MD, MSc, FRCPC1, Holger Schunemann, MD, MSc, PhD1, Chris
Hillis, MD, MSc, FRCPC1, Cindy Yeung, BSc, MSc1, Elie A. Akl, MD, MPH, PhD1,2, Marc
Carrier, MD, MSc, FRCPC3, Ricard Cervera, MD, PhD, FRCP4, Mark Crowther, MD, MSc,
FRCPC1, Francesco Dentali, MD5, Doruk Erkan, MD, MPH6, Gerard Espinosa, MD, PhD4,
Munther Khamashta, MD, PhD, FRCP7, Joerg J Meerpohl, MD8, Karen Moffat, BEd, MSc,
FCSMLS(D)1,9, Sarah O’Brien, MD10, Vittorio Pengo, MD11, Jacob H Rand, MD6, Ignasi Ro-
driguez Pinto, MD, MSc12, Lisa Thom, Alfonso Iorio, MD, PhD, FRCPC1

Affiliations: 1McMaster University, Hamilton (Canada), 2American University of Beirut, Bei-

rut (Lebanon), 3University of Ottawa, Ottawa (Canada), 4University of Barcelona, Barcelona
(Spain), 5Insubria University, Insubria (Italy), 6Hospital for Special Surgery, Weill Cornell
Medicine, New York, NY, 7King’s College London, London (UK), 8Cochrane Germany, Med-
ical Center - University of Freiburg; Faculty of Medicine, University of Freiburg, Freiburg
(Germany), 9Hamilton Regional Laboratory Medicine Program, Hamilton (Canada),
10
Nationwide Children’s, Columbus (USA), 11University of Padova, Padua (Italy), 12Hospital
Clínic, Barcelona (Spain)

Correspondance and reprint requests to:

Dr. K. Legault, MD
A3-14, Juravinski Hospital, 711 Concession St., Hamilton, ON, L8V 1C3
(p) 905-521-2100 x43778, (f) 905-297-9000
legauk2@mcmaster.ca

This article has been accepted for publication and undergone full peer review but has not
been through the copyediting, typesetting, pagination and proofreading process, which may
lead to differences between this version and the Version of Record. Please cite this article as
doi: 10.1111/jth.14192
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 Summary

Background
Accepted Article
The McMaster RARE-Bestpractices project group selected the catastrophic

antiphospholipid syndrome (CAPS) for a pilot exercise in guideline development for a

rare disease.

Objectives

The objectives of this exercise were to provide a proof of principle that guidelines

can be developed for rare diseases, and assist in clinical decision-making for CAPS.

Patients/Methods

The GIN-McMaster Guideline Development checklist and GRADE methodology were

followed throughout the guideline process. The CAPS guideline was coordinated by

a steering committee, and the guideline panel was formed with representation from

all relevant stakeholder groups. Systematic reviews were performed for the key

questions. To supplement the published evidence, we piloted novel methods includ-

ing use of an expert-based evidence elicitation process, and ad hoc analysis of reg-

istry data.

Results

This paper describes the CAPS guideline recommendations, including evidence ap-

praisal, and discussion of special circumstances and implementation barriers identi-

fied by the panel. Many of these recommendations are conditional, due to subgroup

considerations in this heterogeneous disease, as well as variability in patient values

and preferences.

This article is protected by copyright. All rights reserved.

 Conclusions

The CAPS clinical practice guideline initiative met the objective of the successful de-
Accepted Article
velopment of a clinical practice guideline in a rare disease using GRADE methodolo-

gy. We expect that clinicians caring for patients with suspected CAPS will find the

guideline useful to assist with diagnosis and management in this rare disease.

Keywords

Antibodies, Antiphospholipid; Antiphospholipid Syndrome; Practice Guideline; Rare

Diseases; Thrombosis

Catastrophic Antiphospholipid Syndrome (CAPS) is a complex clinical syn-

drome characterized by the rapid onset of multifocal thrombosis associated with mul-

ti-organ failure in patients meeting the serological criteria for antiphospholipid syn-

drome (APS) [1,2]. CAPS is a rare (prevalence of less than one in 2,000) disease

with approximately 600 reported cases and mortality estimated at 50% [3-5]. An in-

ternational consensus process involving experts in the field issued the Preliminary

Criteria for Classification of CAPS in 2003 (Table 1) [6].

Developing evidence-based clinical guidelines in the field of rare diseases such

as CAPS is challenging due to limited primary evidence; lack of randomized trials;

reluctance to make ‘weak’ recommendations which could jeopardize the chance of

getting treatment funding; and limited patients available for involvement [7]. Howev-

er, clinical practice guidelines are critical in assisting clinicians in management of ra-

re disorders, where they may have limited experience. Systematically created guide-

lines are invaluable in providing this assistance using all available evidence while

communicating the quality of the evidence and highlighting where clinical judgement

is required.

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 The RARE-Bestpractices project is a European Commission funded project that

prioritized CAPS for a pilot exercise in guideline development for a rare disease, to
Accepted Article
assist in clinical decision-making, and as proof of principle that guidelines can be de-

veloped for rare diseases. To accomplish this, a panel of international experts uti-

lized the GIN-McMaster Guideline Development checklist and GRADE methodology

to attempt to develop guidelines on rare diseases [8,9].

MATERIALS AND METHODS

A detailed description of the methods to produce this guideline, and the Evidence to

Recommendation Frameworks are contained in Data S1-S5. The multidisciplinary

guideline panel convened in Barcelona on April 27, 2016 followed by web-

conferencing and online voting.

Using a consensus process, the panel selected ten questions, and seven out-

comes (Table 2).

The Panel graded recommendations as “strong” (“the panel recommends”), or

“conditional” (“the panel suggests”), for or against a specific intervention (Table 3)[9].

The draft recommendations underwent a public comment period from April 26 - May

19, 2017 on the American Society of Hematology website, and suggestions were

used to clarify recommendations, and to highlight circumstances requiring special

consideration. These guidelines were endorsed by the American Society of Hema-

tology on July 21, 2017.

Role of funding source: The funding source had no role in study design, collection,

analysis, or interpretation of data, in writing the report, nor in the decision to submit

the paper for publication.

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 RESULTS

A summary of all recommendations is presented in table 4.

Accepted Article
Section 1: Diagnosis

Recommendation 1: For patients suspected of having CAPS, the panel sug-

gests using the Preliminary Criteria for Classification of the Catastrophic

Antiphospholipid Syndrome for diagnosis of CAPS. (conditional recommenda-

tion, very low certainty of evidence).

Explanation and special considerations: The panel felt the balance of desirable and

undesirable effects of use of the Preliminary Criteria for diagnosis of CAPS favored a

conditional recommendation for its use [6]. While the classification criteria were de-

veloped for research, there is not another systematic approach to CAPS diagnosis.

Because diseases on the differential diagnosis for CAPS would often be treated with

anticoagulation and immunomodulation, the risk of adverse effects secondary to

false positives may be acceptable. The main concern with a false negative result is

that anticoagulation or immunomodulation may be withheld. However, these thera-

pies may be employed regardless for aspects of the clinical presentation, e.g. anti-

coagulation for thrombosis. Treatment should not be delayed until all criteria are

filled as some criteria (e.g. antiphospholipid antibody (aPL) testing) take time to re-

sult.

Summary of evidence: There is one study validating the Preliminary Criteria in 220

CAPS Registry patients compared to 175 unselected SLE and APS patients [10].

Sensitivity was 90% and specificity 99%. Certainty of evidence was low), due to risk

This article is protected by copyright. All rights reserved.

 of bias (investigators were not blinded to the underlying diagnosis), and indirectness

(the control group did not include mimickers of CAPS).

Accepted Article
The adverse effects associated with administering the Preliminary Criteria are

the risks of the individual tests such as biopsy.

There were no studies evaluating cost of use of the Preliminary Criteria in

CAPS.

Recommendation 2: For patients suspected of having CAPS, the panel sug-

gests using biopsy to diagnose CAPS in select cases (conditional recommen-

dation, very low certainty of evidence).

Explanation and special considerations: The panel felt that a positive biopsy would

be helpful to rule in CAPS (high specificity), a negative biopsy would not rule out

CAPS (low sensitivity), and thus biopsy results may not guide treatment. Moreover,

since the risk of biopsy differs depending on site, severity of illness and bleeding risk,

the decision to biopsy will vary.

Summary of evidence: No articles comparing biopsy versus no biopsy for CAPS di-

agnosis were identified. A search for sensitivity and specificity of biopsy in detecting

small vessel thrombosis did not yield any results. The adverse effects associated

with biopsy will differ depending on the organ involved. There are no studies as-

sessing cost of a biopsy in CAPS.

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 Recommendation 3: For patients suspected of having CAPS, the panel sug-

gests using antiphospholipid antibodies to confirm the diagnosis of CAPS,

Accepted Article
without delaying empiric treatment (conditional recommendation, very low cer-

tainty of evidence).

For patients suspected of having CAPS, the panel suggests using antiphospholipid

antibodies to confirm the diagnosis of CAPS, without delaying empiric treatment

(conditional recommendation, very low certainty of evidence).

Explanation and special considerations: The panel suggested aPL testing

(antiphospholipid antibody immunoassays and lupus anticoagulant assays) in pa-

tients with suspected CAPS, as a strongly positive aPL test would help narrow the

differential diagnosis, but testing should not delay initiation of therapy. It is recom-

mended that testing be carried out in accordance with International Society of

Thrombosis and Hemostasis guidelines [11,12]. Consideration needs to be made for

appropriate timing of sample collection, e.g. prior to initiation of plasmapheresis or

anticoagulation.

Summary of evidence: No studies evaluating the sensitivity or specificity of aPL in

the diagnosis of CAPS were identified. The International Consensus Guidelines on

Anticardiolipin and Anti-beta2 glycoprotein-I testing states that laboratory diagnostic

testing should include IgG and IgM anticardiolipin (ACL) kits, with anti-beta2 glyco-

protein-I (β2GPI) in the assay as a cofactor, and designation of positive aPL includes

confirmation of persistent positivity after >12 weeks [2,13]. The adverse effects as-

sociated with aPL testing are minimal, unless it delays diagnosis. There are no stud-

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 ies assessing costs of aPL testing in CAPS. Cost of aPL testing differs between

countries (e.g. in 2016, CAN$14-20 and €27-61 per test).

Accepted Article
Section 2: Treatment

Recommendation 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).

Explanation and special considerations: The significantly lower mortality with this

combination supports its recommendation in CAPS. The recommendation is condi-

tional due to very low quality evidence. The panel noted the incongruence of recom-

mending against glucocorticoids when given alone, and in favor when combined with

other medications (see Recommendation 10). Components of the combination may

be given stronger recommendations in subsets of CAPS patients. For example, with

thrombotic microangiopathy, the panel recommends stronger consideration for

plasmapheresis over IVIG.

Summary of evidence: Four studies, mainly of CAPS Registry patients, were re-

trieved [5,14-16]. The meta-analysis (n=357) revealed significantly lower mortality in

the group receiving this combination therapy compared to those receiving other

treatments [OR 0.51, 95% CI (0.27, 0.95)]. There are no studies evaluating harms of

this combination of therapies in CAPS. Harms of individual therapies are reviewed in

the respective sections of this manuscript. There are no published studies evaluating

cost of this therapy combination.

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 Recommendation 5: For first-line treatment of patients with CAPS, the panel

recommends using therapeutic dose anticoagulation, particularly unfraction-

Accepted Article
ated heparin (strong recommendation, very low certainty of evidence).

Explanation and special considerations: The panel gave a strong recommendation

for anticoagulation in patients with CAPS despite very low certainty of evidence, as it

fulfilled the first paradigmatic situation defined by GRADE allowing for a strong rec-

ommendation despite very low certainty of evidence: CAPS is a life-threatening con-

dition, the risk of anticoagulation is likely outweighed by the potential mortality bene-

fit, the intervention is acceptable to all stakeholders and cost is low (Table 5) [17].

There were insufficient data to analyze subgroups according to anticoagulant used,

though unfractionated heparin was most commonly used. The panel cautioned

against use of the direct oral anticoagulants as their effectiveness in CAPS is un-

known. Caution should be exercised and treatment individualized in patients who are

bleeding or who are at increased bleeding risk.

Summary of evidence: Two studies representing 325 CAPS registry patients were

retrieved [5,14]. The meta-analysis revealed significantly lower mortality in

anticoagulated patients [OR 0.18, 95% CI (0.09, 0.38)]. Comparative estimates were

not available for other outcomes. Bleeding events were not reported in any study. In

patients without CAPS receiving anticoagulation, the risk of bleeding is variable, and

dependent on the presence or absence of risk factors for bleeding such as anticoag-

ulant dose, hemostatic defects, age, comorbidities, and hepatic dysfunction

[18]. There are no published studies evaluating cost of anticoagulants in CAPS.

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 Recommendation 6: For first-line treatment of patients with CAPS, the panel

suggests using plasmapheresis (conditional recommendation, very low cer-

Accepted Article
tainty of evidence).

Explanation and special considerations. The panel determined that the trend towards

lower mortality in CAPS with plasmapheresis supports a conditional recommendation

for first-line use in conjunction with other CAPS therapies, as the majority of patients

studied had plasmapheresis in combination with other therapies. There was insuffi-

cient evidence to provide a direct comparison between IVIG and plasmapheresis.

The panel supports either first-line allowing adequate time for evidence of clinical ef-

fect prior to switching from plasmapheresis to IVIG or vice versa. The panel consid-

ered that the higher risk of permanent organ dysfunction and neurological deficit in

survivors receiving plasmapheresis was related to competing risk (higher chance of

survival, but survive with some degree of chronic impairment). Patients with

microangiopathic hemolytic anemia should be given strong consideration for

plasmapheresis.

Note that there were insufficient data to make any recommendation on choice of re-

placement fluid, timing and number of sessions.

Supporting evidence: Six studies were retrieved [4] [14-16,19,20]. Most patients

(319/343) were from the CAPS Registry. The meta-analysis found a non-significantly

lower mortality rate in the group receiving plasmapheresis compared to those not

[OR 0.68, 95% CI (0.41, 1.12)]. Data for the other outcomes were available from 24

or fewer patients and revealed higher odds of permanent organ dysfunction [OR

5.01, 95% CI (0.72, 34.75)], and permanent neurological deficit [OR 8.00, 95% CI

(0.25, 255.75)] in survivors, with lower odds of a complete recovery [OR 0.27, 95%

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 CI (0.04, 1.85)]. No study reported harms of plasmapheresis in CAPS. Common ad-

verse of plasmapheresis include fever (7.7%), urticaria (7.4%), and symptomatic

Accepted Article
hypocalcemia (7.3%) [21]. Adverse events occurred in 36% of all patients. Mortality

is estimated at 0.03-0.05%. There are no studies evaluating the cost of

plasmapheresis in CAPS. The reported cost is US$445-7000 per plasmapheresis in

other indications.

Recommendation 7: For first-line treatment of patients with CAPS, the panel

suggests using IVIG (conditional recommendation, very low certainty of evi-

dence).

Explanation and special considerations. The panel determined that the trend towards

lower mortality in CAPS with IVIG supports a conditional recommendation for first-

line therapy in conjunction with other CAPS therapies. There was insufficient evi-

dence to compare IVIG and plasmapheresis first-line. The panel felt that the sub-

group of CAPS patients with immune thrombocytopenia should be given stronger

consideration for IVIG, given evidence of benefit in ITP [22]. IVIG should be avoided

in elderly patients and patients with renal insufficiency due to the increased risk of

adverse renal effects.

Summary of evidence: Six studies were retrieved [4] [14-16,19,20]. CAPS Registry

patients comprised 319/343. The meta-analysis revealed a non-significantly lower

mortality rate in the group receiving IVIG [OR 0.86, 95% CI (0.50, 1.48)]. There were

no studies specifically evaluating harms of IVIG in CAPS. In other indications, reac-

tions occur in 5-15% of infusions including flu-like symptoms, anaphylactoid or ana-

phylactic reactions [23]. Other more delayed reactions included thromboembolic

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 events, aseptic meningitis, acute kidney injury, and hemolysis. There are no pub-

lished studies evaluating cost of IVIG in CAPS. The cost of IVIG is estimated at
Accepted Article
US$8,000-20,000 for a 2g/kg course.

Recommendation 8: For first-line treatment of patients with CAPS, the panel

suggests using antiplatelet agents as add-on therapy (conditional recommen-

dation, very low certainty of evidence). In patients for whom anticoagulation is

contraindicated for reasons other than bleeding, the CAPS guideline panel

recommends using antiplatelet agents as an alternative (strong recommenda-

tion, very low certainty of evidence).

Explanation and special considerations: For first-line treatment of patients with

CAPS, the panel made a conditional recommendation for using antiplatelet agents

as add-on therapy, due to its moderate survival benefit tempered by the increased

risk of bleeding with both anticoagulants and antiplatelet therapy. The recommenda-

tion is conditional on a bleeding risk assessment. Patients for whom anticoagulation

is contraindicated for reasons other than bleeding, the panel made a strong recom-

mendation for antiplatelet agents as an alternative, given that in the absence of anti-

coagulants the risk is low, and antiplatelet agents fulfilled the first paradigmatic situa-

tion in GRADE (table 5) [17].

Summary of evidence: Three studies were retrieved [4,15,19]. CAPS Registry pa-

tients comprised 265/252. Results suggests lower mortality in the group receiving

antiplatelet agents [OR 0.79, 95% CI (0.36, 1.73)]. It is not clear from all studies

which antiplatelet agents were used. Of the studies that did specify, aspirin was the

agent studied. Bleeding events were not captured. Studies in other indications have

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 shown that taking 325mg of aspirin daily carries a 1% absolute annual risk of gastro-

intestinal bleeding [24]. Risk of major bleeding is higher in patients on antiplatelet

Accepted Article
agents combined with anticoagulant therapy [25]. There are no studies evaluating

cost of antiplatelet agents in CAPS.

Recommendation 9: For first-line treatment of patients with CAPS, the panel

suggests not using rituximab (conditional recommendation, very low certainty

of evidence).

Explanation and special considerations: Due to the small numbers of patients who

have received rituximab in CAPS, the uncertainty regarding the potential long-term

consequences, and the cost of therapy, the panel suggested against use of rituxi-

mab. However, many of the panel members supported rituximab in refractory cases.

The panel considered its use to be potentially advantageous in patients with throm-

bocytopenia, due to use in immune thrombocytopenia [26].

Summary of evidence: Two studies were retrieved [16,19]. In one study a compari-

son of mortality between one CAPS patient who received and ten who did not re-

ceive rituximab revealed sizeable imprecision [OR 1.13, 95% CI (0.03, 37.44)] [16].

The other, a non-comparative study, with four of 20 relapsed/refractory CAPS pa-

tients who received rituximab (20%) died, while 13/20 (65%) recovered after rituxi-

mab use [19]. Ad hoc analysis of the CAPS Registry revealed 30 rituximab treated

patients, with five deaths (16.7%). When compared with contemporaneous patients

within the CAPS Registry who had not received rituximab, the comparative odds ra-

tio for survival was 0.41 (95% CI 0.15, 1.11). There are no studies evaluating ad-

verse effects of rituximab in CAPS patients. These are well reported for other indica-

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 tions [27]. There are no published cost data for rituximab in CAPS. In Canada, the

cost for a treatment course of 375mg/m2 weekly x four weeks is $9,440.70 US; in the
Accepted Article
UK, it cost $7,037.11 US (MIMS, Nov 2014).

Recommendation 10: For first-line treatment of patients with CAPS, the panel

suggests not using glucocorticoids (conditional recommendation, very low

certainty of evidence).

Explanation and special considerations. The panel decided that the lack of benefit in

CAPS patients, coupled with adverse effects, warranted a conditional recommenda-

tion against the use of glucocorticoids. The panel acknowledged there are circum-

stances where glucocorticoids are indicated in CAPS patients. For example, clini-

cians could consider glucocorticoid therapy in patients with concomitant active sys-

temic lupus erythematosus, immune thrombocytopenia, or small vessel vasculitis,

given benefit in these conditions [26]. The panel noted the incongruence of recom-

mending against glucocorticoids when given alone, and in favour when combined

with other medications (Recommendation 4, and discussion).

Summary of evidence: Five studies were retrieved [4] [14,15,19,20]. CAPS Registry

patients comprised 308/332 patients. There was no difference in mortality [OR 0.97,

95% CI (0.56, 1.66)]. There are no studies evaluating harms of glucocorticoids in

CAPS patients, however glucocorticoids have many adverse effects such as immu-

nosuppression, mood disturbance, hyperglycemia, and fluid retention. There are no

published studies evaluating cost of glucocorticoid in CAPS patients, however cost of

glucocorticoids worldwide is low.

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 DISCUSSION

These recommendations provide guidance to clinicians caring for confirmed or sus-

Accepted Article
pected CAPS patients. They will not apply to every patient in all circumstances.

CAPS is heterogeneous, and the relative benefits and harms of diagnostic tests and

therapies will differ across subgroups. Clinicians should engage in a shared deci-

sion-making process, considering the urgency for treatment initiation. Consultation

with specialists with expertise in CAPS should be considered.

The panel noted the apparent incongruence of recommending against gluco-

corticoids when given alone, and in favour when in combination (Recommendations

4 and 10). While review of the evidence for glucocorticoid did not show a favorable

risk/benefit ratio for mortality, the reviewed evidence for the combination of anticoag-

ulation, glucocorticoids and plasmapheresis and/or IVIG did. A subgroup analysis of

treatment combinations to separate the individual treatment effects of each therapy

in the combination group could not be performed, thus the panel considered it rea-

sonable to retain inclusion of glucocorticoids within the treatment combination. Fur-

thermore, glucocorticoids alone may be ineffective, but have a synergistic effect in

combination. This situation may be analogous to that of combination antimicrobial

therapy in Helicobacter Pylori eradication, where individual anti-microbial agents as

monotherapy did not lead to acceptable eradication rates, though combination thera-

py lead to eradication rates of >90% [28].

Similarly, the panel noted the apparent incongruence of indirectly recom-

mending use of the biopsy as part of the criteria in the Preliminary Criteria for Classi-

fication of the Catastrophic Antiphospholipid Syndrome (Recommendation 1) while

recommending either using or not using the biopsy for diagnosis (Recommendation

This article is protected by copyright. All rights reserved.

 2). The use of the criteria as a whole is encouraged, however the decision for biopsy

should be tailored to the clinical scenario.

Accepted Article
Available evidence did not allow for temporal analysis of treatments to desig-

nate therapies as “first-line” versus “second-line”. However, the panel opted to retain

the designation of “first-line” within the recommendations, as the scenario under

consideration was “first” presentation of CAPS, as opposed to a refractory or relaps-

ing scenario.

A strength of this guideline was rigor of the development process, with trans-

parent management of conflict of interest. Established methods were used, support-

ed by other methods of evidence gathering. Another strength was key stakeholder

representation, including patient representation. Patient representation is an im-

portant component of clinical practice guideline development, and is expected to

contribute to more patient-centered, trustworthy guidelines leading to improved im-

plementation and quality of care [29]. However, recruitment of patients to guideline

panels is difficult in rare diseases.

The main challenge in developing this guideline was the low certainty of evi-

dence. Studies are difficult to perform in patients with rare diseases due to low inci-

dence and typically have a high risk of bias, low power to detect treatment differ-

ences, and a high risk of spurious results [30]. The CAPS Registry has over 500

cases compiled, however due to the self-report nature of case acquisition there is a

high risk of bias. The judgments of the panel are by necessity supplemented with

expertise from the panel members, and the strength of recommendations reflects the

uncertainty of evidence.

This article is protected by copyright. All rights reserved.

 The CAPS clinical practice guideline initiative met the objective of the suc-

cessful development of a clinical practice guideline in a rare disease using GRADE

Accepted Article
methodology. We expect that clinicians caring for patients with suspected CAPS will

find the CAPS guideline useful to assist with diagnosis and management in this rare

and complex disease. Future research, particularly arising from the growing CAPS

Registry, will hopefully increase evidence quality, strengthen recommendations, and

ultimately improve patient outcomes in CAPS.

Addendum

The manuscript has been read and approved for submission to JTH™ by all qualified
authors.
K. Legault coordinated the steering committee and panel, co-chaired the panel, de-
signed and performed systematic reviews and SOF's, analyzed data, and wrote the
paper. H. Schunemann proposed the guideline effort, secured funding, sat on the
steering committee, co-chaired the panel, and edited the paper. C. Hillis sat on the
steering committee, coordinated the panel, was a panel member, designed system-
atic reviews, and edited the paper. C. Yeung designed and performed expert evi-
dence surveys, performed registry research, and edited the paper. E. Akl was a pan-
el member and edited the paper. M. Carrier was a panel member and edited the pa-
per. R. Cervera provided access to and expertise on the registry, was a panel mem-
ber, and edited the paper. M. Crowther sat on the steering committee, was a panel
member, and edited the paper. F. Dentali was a panel member and edited the paper.
D. Erkan was a panel member and edited the paper. G. Espinosa was a panel mem-
ber and edited the paper. M. Khamashta was a panel member and edited the paper.
J. Meerpohl was a panel member and edited the paper. K. Moffat was a panel mem-
ber and edited the paper. S. O'Brien was a panel member and edited the paper. V.
Pengo was a panel member and edited the paper. J. Rand was a panel member and
edited the paper. I. Rodriguez Pinto provided access to and expertise on the registry,
was a panel member, and edited the paper. L. Thom was a panel member and edit-
ed the paper. A. Iorio sat on the steering committee, coordinated the systematic re-
views and SOF's, was a panel member, and edited the paper.

Acknowledgements

Institution where the work was carried out:

Systematic reviews: McMaster University, Hamilton (Canada)
Panel meeting: University of Barcelona, Barcelona (Spain)

This article is protected by copyright. All rights reserved.

 Disclosure of Conflict of Interests
H. Schunemann received European Union funding for this project
M. Carrier has received consulting fees from Leo Pharma, Bayer, Pfizer; and has re-
Accepted Article
ceived in-kind research support from Leo Pharma and BMS
M. Crowther and K. Legault have received grant support from Heart and Stroke
Foundation and in-kind support from Bayer.
D. Erkan has received consulting and research support from Alexion
S. O'Brien had her registration fee waived for American Society of Hematology 2015
Annual General Meeting for educational contribution.

REFERENCES

1 Asherson RA. The catastrophic antiphospholipid syndrome. J Rheumatol 1992;

19: 508-12.

2 Miyakis S, Lockshin MD, Atsumi T, Branch DW, Brey RL, Cervera R, Derksen

RHWM, de Groot PG, Koike T, Meroni PL, Reber G, Shoenfeld Y, Tincani A,

Vlachoyiannopoulos PG, Krilis SA. International consensus statement on an

update of the classification criteria for definite antiphospholipid syndrome

(APS). 2006; 4: 295–306.

3 REGULATION (EC) No 141/2000 OF THE EUROPEAN PARLIAMENT AND

OF THE COUNCIL of 16 December 1999 on orphan medicinal products.

ec.europa.eu.

4 Bucciarelli S, Espinosa G, Cervera R, Erkan D, Gómez-Puerta JA, Ramos-

Casals M, Font J, Asherson RA, CAPS Registry Project Group (European Fo-

rum on Antiphospholipid Antibodies). Mortality in the catastrophic

antiphospholipid syndrome: Causes of death and prognostic factors in a se-

ries of 250 patients. Arthritis Rheum 2006; 54: 2568–76.

This article is protected by copyright. All rights reserved.

 5 Cervera R, Bucciarelli S, Plasín MA, Gómez-Puerta JA, Plaza J, Pons-Estel G,

Shoenfeld Y, Ingelmo M, Espinos G, Catastrophic Antiphospholipid Syndrome

Accepted Article
(CAPS) Registry Project Group (European Forum On Antiphospholipid Anti-

bodies). Catastrophic antiphospholipid syndrome (CAPS): descriptive analysis

of a series of 280 patients from the "CAPS Registry". J Autoimmun 2009; 32:

240–5.

6 Asherson RA, Espinosa G, Cervera R, Font J, Reverter JC. Catastrophic

antiphospholipid syndrome: proposed guidelines for diagnosis and treatment.

J Clin Rheumatol 2002; 8: 157–65.

7 Pai M, Iorio A, Meerpohl J, Taruscio D, Laricchiuta P, Mincarone P, Morciano

C, Leo C, Sabina S, Akl EA, Treweek S, Djulbegovic B, Schunemann HJ. De-

veloping methodology for the creation of clinical practice guidelines for rare

diseases: A report from RARE-Bestpractices. Rare Diseases 2015; :

e1058463.

8 Schünemann HJ, Wiercioch W, Etxeandia I, Falavigna M, Santesso N, Mustafa

R, Ventresca M, Brignardello-Petersen R, Laisaar K-T, Kowalski S, Baldeh T,

Zhang Y, Raid U, Neumann I, Norris SL, Thornton J, Harbour R, Treweek S,

Guyatt G, Alonso-Coello P, et al. Guidelines 2.0: systematic development of a

comprehensive checklist for a successful guideline enterprise. CMAJ 2014;

186: E123–42.

9 Guyatt GH, Oxman AD, Vist GE, Kunz R, Falck-Ytter Y, Alonso-Coello P,

Schünemann HJ, GRADE Working Group. GRADE: an emerging consensus

on rating quality of evidence and strength of recommendations. BMJ 2008;

336: 924–6.

This article is protected by copyright. All rights reserved.

 10 Cervera R, Font J, Gómez-Puerta JA, Espinosa G, Cucho M, Bucciarelli S,

Ramos-Casals M, Ingelmo M, Piette JC, Shoenfeld Y, Asherson RA, Cata-

Accepted Article
strophic Antiphospholipid Syndrome Registry Project Group. Validation of the

preliminary criteria for the classification of catastrophic antiphospholipid syn-

drome. Ann Rheum Dis 2005; 64: 1205–9.

11 Devreese KMJ, Pierangeli SS, de Laat B, Tripodi A, Atsumi T, Ortel TL, Sub-

committee on Lupus Anticoagulant/Phospholipid/Dependent Antibodies. Test-

ing for antiphospholipid antibodies with solid phase assays: guidance from the

SSC of the ISTH. J Thromb Haemost 2014; 12: 792–5.

12 Pengo V, Tripodi A, Reber G, Rand JH, Ortel TL, Galli M, de Groot PG, Sub-

committee on Lupus Anticoagulant/Antiphospholipid Antibody of the Scientific

and Standardisation Committee of the International Society on Thrombosis

and Haemostasis. Update of the guidelines for lupus anticoagulant detection.

Subcommittee on Lupus Anticoagulant/Antiphospholipid Antibody of the Sci-

entific and Standardisation Committee of the International Society on Throm-

bosis and Haemostasis. J Thromb Haemost 2009; 7: 1737–40.

13 Lakos G, Favaloro EJ, Harris EN, Meroni PL, Tincani A, Wong RC, Pierangeli

SS. International consensus guidelines on anticardiolipin and anti-β2-

glycoprotein I testing: report from the 13th International Congress on

Antiphospholipid Antibodies. Arthritis Rheum 2012; 64: 1–10.

14 Berman H, Rodríguez-Pintó I, Cervera R, Gregory S, de Meis E, Rodrigues

CEM, Aikawa NE, de Carvalho JF, Springer J, Niedzwiecki M, Espinosa G,

Catastrophic Registry Project Group (European Forum on Antiphospholipid

Antibodies). Pediatric catastrophic antiphospholipid syndrome: descriptive

This article is protected by copyright. All rights reserved.

 analysis of 45 patients from the "CAPS Registry". Autoimmun Rev 2014; 13:

157–62.
Accepted Article
15 Hanouna G, Morel N, Le THD, Josselin L, Vauthier-Brouzes D, Saadoun D,

Kettaneh A, Levesque K, Le Guern V, Goffinet F, Carbonne B, Amoura Z,

Piette J-C, Nizard J, Costedoat-Chalumeau N. Catastrophic antiphospholipid

syndrome and pregnancy: an experience of 13 cases. Rheumatology (Oxford)

2013; 52: 1635–41.

16 Shiber S, Yair M. Catastrophic antiphospholipid syndrome: a case series. Isr

Med Assoc J 2013; 15: 481–4.

17 Andrews JC, Schünemann HJ, Oxman AD, Pottie K, Meerpohl JJ, Coello PA,

Rind D, Montori VM, Brito JP, Norris S, Elbarbary M, Post P, Nasser M,

Shukla V, Jaeschke R, Brozek J, Djulbegovic B, Guyatt G. GRADE guide-

lines: 15. Going from evidence to recommendation-determinants of a recom-

mendation's direction and strength. Journal of Clinical Epidemiology 2013; 66:

726–35.

18 Garcia DA, Baglin TP, Weitz JI, Samama MM, American College of Chest Phy-

sicians. Parenteral anticoagulants: Antithrombotic Therapy and Prevention of

Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based

Clinical Practice Guidelines. Chest 2012; 141: e24S–43S.

19 Berman H, Rodríguez-Pintó I, Cervera R, Morel N, Costedoat-Chalumeau N,

Erkan D, Shoenfeld Y, Espinosa G, Catastrophic Antiphospholipid Syndrome

(CAPS) Registry Project Group (European Forum On Antiphospholipid Anti-

bodies). Rituximab use in the catastrophic antiphospholipid syndrome: de-

This article is protected by copyright. All rights reserved.

 scriptive analysis of the CAPS registry patients receiving rituximab.

Autoimmun Rev 2013; 12: 1085–90.

Accepted Article
20 Stojanovich L. The catastrophic antiphospholipid syndrome in Serbia: diagnos-

tic and management problems. Clin Rev Allergy Immunol 2009; 36: 98–103.

21 Shemin D, Briggs D, Greenan M. Complications of therapeutic plasma ex-

change: a prospective study of 1,727 procedures. J Clin Apher 2007; 22: 270–

6.

22 Neunert C, Lim W, Crowther M, Cohen A, Solberg L, Crowther MA, American

Society of Hematology. The American Society of Hematology 2011 evidence-

based practice guideline for immune thrombocytopenia. Blood 2011; 117:

4190–207.

23 Stiehm ER. Adverse effects of human immunoglobulin therapy. Transfus Med

Rev 2013; 27: 171–8.

24 García Rodríguez LA, Martín-Pérez M, Hennekens CH, Rothwell PM, Lanas A.

Bleeding Risk with Long-Term Low-Dose Aspirin: A Systematic Review of

Observational Studies. PLoS ONE 2016; 11: e0160046.

25 Eikelboom JW, Hirsh J. Combined antiplatelet and anticoagulant therapy: clini-

cal benefits and risks. J Thromb Haemost 2007; 5 Suppl 1: 255–63.

26 Kasper D, Fauci AS, Hauser S, Longo DL, Jameson JL, Loscalzo J, editors.

Harrison's Principles of Internal Medicine, 19e. 19 ed. New York: McGraw-Hill;

2014.

This article is protected by copyright. All rights reserved.

 27 van Vollenhoven RF, Emery P, Bingham CO, Keystone EC, Fleischmann R,

Furst DE, Macey K, Sweetser M, Kelman A, Rao R. Longterm safety of pa-

Accepted Article
tients receiving rituximab in rheumatoid arthritis clinical trials. J Rheumatol

2010; 37: 558–67.

28 Chey WD, Wong BCY, Practice Parameters Committee of the American Col-

lege of Gastroenterology. American College of Gastroenterology guideline on

the management of Helicobacter pylori infection. Am J Gastroenterol 2007;

102: 1808–25.

29 G-I-N PUBLIC Toolkit: Patient and Public Involvement in Guidelines. 2015.

http:// www.g-i-n.net/working-groups/gin-public/toolkit. (accessed May 3,

2017).

30 Bell SA, Tudur Smith C. A comparison of interventional clinical trials in rare ver-

sus non-rare diseases: an analysis of ClinicalTrials.gov. Orphanet J Rare Dis

2014; 9: 170.

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 TABLES

Table 1: The Preliminary Criteria for Classification of the Catastrophic

Accepted Article
Antiphospholipid Syndrome

Criteria

Evidence of involvement of three or more organs, systems and/or tissues(a)

Development of manifestations simultaneously or in less than a week

Confirrmation by histopathology of small vessel occlusion in at least one organ or

tissue(b)

Laboratory confirmation of the presence of antiphospholipid antibodies (lupus anti-

coagulant and/or anticardiolipin antibodies)(c)

Definite catastrophic APS

· All four criteria

Probable catastrophic APS

· All four criteria, except for only two organs, systems and/or tissues involved

· All four criteria, except for the absence of laboratory confirrmation at least six
weeks apart due to the early death of a patient never tested for aPL before the
catastrophic APS

· 1, 2 and 4

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

(a) Usually, clinical evidence of vessel occlusions, confirmed by imaging techniques when appro-
priate. Renal involvement is defined by a 50% rise in serum creatinine, severe systemic
hypertension (>180/100mmHg) and/or proteinuria (>500mg/24hours).
(b) For histopathological confirmation, significant evidence of thrombosis must be present, alt-
hough vasculitis may coexist occasionally.
(c) f the patient had not been previously diagnosed as having an APS, the laboratory confirma-
tion requires that presence of antiphospholipid antibodies must be detected on two or
more occasions at least six weeks apart (not necessarily at the time of the event), ac-
cording to the proposed preliminary criteria for the classification of definite APS.

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 Table 2: Key questions prioritized by the guideline panel and covered in the CAPS guideline
Accepted Article
Diagnosis Questions

1. Should the Preliminary Criteria for Classification of CAPS be used to diagnose CAPS in pa-
tients 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?t

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?

*compared to physician expertise, ^compared to diagnosing CAPS without biopsy,

t
compared to diagnosing CAPS using criteria that don’t include antiphospholipid antibodies,
CAPS=catastrophic antiphospholipid syndrome; IVIG=intravenous immune globulin

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 Table 3: Grading recommendations (adapted from Guyatt, 2006)
Accepted Article
Strength of rec-
Benefit versus risk Methodological quality
ommendation and Implications
and burdens of supporting evidence
quality of evidence

Strong recommenda-
Benefits clearly RCTs without important
Strong recommen- tion, can apply to most
outweigh risk and limitations or overwhelm-
dation, high-quality patients in most circum-
burdens, or vice ing evidence from obser-
evidence stances without reserva-
versa vational studies
tion

RCTs with important limi-

tations (inconsistent re- Strong recommenda-
Benefits clearly
Strong recommen- sults, methodological tion, can apply to most
outweigh risk and
dation, moderate- flaws, indirect, or impre- patients in most circum-
burdens, or vice
quality evidence cise) or exceptionally stances without reserva-
versa
strong evidence from ob- tion
servational studies

Benefits clearly Strong recommendation

Strong recommen-
outweigh risk and Observational studies or but may change when
dation, low- or very
burdens, or vice case series higher quality evidence
low-quality evidence
versa becomes available

Weak recommendation,
RCTs without important
Conditional recom- Benefits closely best action may differ
limitations or overwhelm-
mendation, high- balanced with risks depending on circum-
ing evidence from obser-
quality evidence and burden stances or patients’ or
vational studies
societal values

RCTs with important limi-

tations (inconsistent re- Weak recommendation,
Conditional recom- Benefits closely sults, methodological best action may differ
mendation, moder- balanced with risks flaws, indirect, or impre- depending on circum-
ate-quality evidence and burden cise) or exceptionally stances or patients’ or
strong evidence from ob- societal values
servational studies

Uncertainty in the
Conditional recom- estimates of bene- Very weak recommen-
mendation, low- or fits, risks, and bur- Observational studies or dations; other alterna-
very low-quality evi- den; benefits, risk, case series tives may be equally
dence and burden may be reasonable
closely balanced

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 Table 4: Summary of Recommendations
Accepted Article
Strength of recommendation,
Recommendation
certainty of evidence

Diagnosis

1. For patients suspected of having CAPS, the panel sug- conditional recommendation, very
gests using the Preliminary Criteria for Classification of the
Catastrophic Antiphospholipid Syndrome for diagnosis of low certainty of evidence
CAPS

2. For patients suspected of having CAPS, the panel sug- conditional recommendation,
gests either using or not using biopsy to diagnose CAPS very low certainty of evidence

conditional recommendation,
3. For patients suspected of having CAPS, the panel sug-
gests using antiphospholipid antibodies to diagnose CAPS very low certainty of evidence

4. For first-line treatment of patients with CAPS, the panel conditional recommendation,
suggests combination therapy with glucocorticoid, heparin,
and plasmapheresis or IVIG over single agents or other very low certainty of evidence
combinations of therapies

strong recommendation,
5. For first-line treatment of patients with CAPS, the panel
recommends using therapeutic dose anticoagulation very low certainty of evidence

conditional recommendation,
6. For first-line treatment of patients with CAPS, the panel
suggests using plasmapheresis very low certainty of evidence

conditional recommendation,
7. For first-line treatment of patients with CAPS, the panel
suggests using intravenous immune globulin very low certainty of evidence

for add-on therapy:

8. For first-line treatment of patients with CAPS, the panel conditional recommendation,
suggests using antiplatelet agents as add-on therapy. In pa- very low certainty of evidence
tients for whom anticoagulation is contraindicated for rea- for alternative therapy to antico-
sons other than bleeding, the CAPS guideline panel recom- agulation:
mends using antiplatelet agents as an alternative strong recommendation,
very low certainty of evidence

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 conditional recommendation,
9. For first-line treatment of patients with CAPS, the panel
suggests not using rituximab. very low certainty of evidence
Accepted Article
conditional recommendation,
10. For first-line treatment of patients with CAPS, the panel
suggests not using glucocorticoids. very low certainty of evidence

Table 5: GRADE First paradigmatic situation with example [17]

Life-threatening situation

Benefits: Low or very low confidence (ie. low or very

Confidence in effect estimates for low quality evidence)
health outcomes
Harms: Immaterial (very low to high)

Intervention may reduce mortality in a life-threatening

Balance of benefits and harms situation. Adverse events not prohibitive.

A very high value is placed on an uncertain but po-

Values and preferences
tentially life-preserving benefit

Small incremental cost (or resource use) relative to

Resource considerations
the benefits justify the intervention

Recommendation Strong recommendation in favour

Indirect evidence from seasonal influenza suggests

that patients with avian influenza may benefit from
the use of oseltamivir (low confidence in effect esti-
mates). Given the high mortality of the disease and
Example the absence of effective alternatives, the WHO made
a strong recommendation in favor of the use of
Oseltamivir rather than no treatment in patients with
avian influenza

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