Diagnosis and Management of Catastrophic Antiphospholipid Syndrome: a Clinical Practice Guideline

Diagnosis and Management of Catastrophic Antiphospholipid Syndrome: a Clinical Practice Guideline Introduction The public comment period occurs after recommendations are formed but before a manuscript report of the guidelines has been finalized and before organizational approval of the guidelines. Comments collected during the open comment period are provided to the guideline panel for review prior to finalizing the guidelines. These draft recommendations are not final and therefore are not intended for use or citation. To submit comments on the draft recommendations, please visit http://caps.questionpro.com. Only comments submitted via the online survey will be reviewed by the guideline panel. The public comment period for these draft recommendations is May 26 June 19, 2017. Question 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). Explanation and special considerations: The panel felt the balance of desirable and undesirable effects of use of the Preliminary Criteria for the classification of Catastrophic Antiphospholipid Syndrome (table 1) for diagnosis of CAPS favored a conditional recommendation for its use. While the classification criteria were developed for research, they were selected based on a review of the literature which failed to yield another systematic approach to CAPS diagnosis. Because many of the diseases on the differential diagnosis for CAPS would be similarly treated with anticoagulation and immunomodulation, the risk of adverse effects to the patient secondary to false positives may be acceptable. Two exceptions are thrombotic thrombocytopenic purpura (TTP), if the treating team delays TPE, and bacterial infections if antibiotics are withheld. For a false negative result, anticoagulation or immunomodulation may be withheld, however this is unlikely as these therapies may be employed regardless, e.g. anticoagulation in large-vessel thrombosis. The panel noted that treatment should not be delayed until all criteria are filled as some criteria, such as antiphospholipid antibody (apl) testing, can take some time to result, and prompt initiation of therapy may improve outcomes. Question 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). Explanation and special considerations: The panel determined that depending on the clinical situation, clinicians may or may not want to pursue an organ biopsy to diagnose CAPS. The panel felt that the specificity of thrombotic microangiopathy on biopsy would be high, however the sensitivity may be low. A

positive biopsy would be helpful to rule in CAPS, a negative biopsy would not rule out CAPS, and thus treatment should not be guided by biopsy results. Moreover, since the risk of biopsy differs depending on site, severity of illness and bleeding risk, the decision to biopsy will vary. Question 3: For patients suspected of having CAPS, the panel suggests using antiphospholipid antibodies to diagnose CAPS (conditional recommendation, very low certainty of evidence). Explanation and special considerations: The panel felt that apl testing (antiphospholipid antibody immunoassays and lupus anticoagulant assays) is suggested in a patient with suspected CAPS and it should not delay initiation of therapy. Particularly when considering the confirmatory test at 12 weeks after the initial positive test, but moreover, therapy may need to be initiated prior to a single positive test due to laboratory turnaround time. However, the panel felt that a strongly positive apl testing during the course of therapy would help narrow the differential diagnosis. Question 4: For first-line treatment of patients with CAPS, the panel suggests combination therapy with glucocorticoid, heparin, and plasma exchange or IVIG over single agents or other combinations of therapies (conditional recommendation, very low certainty of evidence). Explanation and special considerations: The panel determined that the significantly lower mortality with this combination compared to other combinations of therapy supports its recommendation in CAPS. The recommendation is conditional as the evidence is of very low quality. The panel noted the apparent incongruence of recommending against glucocorticoids when given alone, and in favor when combined with other medications (see Recommendation 10); this apparent discrepancy is addressed in the discussion section. As with the recommendations for individual therapies, components of the combination may be given stronger recommendations in some subsets of CAPS patients. For example, in those with microangiopathic hemolytic anemia, the panel recommends stronger consideration for TPE in lieu of IVIG. Question 5: For first-line treatment of patients with CAPS, the panel recommends using therapeutic dose anticoagulation (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 that allows formulating a strong recommendation in the face of very low certainty of evidence: CAPS is a life-threatening condition, the risk of anticoagulation is likely outweighed by the potential mortality benefit, the is acceptable to all stakeholders and cost is low. Caution should be exercised and treatment individualized in patients who are bleeding or who are at increased risk for a bleeding event. There was insufficient information available to address whether anticoagulation

was equally effective in the subgroup of patients who experience microthrombosis rather than macrothrombosis. There were insufficient data to analyze subgroups according to anticoagulant used, though heparin was most commonly used in patients in the CAPS Registry; the panel cautioned against use of the direct oral anticoagulants as their effectiveness in CAPS is unknown. Question 6: For first-line treatment of patients with CAPS, the panel suggests using therapeutic plasma exchange (TPE) (conditional recommendation, very low certainty of evidence). Explanation and special considerations. The panel determined that the trend towards lower mortality in CAPS with therapeutic plasma exchange supports a conditional recommendation for first-line use. The panel advocated for its use in conjunction with other CAPS therapies, not as monotherapy, as the majority of patients studied had TPE in combination with other therapies. There was insufficient evidence to provide a direct comparison between IVIG and TPE. Typically patients receive either as first-line therapy. The panel supports this approach, and recommends that whenever possible, to allow adequate time for evidence of clinical effect prior to switching from TPE to IVIG or vice versa. The panel considered that the higher risk of permanent organ dysfunction and neurological deficit seen with use of TPE with lower odds of a complete recovery was related to competing risk, where the patients have a higher chance of survival, but survive with some degree of chronic impairment. The panel felt that the subgroup of CAPS patients with microangiopathic hemolytic anemia should be given strong consideration for TPE, given evidence of the potential that patients with other disorders, such as TTP, may be difficult to differentiate from CAPS acutely. Question 7: For first-line treatment of patients with CAPS, the panel suggests using IVIG (conditional recommendation, very low certainty of evidence). 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. The panel advocated for its use in conjunction with other CAPS therapies, as the majority of the patients studied received IVIG with other therapies (i.e. anticoagulation). There was insufficient evidence to provide a direct comparison between IVIG and TPE first-line. As TPE removes IVIG from the circulation, they should not be used concurrently. The panel recommends a treatment course of appropriate duration (to allow time for evidence of clinical efficacy or lack thereof) prior to switching from TPE to IVIG or vice versa. The panel felt that the subgroup of patients with immune thrombocytopenia in the setting of CAPS should be given stronger consideration for IVIG, given evidence of benefit in ITP. Importantly, IVIG use may be of particular concern in elderly patients and patients with renal insufficiency due to the increased risk of adverse renal effects in these populations.

Question 8: For first-line treatment of patients with CAPS, the panel suggests using antiplatelet agents as add-on therapy (conditional recommendation, 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 recommendation, 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 in patients who are receiving both anticoagulants and antiplatelet therapy. The recommendation is conditional on a bleeding risk assessment. However, in patients for whom anticoagulation is contraindicated for reasons other than bleeding, the CAPS guideline panel made a strong recommendation for antiplatelet agents as an alternative to anticoagulation, given that in the absence of anticoagulants the risk is low, and antiplatelet agents fulfilled the first paradigmatic situation in GRADE: CAPS is a potentially life-threatening condition, the risk profile for antiplatelets is likely outweighed by the potential benefits to mortality, the is acceptable to all stakeholders and cost is low. Question 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 decided to suggest against use of rituximab as first-line therapy in CAPS. However, many of the panel members supported considering rituximab in refractory cases with ongoing disease activity where other therapies have been insufficient. The panel considered its use to be potentially advantageous in patients with thrombocytopenia. Rituximab has been widely used in other patients with immune thrombocytopenia, though with limited effect. Use in the setting of CAPS with associated severe thrombocytopenia might be considered to treat both thrombocytopenia and mitigate the severity of CAPS. Question 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 the adverse effects of glucocorticoids, warranted a conditional recommendation against the use of glucocorticoids. The panel acknowledged that there are circumstances where glucocorticoids may be indicated in CAPS patients. For example, clinicians could consider glucocorticoid therapy in patients

with concomitant active systemic lupus erythematosus, immune thrombocytopenia, or small vessel vasculitis, given evidence of benefit in these conditions. The panel noted the apparent incongruence of recommending against glucocorticoids when given alone, and in favor when combined with other medications (see Recommendation 4); this apparent discrepancy is addressed in the discussion section. Table 1: The Preliminary Criteria for Classification of the Catastrophic Antiphospholipid Syndrome 1 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 anticoagulant 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 appropriate. 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, although vasculitis may coexist occasionally. (c) If the patient had not been previously diagnosed as having an APS, the laboratory confirmation 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), according to the proposed preliminary criteria for the classification of definite APS.

1 Asherson RA, Cervera R, de Groot PG, et al. Catastrophic antiphospholipid syndrome: international consensus statement on classification criteria and treatment guidelines. Lupus 2003;12:530 4. References for included studies: Bucciarelli S, Espinosa G, Cervera R, et al. Mortality in the catastrophic antiphospholipid syndrome: Causes of death and prognostic factors in a series of 250 patients. Arthritis Rheum 2006;54:2568 76. Cervera R, Bucciarelli S, Plasín MA, et al. Catastrophic antiphospholipid syndrome (CAPS): descriptive analysis of a series of 280 patients from the "CAPS Registry". J Autoimmun 2009;32:240 5. Cervera R, Font J, Gómez-Puerta JA, et al. Validation of the preliminary criteria for the classification of catastrophic antiphospholipid syndrome. Ann Rheum Dis 2005;64:1205 9. Berman H, Rodríguez-Pintó I, Cervera R, et al. Rituximab use in the catastrophic antiphospholipid syndrome: descriptive analysis of the CAPS registry patients receiving rituximab Autoimmun Rev 2013;12:1085-1090. Berman H, Rodríguez-Pintó I, Cervera R, et al. Pediatric catastrophic antiphospholipid syndrome: descriptive analysis of 45 patients from the "CAPS Registry". Autoimmun Rev 2014;13:157 62. Gómez-Puerta JA, Cervera R, Espinosa G, et al. Catastrophic antiphospholipid syndrome during pregnancy and puerperium: maternal and fetal characteristics of 15 cases. Ann Rheum Dis 2007;66:740 6. Hanouna G, Morel N, Le THD, et al. Catastrophic antiphospholipid syndrome and pregnancy: an experience of 13 cases. Rheumatology (Oxford) 2013;52:1635 41. Shiber S, Yair M. Catastrophic antiphospholipid syndrome: a case series. Isr Med Assoc J 2013;15:481 4. Stojanovich L. The catastrophic antiphospholipid syndrome in Serbia: diagnostic and management problems. Clin Rev Allergy Immunol 2009;36:98 103.

Question Should the Preliminary Criteria for Classification of the Catastrophic Antiphospholipid Syndrome be us ed to diagnos e CAPS in patients presenting with features suggestive of CAPS? POPULATION: patients presenting with features suggestive of CAPS BACKGROUND: There is heterogeneity in presentation of CAPS patients, with both large and small vessel occlusions that can affect virtually any organ INTERVENTION: the Preliminary Criteria for Clas s ification of the Catas trophic system. In Asherson's 2001 review of 80 patients, the Antiphos pholipid Syndrome manifestations and serology were diverse: thrombosis most commonly involved kidney, lung, or brain, though could involve PURPOSE OF to determine whether the panel would recommend the virtually any organ, disseminated intravascular coagulation THE TEST: Preliminary Criteria when diagnos ing CAPS at the beds ide occurred in 19%, hemolysis in 39%, thrombocytopenia in 60%, and LINKED anti-nuclear antibodies were present in >50% (Asherson, 2001). TREATMENTS: Due to this diversity of presentation, there could be a delay in diagnosis, particularly if the manifestations are subtle, such as ANTICIPATED OUTCOMES: The aim of the question is to determine whether the test characteristics are such that the test would be useful to help diagnose CAPS if applied to the population of patients with suspected CAPS, as per the judgment of the panel, and whether diagnosis with this criteria changes patient-important outcomes. mesenteric ischemia or renal microangiopathy. The Preliminary Criteria for Classification of the Catastrophic Antiphospholipid Syndrome were first proposed by Asherson et al. in 2002 and accepted by all participants in the pre- symposium workshop on APS consensus, held at the 10th International Congress on apl (Asherson 2003). The criteria are as follows: SETTING: PERSPECTIVE: 1) Evidence of involvement of three or more organs, systems and/or tissues(a) 2) Development of manifestations simultaneously or in less than a week 3) Confirrmation by histopathology of small vessel occlusion in at least one organ or tissue(b) 4) Laboratory confirmation of the presence of antiphospholipid antibodies (lupus anticoagulant 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 appropriate. Renal involvement is defined by a 50% rise in serum creatinine, severe systemic hypertension (>180/100mmHg) and/or proteinuria

Assessment PROBLEM ACCURACY (>500mg/24hours). (b) For histopathological confirmation, significant evidence of thrombosis must be present, although vasculitis may coexist occasionally. (c) If the patient had not been previously diagnosed as having an APS, the laboratory confirmation 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), according to the proposed preliminary criteria for the classification of definite APS. The comparison group in this context is clinical diagnosis by attending physician, as there are currently no other published criteria for diagnosis or classification of CAPS. JUDGEMENT RESEARCH EVIDENCE ADDITIONAL CONSIDERATIONS Is the problem a priority? No Probably no Probably yes Yes How accurate is the test? Very inaccurate Inaccurate Accurate Very accurate Varies In the most recently published full series of CAPS Registry patients, mortality in the 280 patient cohort was 44% (Cervera 2009). Furthermore, many of these patients are critically ill, and early diagnosis to differentiate CAPS from other mimicking conditions (thrombotic thrombocytopenic purpura; heparin-induced thrombocytopenia; DIC; hemolysis, elevated liver enzyme, low platelet syndrome; infective endocarditis; vasculitis; cryoglobulinemia; cholesterol emboli) could allow for institution of therapies that may impact mortality, and may avoid inappropriate therapies instituted upon misdiagnosis as a mimicking condition. Outcome True pos itives Study design casecontrol type Test accuracy QoE LOW Effect per 1000 patients/year for pre-test probability of 10% the Preliminary Criteria for Classification of the Catastrophic Antiphospholipid Syndrome 90 (0 to 0) Importance Systematic observations Number of responding experts: 7 2x2 table summary T+ T- D+ 28 10 38 D- 2 2 4 30 12 42

TEST A False negatives True negatives False pos itives accuracy study casecontrol type accuracy study 10 (100 to 100) - 895 (0 to 0) 5 (900 to 900) Prevalence = (TP + FN) / total = 0.905 Sensitivity = TP / (TP + FN) = 0.737 Specificity = TN / (TN + FP) = 0.5 PPV = TP / (TP + FP) = 0.93 NPV = TN / (TN + FN) = 0.167 DESIRABLE EFFECTS UNDESIRABLE EFFECTS F THE TEST Y How substantial are the desirable anticipated effects? Trivial Small Moderate Large How substantial are the undesirable anticipated effects? Large Moderate Small Trivial What is the overall certainty of the evidence of test accuracy? Very low Using a model incorporating the Preliminary Criteria compared to physician-based expert diagnosis, out of 1000 patients with possible CAPS, 90 patients would be appropriately diagnosed as having CAPS (true positives), 5 would be misdiagnosed as having CAPS rather than another mimicking condition (false positives), 895 would be appropriately thought not to have CAPS (true negatives), and 10 would be missed diagnoses of CAPS (false negatives). Risk to patients misdiagnosed as having CAPS (false positives) include potential adverse effects of therapy (glucocorticoid, anticoagulation, plasmapheresis, etc - see EtD's for therapy outlining harms of therapy), and risk if omission of therapy for the true underlying condition. The risks in this scenario would range from minimal effects (e.g. if the true diagnosis was TTP and the patient was treated with TPE for presumed CAPS, which is appropriate therapy for TTP) to a potentially fatal situation (e.g. if the true diagnosis was infective endocarditis and appropriate antibiotics were not administered). Patients with missed diagnoses of CAPS (false negatives) may be faced with a mortality rate as high as that shown in the systematic review of patients who did not receive anticoagulant therapy (72% - see EtD for anticoagulation - note that evidence for this was evaluated as being of very low quality). However, it is conceivable that the mortality risk may be less than this, as patients may receive therapies that would be of benefit in CAPS even if diagnosed with another condition. The adverse effects associated with administering the Preliminary Criteria for Classification of CAPS include the risks associated with the individual tests themselves. The main risks are thus those that are associated with biopsy of affected organs, which will differ depending on the organ involved. For example, Renal biops y: -risk of bleeding 1.2% -requirement for blood trans fus ion 0.9% -requirement for angiographic procedure to manage bleeding 0.6% -requirement for nephrectomy to manage bleeding 0.01% -risk of death 0.02% -arteriovenous fis tula 18% (mos t clinically ins ignificant) -perirenal soft tissue infection 0.2% [Whittier WL, Korbet SM. Indications for and complications of renal biopsy. In: UpToDate, Post TW (Ed), UpToDate, Glassock RJ, Rovin BH. (Accessed on March 22, 2016.) Skin biopsy complications include bleeding and infection, with risk dependent on location and depth. The overall certainty of the evidence of test accuracy was rated as being low due to several factors. The evidence was rated down for indirectness, as the control group used for the comparator was patients with known SLE or APS, and did not include patients with mimickers of CAPS such as those described above (e.g. thrombotic microangiopathies like TTP, HIT, endocarditis, etc). The Preliminary Criteria may have different test characteristics when used to differentiate these populations, which is more likely to be the case in clinical

CERTAINTY OF EVIDENCE OF T ACCURACY CERTAINTY OF THE EVIDENCE OF TEST'S EFFECTS CERTAINTY OF THE EVIDENCE OF MANAGEMENT'S EFFECTS RTAINTY OF THE IDENCE OF TEST ULT/MANAGEMENT Low Moderate High No included studies What is the overall certainty of the evidence for any critical or important direct benefits, adverse effects or burden of the test? Very low Low Moderate High No included studies What is the overall certainty of the evidence of effects of the management that is guided by the test results? Very low Low Moderate High No included studies How certain is the link between test results and management decisions? Very low Low Moderate High practice. There was also possibility of risk of bias in the included study - it was not clear whether patients were blinded to the reference standard diagnosis, which could affect classification and falsely increase apparent sensitivity and specificity. In addition, the reference standard of "physician diagnosis" in the CAPS registry involves cases submitted by various physicians, thus the reference standard of "physician diagnosis" was not necessarily applied evenly to all cases. The overall certainty of the evidence for adverse effects of the test is low, as it is indirect evidence extrapolated from observational data from other situations and may not apply directly to patients with CAPS, who are often critically ill and receiving concurrent medications and may have different risks associated with investigations such as biopsy. No studies were found discussing direct benefit or burden otherwise from the tests. The overall certainty is very low, for two reasons: 1) No studies were found addressing the patient-important outcomes related to diagnosing CAPS us ing the Preliminary Criteria. 2) The evidence relating to benefit of therapies in CAPS is itself very low (see EtD's for therapy), thus direct benefits of an appropriate diagnosis carry a similar uncertainty relating to consequences of diagnosis and treatment. Uncertain, as even with a diagnosis of CAPS, patients receive a wide variety of treatments and treatment combinations (Cervera 2009). in treatment practices noted

CER EVI RESU No included studies CERTAINTY OF EFFECTS VALUES What is the overall certainty of the evidence of effects of the test? Very low Low Moderate High No included studies Is there important uncertainty about or in how much people value the main outcomes? Important uncertainty or Pos s ibly important uncertainty or Probably no important uncertainty or No important uncertainty or Does the balance between desirable and undesirable effects favor the or the comparison? {Panel to comment} A systematic literature search was performed using the Medline and Embase databases to retrieve values and preferences pertaining to the outcomes in CAPS patients. The databases were searched to February 2016. There were no published studies evaluating the importance of the outcomes in CAPS patients. The outcomes have been shown to have an appreciable effect on quality of life as evidenced by studies in other disorders. For example, in studies of patients with diabetes, complications such as amputation and chronic neurologic deficit such as stroke have been associated with among the highest decrements in health utilities (Coffey 2002). A systematic review of the health utilities of stroke has shown that the utilities for minor stroke range from 0.50-0.70, and those for major stroke range from 0-0.30, and may even be negative, indicating a state worse than death (Post 2001). Acute thromboembolism has been shown to lead to moderate decrements in health utilities, and bleeding events have been associated with differing levels of decrements in health utility scores, depending on the site and severity of bleeding. The most severe bleeding episodes, such as major intracranial bleeds have been associated with median health utilities as low as 0.15 (Hogg 2013). {Panel to comment} LANCE OF EFFECTS Favors the comparison Probably favors the comparis on Does not favor either the or the comparis on Probably favors the

BAL Favors the RESOURCES REQUIRED CE CES How large are the resource requirements (costs)? Large costs Moderate costs Negligible costs and savings Moderate s avings Large savings What is the certainty of the evidence of resource requirements (costs)? There are no studies assessing cost of use of the Preliminary Criteria. It is difficult to estimate the costs associated with patient-important outcomes given the uncertainty involved in treatment effects and costs of treatment for CAPS patients (see EtD's for therapy). Given the number of organs that may be affected, biopsy costs will vary depending on the organ involved. In the US, renal biopsy costs range from $3,000-10,000. Skin biopsy ranges from $100-1,000. Liver biops y ranges from $2,000-7,000. The costs for APLA testing depend on the particular assays used. Charges for APLA testing at 2 labs in the US are as follows: - Stand alone APTT mixing study immediate and incubated - $208.24 - DRVVT Test (low phospholipid) - $122.37 - $127.00 - DRVVT Confirm (high phos pholipid) - $122.37 - $127.00 - Hexagonal phospholipid assay - $135.00 - ACL IgG - $360.00 - ACL IgM - $360.00 - ACL IgM - $360.00 - ACL IgA - $360.00 - B2GPI IgG - $134.00 - B2GPI IgM - $134.00 - B2GPI IgA - $271.50 (note: these values represent the amount that the lab charges for the test - this does not necessarily represent the cost of performing the test.) Charges for APLA at one centre in Canada are as follows: - NSI (includes PTT-LA and RVVT; PTT-LA 1:1 immediate mix and DRVVT Confirm, when appropriate) - $20.00 - ACL IgG - $14.00 - ACL IgM - $14.00 - B2GPI IgG - $17.50 Charges at one centre in Europe are as follows: - APTT - Screen, mix, confirm - 61.17 - drvvt - Screen, mix, confirm - 61.17 - ACL IgG - 27.68 - ACL IgM - 27.68 - ACL IgA - 27.68 - B2GPI IgG - 27.68 - B2GPI IgM - 27.68 - B2GPI IgA - 27.68 The certainty of the evidence of resource requirements is very low, as the studies presented only describe costs of assessment of the components of the Preliminary Criteria. The data presented are not necessarily representative of costs for CAPS patients. Furthermore the studies do not present data regarding any cost-benefit or similar

CERTAINTY OF EVIDENC OF REQUIRED RESOURC COST EFFECTIVENESS EQUITY Very low Low Moderate High No included studies Does the cost-effectiveness of the favor the or the comparison? Favors the comparison Probably favors the comparis on Does not favor either the or the comparis on Probably favors the Favors the No included studies What would be the impact on health equity? Reduced Probably reduced Probably no impact Probably increas ed Increased type analysis, thus there is no analysis relating to the implications of resource use in this population. {Panel to comment} Some areas may not have access to antiphospholipid testing, or the test may not be resulted in a timely fashion due to financial constraints. In areas where testing is available, patients may obtain a faster diagnosis and definitive therapy in a more timely fashion compared to patients in areas where these are not as readily available. This could lead to regional health inequities.

Is the acceptable to key stakeholders? {Panel to comment} ACCEPTABILITY FEASIBILITY No Probably no Probably yes Yes Is the feasible to implement? No Probably no Probably yes Yes Summary of judgements JUDGEMENT {Panel to comment} PROBLEM No Probably no Probably yes Yes Varies Don't know IMPLICATIONS TEST ACCURACY Very inaccurate Inaccurate Accurate Very accurate Varies Don't know DESIRABLE EFFECTS Trivial Small Moderate Large Varies Don't know UNDESIRABLE EFFECTS Large Moderate Small Trivial Varies Don't know CERTAINTY OF THE EVIDENCE OF TEST ACCURACY Very low Low Moderate High No included studies

CERTAINTY OF THE EVIDENCE OF TEST'S EFFECTS Very low Low Moderate High No included studies CERTAINTY OF THE EVIDENCE OF MANAGEMENT'S EFFECTS CERTAINTY OF THE EVIDENCE OF TEST RESULT/MANAGEMENT Very low Low Moderate High Very low Low Moderate High CERTAINTY OF EFFECTS Very low Low Moderate High VALUES BALANCE OF EFFECTS Important uncertainty or Favors the comparis on Possibly important uncertainty or Probably favors the comparis on RESOURCES REQUIRED Large cos ts Moderate cos ts CERTAINTY OF EVIDENCE OF REQUIRED RESOURCES COST EFFECTIVENESS Probably no important uncertainty or Does not favor either the or the comparis on Negligible costs and savings No important uncertainty or Probably favors the Moderate savings Very low Low Moderate High Favors the comparis on Probably favors the comparis on Does not favor either the or the comparis on Probably favors the Favors the Varies No included studies No included studies No included studies Don't know Large s avings Varies Don't know Favors the Varies No included studies No included studies EQUITY Reduced Probably reduced Probably no impact Probably increas ed Increas ed Varies Don't know ACCEPTABILITY No Probably no Probably yes Yes Varies Don't know FEASIBILITY No Probably no Probably yes Yes Varies Don't know

Conclusions Should the Preliminary Criteria for Classification of the Catastrophic Antiphospholipid Syndrome be used to diagnose CAPS in patients presenting with features suggestive of CAPS? TYPE OF RECOMMENDATION Strong recommendation against the Conditional recommendation against the Conditional recommendation for either the or the comparison Conditional recommendation for the Strong recommendation for the RECOMMENDATION JUSTIFICATION SUBGROUP CONSIDERATIONS IMPLEMENTATION CONSIDERATIONS MONITORING AND EVALUATION RESEARCH PRIORITIES For patients suspected of having CAPS, the CAPS guideline panel suggests/recommends using/not using the Preliminary Criteria for Classification of the Catastrophic Antiphospholipid Syndrome over physician expertise for diagnosis of CAPS (conditional/s trong recommendation, xx certainty in the evidence).

Question Should no biopsy vs. biopsy be used to diagnose CAPS in patients with suspected CAPS? POPULATION: patients with suspected CAPS BACKGROUND: In a 2001 publication of a cohort of 80 CAPS patients, Asherson et al identified that the majority of patients had biopsies revealing INTERVENTION: no biops y evidence of multiple small vessel occlusion, in contrast to the predominantly large vessel thrombosis afflicting patients with APS. COMPARISON: biops y The majority of thromboses in CAPS patients were intra-abdominal PURPOSE OF (occurring in 83% of patients), particularly renal (72%). Other intraabdominal thrombosis sites included hepatic (37%), splenic (17%), THE TEST: gastrointestinal (14%), pancreatic (11%), and adrenal (10%). Other LINKED sites involved included pulmonary (64%), cerebrovascular (61%), TREATMENTS: cardiac (55%), cutaneous (52%), venous thrombosis (27%), peripheral arterial thrombosis (17%), and bone marrow necrosis ANTICIPATED (7%). OUTCOMES: The Preliminary Criteria for Classification of the Catastrophic Antiphospholipid Syndrome were first proposed by Asherson et al. SETTING: in 2002 and accepted by all participants in the pre- symposium PERSPECTIVE: Population workshop on APS consensus, held at the 10th International Congress on apl (Asherson 2003). The criteria are as follows: 1) Evidence of involvement of three or more organs, systems and/or tissues(a) 2) Development of manifestations simultaneously or in less than a week 3) Confirrmation by histopathology of small vessel occlusion in at least one organ or tissue(b) 4) Laboratory confirmation of the presence of antiphospholipid antibodies (lupus anticoagulant and/or anticardiolipin antibodies)(c) The designation of a patient having definite catastrophic APS requires all four criteria. If no biopsy was performed, the patient is classified as having probable catastrophic APS. For histopathological confirmation, significant evidence of thrombosis must be present, although vasculitis may coexist occas ionally. The 2005 study by Cervera et al. validated the Preliminary Criteria. In their cohort of 176 patients, 133 (76%) of patients fulfilled the 3rd criteria of confirmation by histopathology of small vessel occlusion in at least 1 organ or tissue. Assessment JUDGEMENT RESEARCH EVIDENCE ADDITIONAL

FFECTS DESIRABLE EFFECTS TEST ACCURACY PROBLEM Is the problem a priority? No Probably no Probably yes Yes How accurate is the test? Very inaccurate Inaccurate Accurate Very accurate Varies How substantial are the desirable anticipated effects? Trivial Small Moderate Large How substantial are the undesirable anticipated effects? Large Moderate In the most recently published full series of CAPS Registry patients, mortality in the 280 patient cohort was 44% (Cervera 2009). Furthermore, many of these patients are critically ill, and early diagnosis to differentiate CAPS from other mimicking conditions (thrombotic thrombocytopenic purpura; heparin-induced thrombocytopenia; DIC; hemolysis, elevated liver enzyme, low platelet syndrome; infective endocarditis; vasculitis; cryoglobulinemia; cholesterol emboli) could allow for institution of therapies that may impact mortality, and may avoid inappropriate therapies instituted upon misdiagnosis as a mimicking condition. A systematic review was performed using the Cochrane Highly Sensitive Search strategy to retrieve articles pertaining to diagnosis/classification of CAPS. The search yielded 213 abstracts, and two researchers (KL & CH) performed abstract screen in duplicate, identifying 20 abstracts for full text screen. Screening of full texts was performed in duplicate, and no articles comparing biopsy versus no biopsy in diagnosis/classification of CAPS were identified. A non-systematic search for sensitivity and specificity of biopsy in detecting small vessel thrombosis did not yield any results. As no studies were identified discussing outcomes of use of biopsy in diagnosing CAPS, no es timate of benefit on patient-important outcomes was pos s ible. The adverse effects associated with biopsy of affected organs, will differ depending on the organ involved. For example, Renal biops y: -risk of bleeding 1.2% -requirement for blood trans fus ion 0.9% -requirement for angiographic procedure to manage bleeding 0.6% -requirement for nephrectomy to manage bleeding 0.01% -risk of death 0.2% -arteriovenous fis tula 18% (mos t clinically ins ignificant) -perirenal soft tissue infection 0.2% [Whittier WL, Korbet SM. Indications for and complications of renal biopsy. In: UpToDate, Post TW (Ed), UpToDate, Glassock RJ, Rovin BH. (Accessed on March 22, 2016.) Skin biopsy complications include bleeding and infection, with risk dependent on location and depth. Liver biops y: -risk of severe bleeding 0.32% -bile peritonitis 0.09% -pneumothorax 0.0078% -risk of death 0.02% CONSIDERATIONS

UNDESIRABLE EF Small Trivial Varies -arteriovenous fis tula 18% (mos t clinically ins ignificant) -perirenal soft tissue infection 0.2% [Whittier WL, Korbet SM. Indications for and complications of renal biopsy. In: UpToDate, Post TW (Ed), UpToDate, Glassock RJ, Rovin BH. (Accessed on March 22, 2016.) CERTAINTY OF THE EVIDENCE OF TEST ACCURACY CERTAINTY OF THE EVIDENCE OF TEST'S EFFECTS TAINTY OF THE VIDENCE OF EMENT'S EFFECTS What is the overall certainty of the evidence of test accuracy? Very low Low Moderate High No included studies What is the overall certainty of the evidence for any critical or important direct benefits, adverse effects or burden of the test? Very low Low Moderate High No included studies What is the overall certainty of the evidence of effects of the management that is guided by the test results? Very low Low Moderate High No res earch identified. patchy disease excess FN specificity No research identified for direct benefits. The evidence regarding adverse effects of biopsy is derived from studies of patients having renal biopsies for a variety of indications, and are not specific to CAPS patients. It is possible that the risks are higher for CAPS patients, who are often critically ill, and may not tolerate an invasive procedure. CAPS patients may also be receiving concomitant medications such as anticoagulants, which may increase bleeding, or immunomodulatory agents which may increase the risk of infection. The overall certainty is very low, for two reasons: 1) No studies were found addressing the patient-important outcomes related to diagnosing CAPS using biopsy compared to diagnosing CAPS without biopsy. 2) The evidence relating to benefit of therapies in CAPS is itself very low (see EtD's for therapy), thus direct benefits of an appropriate diagnosis carry a similar uncertainty relating to consequences of diagnosis and treatment. no included studies for benefit indirect evidence for harms

CERT EV MANAGE No included studies CERTAINTY OF THE EVIDENCE OF TEST RESULT/MANAGEMENT CERTAINTY OF EFFECTS VALUES How certain is the link between test results and management decisions? Very low Low Moderate High No included studies What is the overall certainty of the evidence of effects of the test? Very low Low Moderate High No included studies Is there important uncertainty about or in how much people value the main outcomes? Important uncertainty or Pos s ibly important uncertainty or Probably no important uncertainty or No important uncertainty or Uncertain, as even with a diagnosis of CAPS, patients receive a wide variety of treatments and treatment combinations (Cervera 2009). {Panel to comment} very low = large enough confidence to biopsy if low harm (i.e. cutaneous, anticoag) A systematic literature search was performed using the Medline and Embase databases to retrieve values and preferences pertaining to the outcomes in CAPS patients. The databases were searched to February 2016. There were no published studies evaluating the importance of the outcomes in CAPS patients. The outcomes have been shown to have an appreciable effect on quality of life as evidenced by studies in other disorders. For example, in studies of patients with diabetes, complications such as amputation and chronic neurologic deficit such as stroke have been associated with among the highest decrements in health utilities (Coffey 2002). A systematic review of the health utilities of stroke has shown that the utilities for minor stroke range from 0.50-0.70, and those for major stroke range from 0-0.30, and may even be negative, indicating a state worse than death (Post 2001). Acute thromboembolism has been shown to lead to moderate decrements in health utilities, and bleeding events have been associated with differing levels of decrements in health utility scores, depending on the site and severity of bleeding. The most severe bleeding episodes, such as major intracranial bleeds have been associated with median health utilities as low as 0.15 (Hogg 2013). Does the balance between {Panel to comment}

desirable and undesirable effects favor the or the comparison? BALANCE OF EFFECTS RESOURCES REQUIRED CERTAINTY OF EVIDENCE OF REQUIRED RESOURCES Favors the comparison Probably favors the comparis on Does not favor either the or the comparis on Probably favors the Favors the How large are the resource requirements (costs)? Large costs Moderate costs Negligible costs and savings Moderate s avings Large savings What is the certainty of the evidence of resource requirements (costs)? Very low Low Moderate High No included studies There are no studies assessing cost of use of biopsy in CAPS. It is difficult to estimate the costs associated with patient-important outcomes given the uncertainty involved in treatment effects and costs of treatment for CAPS patients (see EtD's for therapy). Given the number of organs that may be affected, biopsy costs will vary depending on the organ involved. In the US, renal biopsy costs range from $3,000-10,000. Skin biopsy ranges from $100-1,000. Liver biops y ranges from $2,000-7,000. The certainty of the evidence of resource requirements is very low, as the studies presented only describe costs of biopsies on average for a variety of indications. The data presented are not necessarily representative of costs for CAPS patients. Furthermore the studies do not present data regarding any cost-benefit or similar type analysis, thus there is no analysis relating to the implications of resource use in this population.

COST EFFECTIVENESS EQUITY ACCEPTABILITY Does the cost-effectiveness of the favor the or the comparison? Favors the comparison Probably favors the comparis on Does not favor either the or the comparis on Probably favors the Favors the No included studies What would be the impact on health equity? Reduced Probably reduced Probably no impact Probably increas ed Increased Is the acceptable to key stakeholders? No Probably no Probably yes Yes No research was identified. {No res earch identified; panel to comment} {No res earch identified; panel to comment}

Is the feasible to implement? No As many patients with CAPS are critically ill, a patient may be considered too ill to undergo an invasive procedure such as biopsy. In the subset of patients who are very severely ill, biopsy of an affected organ may not be feasible. FEASIBILITY Probably no Probably yes Yes Summary of judgements JUDGEMENT PROBLEM No Probably no Probably yes Yes Varies Don't know TEST ACCURACY Very inaccurate Inaccurate Accurate Very accurate Varies Don't know DESIRABLE EFFECTS Trivial Small Moderate Large Varies Don't know UNDESIRABLE EFFECTS Large Moderate Small Trivial Varies Don't know CERTAINTY OF THE EVIDENCE OF TEST ACCURACY CERTAINTY OF THE EVIDENCE OF TEST'S EFFECTS Very low Low Moderate High Very low Low Moderate High No included studies No included studies IMPLICATIONS CERTAINTY OF THE EVIDENCE OF MANAGEMENT'S EFFECTS CERTAINTY OF THE EVIDENCE OF TEST RESULT/MANAGEMENT Very low Low Moderate High Very low Low Moderate High No included studies No included studies

CERTAINTY OF EFFECTS Very low Low Moderate High No included studies VALUES Important uncertainty or Possibly important uncertainty or Probably no important uncertainty or No important uncertainty or BALANCE OF EFFECTS RESOURCES REQUIRED CERTAINTY OF EVIDENCE OF REQUIRED RESOURCES COST EFFECTIVENESS EQUITY Favors the comparis on Large cos ts Probably favors the comparis on Moderate costs Does not favor either the or the comparis on Negligible cos ts and savings Probably favors the Moderate savings Very low Low Moderate High Favors the comparis on Reduced Probably favors the comparis on Probably reduced Does not favor either the or the comparis on Probably no impact Probably favors the Probably increas ed Favors the Varies Don't know Large s avings Varies Don't know Favors the Varies No included studies No included studies Increas ed Varies Don't know ACCEPTABILITY No Probably no Probably yes Yes Varies Don't know FEASIBILITY No Probably no Probably yes Yes Varies Don't know Conclusions Should no biopsy vs. biopsy be used to diagnose CAPS in patients with suspected CAPS? TYPE OF RECOMMENDATION Strong recommendation against the Conditional recommendation against the Conditional recommendation for either the or the comparison Conditional recommendation for the Strong recommendation for the RECOMMENDATION For patients suspected of having CAPS, the CAPS guideline panel suggests/recommends using/not using biopsy to diagnos e CAPS (conditional/s trong recommendation, xx certainty in the evidence). JUSTIFICATION

SUBGROUP CONSIDERATIONS IMPLEMENTATION CONSIDERATIONS MONITORING AND EVALUATION RESEARCH PRIORITIES

Question Should criteria with detection of antiphospholipid antibodies vs. without detection of antiphospholipid antibodies be us ed to diagnos e CAPS in patients with suspected CAPS? POPULATION: INTERVENTION: COMPARISON: patients with suspected CAPS criteria with detection of antiphos pholipid antibodies without detection of antiphos pholipid antibodies BACKGROUND: The Preliminary Criteria for Classification of the Catastrophic Antiphospholipid Syndrome were first proposed by Asherson et al. in 2002 and accepted by all participants in the pre- symposium workshop on APS consensus, held at the 10th International Congress on apl (Asherson 2003). The criteria are as follows: PURPOSE OF THE TEST: LINKED TREATMENTS: ANTICIPATED OUTCOMES: SETTING: PERSPECTIVE: Assessment JUDGEMENT RESEARCH EVIDENCE 1) Evidence of involvement of three or more organs, systems and/or tissues(a) 2) Development of manifestations simultaneously or in less than a week 3) Confirmation by histopathology of small vessel occlusion in at least one organ or tissue(b) 4) Laboratory confirmation of the presence of antiphospholipid antibodies (lupus anticoagulant and/or anticardiolipin antibodies) (c) The designation of a patient having definite catastrophic APS requires all four criteria. If no biopsy was performed, the patient is classified as having probable catastrophic APS. For histopathological confirmation, significant evidence of thrombosis must be present, although vasculitis may coexist occas ionally. The 2005 study by Cervera et al. validated the Preliminary Criteria. In their cohort of 176 patients, 159 (90%) of patients fulfilled the 4th criteria of laboratory confirmation of presence of antiphos pholipid antibodies (acl or LA) confirmed 6 weeks apart. ADDITIONAL CONSIDERATIONS Is the problem a priority? No Probably no Probably yes Yes In the most recently published full series of CAPS Registry patients, mortality in the 280 patient cohort was 44% (Cervera 2009). Furthermore, many of these patients are critically ill, and early diagnosis to differentiate CAPS from other mimicking conditions (thrombotic thrombocytopenic purpura; heparin-induced thrombocytopenia; DIC; hemolysis, elevated liver enzyme, low platelet syndrome; infective endocarditis; vasculitis; cryoglobulinemia; cholesterol emboli) could allow for institution of therapies that may impact mortality, and may avoid inappropriate therapies instituted upon misdiagnosis as a mimicking condition.