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Development and initial validation of a damage index (DIAPS) in patients with thrombotic antiphospholipid syndrome (APS) M-C Amigo1, MV Goycochea-Robles2, G Espinosa-Cuervo3, G Medina4, JA Barraga´n-Garfias5, A Vargas6 and L Javier Jara7 1 ABC Medical Center, Department of Rheumatology, Mexico DF, Mexico; 2Hospital General Regional 1, IMSS, Unidad de Invesitigaci0n en Epidemiologı´ a Clı´ nica, Mexico City, Mexico; 3Unidad de Medicina Fı´ sica y Rehabilitaci0n Centro, IMSS, Consulta Externa, Mexico City, Mexico; 4 Centro Me´dico Nacional La Raza, IMSS, Unidad de Investigaci0n, Mexico City, Mexico; 5Hospital General de Zona 48, Departamento de Reumatologı´ a, Mexico City, Mexico; 6Instituto Nacional de Cardiologı´ a Ignacio Cha´vez, Departamento de Reumatologı´ a, Mexico City, Mexico; and 7Hospital de Escpecialidades Centro Me´dico La Raza, IMSS, Departamento de Ensen˜anza e Investigaci0n, Mexico City, Mexico
Introduction: In antiphospholipid syndrome (APS), certain principal manifestations are associated with a worse prognosis and organ damage. Objective: The objective of this paper is to describe the development and initial content, criterion and construct validity of a disease-specific cumulative damage index in patients with thrombotic APS (DIAPS). Methods: Through expert panel agreement, 47 items were considered to reflect damage in APS. This preliminary version of the DIAPS was submitted to four local and international clinical and research experts in APS who ranked each item according to severity. A Delphi exercise resulted in a final 37 item instrument. In the second phase, a cross-sectional study was conducted applying the DIAPS in patients included in a multicenter electronic registry of patients with APS. Quality of life related to health status was evaluated with the EuroQol for construct validation. An a Cronbach and correlation with the EuroQol scale were calculated with SPSS 20.0 (p < 0.05). Results: We evaluated the DIAPS in 156 patients, 77% female, with a mean age at diagnosis 34.7 5.5 years. A total of 69% had primary APS. Common comorbidities included obesity, depression and dyslipidemia. The most frequent manifestations resulting in sequelae were deep venous thrombosis and ischemic stroke. Blindness, retinal occlusive vessel disease, myocardial infarction, cardiac valve requiring replacement, mesenteric thrombosis, and renal insufficiency also occurred. Homogeneity: a Cronbach 0.619. DIAPS items correlated with EuroQol domains with the exception of pulmonary, renal, gastrointestinal, and endocrine systems. Conclusion: This study demonstrates content, criterion and construct validity of a new physician-reported instrument to assess the DIAPS. In addition, the DIAPS correlated with the EuroQol. Lupus (2015) 0, 1–8. Key words: Antiphospholipid syndrome; Damage index; Hughes syndrome
Introduction Antiphospholipid syndrome (APS), an autoimmune-acquired thrombophilia, is defined by the presence of thrombosis and/or pregnancy morbidity plus persistently positive assays for circulating antiphospholipid antibodies (aPL).1 While recurrent thrombosis is the hallmark of APS, recurrent
Correspondence to: Mary-Carmen Amigo, ABC Medical Center, Sur 136 # 116, Las Ame´ricas, Suite # 417, Mackenzie Tower, Mexico City, 01120 Mexico. Email: [email protected] Received 26 July 2014; accepted 12 January 2015
pregnancy loss or cytopenias may be the sole manifestation of the syndrome.2 The long-term prognosis for patients with APS is to a large extent influenced by the risk of recurrent thrombosis or damage caused by mechanisms that are only partially understood.3,4 Certain manifestations of APS carry a worse prognosis, and permanent damage may occur in various organs.5–7 Moreover, a significant impact of the disease on long-term survival has been documented in large, prospective cohort studies of patients with different clinical subsets of APS.8,9 Also, decreased survival has been shown in systemic lupus erythematosus (SLE) patients who in addition had APS.10
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Thus, organ damage in APS needs to be quantified in the clinical setting, and an instrument that measures accumulated damage over time is required. To comply with clinimetric principles, an APS damage measurement instrument must have content validity, which is the ability to reflect the full range of cumulative or irreversible damage that APS may inflict. In addition, it must have construct validity to explain the inter-relationships between all the component items. As an example, the Systemic Lupus International Collaborating Clinics/ American College of Rheumatology (SLICC/ ACR) Damage Index (SDI),11 which was developed for SLE, misses key features of APS, a condition that only partially overlaps with SLE.12,13 An early version of a damage index for APS was previously presented by our group. In this study, 27 clinical items with potential to cause chronic damage in APS were reviewed by local (MC, MCA) and international (MAK) experts. An instrument containing these items was applied to 38 patients with primary APS, 30 patients with SLE-associated APS, and 30 patients with SLE.14 Subsequently, additional items were included, and an early validation of the instrument was performed.15 The present study represents a further improvement of the damage index for thrombotic APS (DIAPS) including the content and construct validity of our instrument.
Patients and methods Phase 1 Development of the DIAPS
Clinimetrics conceptualizes the measurement of clinical phenomena via indices or scales.12 As a first step in developing a clinimetric instrument to measure organ damage in APS, we met with clinical epidemiologists and clinicians to discuss how organ damage could be quantified in this condition. To fulfill content validity we first reviewed the SDI for SLE11 to find items that were also applicable to APS. We then included elements that were considered to reflect damage that is unique to APS. In the first round, experts identified 60 manifestations that could cause irreversible damage in APS. In the second round, an operative definition for each of these clinical manifestations was established (Appendix). Finally, after independent review by three methodology experts (MVGR, GEC, MGP) and three clinical experts in APS (MCA, LJJ, GM), a 47-item instrument was
selected by consensus.15 This preliminary version of the DIAPS was submitted to four local (MCA, LJJ) and international (MAK, DE) experts in APS who ranked the items according to severity (minimal impact, low impact, high impact). A Delphi exercise was then performed to exclude items of low specificity, resulting in a final 37-item instrument. To represent damage, the item had to be present for at least six months, or cause a permanent hearing loss or hemiplegia. The APS-specific elements that are not included in the SDI for SLE are the following: Respiratory system damage: Chronic thromboembolic pulmonary hypertension and respiratory insufficiency caused by multiple lung infarctions. Cardiovascular system damage: Heart valve damage including (a) asymptomatic valve disease (b) symptomatic valve disease, and (c) valve disease requiring valve replacement. It should be mentioned that the SDI, as initially reported, considered only a diastolic murmur or a systolic murmur >3/6. Gladman and Urowitz, in a progress report, clarified that any operation performed after the diagnosis of SLE, such as for heart valve disease, added to the burden of illness and represented additional damage.16 Central nervous system damage: Different from the SDI, which includes only ‘‘cerebrovascular accident ever,’’ the DIAPS includes ischemic stroke with hemiparesis, ischemic stroke with hemiplegia, multi-infarct dementia, sensorineural hearing loss, optic neuropathy, and abnormal movement disorders such as chorea, parkinsonism and dystonia. Eye damage: Different from the SDI, which includes only ‘‘retinal change or optic atrophy,’’ the DIAPS includes arterial/venous retinal vaso-occlusive disease and blindness. Kidney damage: Both chronic renal failure and renal thrombotic microangiopathy (TMA) documented by renal biopsy were included. TMA may manifest clinically with massive proteinuria, which adds to the risk of thrombosis, severe and persistent arterial hypertension, and chronic renal failure (CRF). The SDI includes CRF and proteinuria 3.5 g/24 hours. TMA should be included, in addition to renal insufficiency, because there are patients with TMA without renal insufficiency and cases with renal insufficiency in which a biopsy determination of TMA is critical to prognosis and treatment. Skin damage: Chronic cutaneous ulcers. Bone damage: Avascular necrosis of bone. Gastrointestinal damage: Mesenteric thrombosis, arterial or venous thrombosis involving the liver (including the Budd-Chiari syndrome), the spleen or the intestine, and cirrhosis of the liver secondary to nodular regenerative hyperplasia. Endocrine system damage: Adrenal insufficiency
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and hypopituitarism requiring lifelong treatment caused by APS. Phase 2 The second phase of the study was crosssectional and was conducted using a multicenter online electronic database, the APS Latin American Registry (2009–2012) (http://investigacion.colmexreuma.org.mx/saaf/index.html). This Mexican initiative supported by the Pan American League of Associations for Rheumatology (PANLAR) considered the following variables: general demographics, clinical manifestations at the time of diagnosis, duration of disease, concurrent diagnoses, and treatment. A DIAPS index form was completed by a physician. In addition to completing the DIAPS form, we documented every clinical manifestation of APS as follows: (0) absent, (1) present without sequelae, and (2) or present with sequelae. As an example, regarding deep vein thrombosis, (0) indicates its absence, (1) indicates its presence with symptoms resolved within six months, and (2) indicates its presence with damage, as shown by chronic leg edema. The output rating of the DIAPS considers only two score manifestations. The final score was obtained by adding the output ratings for each domain (i.e. peripheral vascular, pulmonary). This allowed us to establish a ratio (not shown) of individual clinical manifestations/sequelae. In this initial phase of the study, we decided not to weigh the items. Criterion validity requires a concurrent comparison with a gold standard. In its absence, we decided to use an instrument that measured the consequences of damage.17 To this end, we used the EuroQol, a generic, standardized measurement of health18 to determine the quality of life of the patients. The EuroQol describes and rates healthrelated quality of life by measuring five dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. These dimensions may fall short of the entire spectrum of damage that occurs in the DIAPS, but most, directly or indirectly, appear to be covered. We selected the EuroQol because it is short, multilingual, validated, and has shown consistent results in different countries and many chronic diseases including rheumatic diseases.18–20 Finally, the EuroQol is a useful surrogate index to calculate the economic impact of disability. Analysis The general demographics, clinical manifestations and the treatment of APS were analyzed with
descriptive statistics. For the DIAPS, a Spearman’s correlation with the EuroQol scale was calculated, looking for each domain of the EuroQol and the global patient assessment. The internal consistency of the DIAPS items used to assess the damage in APS patients was calculated with a Cronbach (p 0.05). We used SPSS, version 20.0. The study protocol was reviewed and accepted by the Research Committee of the Mexican College of Rheumatology.
Results The original SDI for SLE considered 12 different organ systems with a total of 37 items. The DIAPS used 22 items from SDI plus 15 new elements that were found specific of APS according to the consulted experts. Some SDI items were expanded to show the heterogeneity of some clinical manifestations that are particular to APS. A Delphi panel performed with the international experts showed a high reliability of 35/37 items. However, chronic cutaneous ulcers and retinal vaso-occlusive disease were rated differently by experts. Nevertheless, the final consensus considered that these two items have an irreversible impact in patients with APS and both were included. The DIAPS, which includes 10 organ systems and 37 items, is shown in Table 1. The DIAPS was applied to 156 patients listed in a multicenter, international electronic registry mentioned in Methods. Eleven centers participated: seven from Mexico, two from Venezuela and one each from El Salvador and the Dominican Republic. Demographic and clinical characteristics of these patients are shown in Table 2. There was a preponderance of women, and the dominant ethnic group was Mestizo. More than 60% of the patients had less than 12 years of formal education. The most frequent thrombotic manifestations were stroke and venous thrombosis. In the 156 patients, aPL were present as follows: immunoglobulin (Ig)G anticardiolipin antibodies (aCL) in 73%, IgM aCL in 51%, lupus anticoagulant (LA) in 50%, IgG anti-b2-glycoprotein 1 (ab2GP1) in 18%, and false-positive Venereal Disease Research Laboratory (VDRL) test in 15.6%. The majority of patients were on antithrombotic therapy, 79% were on permanent anticoagulation (international normalized ratio (INR) 2–2.5), 6% on permanent high anticoagulation (INR 3–3.5), and 40% were on low-dose aspirin. In addition, almost 41% of patients received antimalarials, Lupus
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Table 1
Items included in the DIAPS SLICCb damage index
1. Peripheral vascular Deep vein thrombosis Intermittent claudication Tissue loss: minor Tissue loss: major Vascular venous insufficiency 2. Pulmonary Pulmonary infarction Pulmonary arterial hypertension Chronic thromboembolic pulmonary hypertension Respiratory insufficiency 3. Cardiovascular Coronary artery bypass Myocardial infarction Cardiomyopathy aPL-associated heart valve disease: (asymptomatic, symptomatic) aPL-associated heart valve disease requiring valvular replacement 4. Neuropsychiatric Cognitive impairment Seizures Ischemic stroke with hemiparesia Ischemic stroke with hemiplegia Multi-infarct dementia Cranial neuropathy Sudden sensorineural Hearing loss Transverse myelitis Optic neuropathy Peripheral neuropathy Abnormal movements: – Dystonia – Chorea – Parkinsonism 5. Ophthalmologic Retinal vaso-occlusive disease Blindness 6. Renal Chronic renal failure Proteinuria 24 h 3.5 g OR Renal thrombotic microangiopathy 7. Musculoskeletal Avascular necrosis 8. Cutaneous Chronic cutaneous ulcers 9. Gastrointestinal Mesenteric thrombosis Budd-Chiari syndrome Cirrhosis of the liver 10. Endocrine Suprarenal insufficiency Hypopituitarism Infertility
Table 2 Baseline characteristics of 156 APS patients DIAPSa damage index Demographic characteristics Age (years) Age at diagnosis (years) Gender Ethnic group Education
b b b b
Mean SD Mean SD Female Mestizo High school
n
%
43 13.5 34.7 5.5 120 92 95
77.0 59.0 61.0
b
b b a
a
b b b b
b
b b b b a
APS Characteristics Primary APS APS associated with other immunologic disease: SLE SLE Like Sjo¨gren’s syndrome Rheumatoid arthritis Systemic vasculitis
108 48
69.0 31.0
39 3 3 1 2
25.0 1.9 1.9 0.6 1.2
Comorbidities Obesity Hypertension Anxiety/Depression Dyslipidemia Thyroid disease Diabetes mellitus Fybromyalgia
37 30 33 46 16 13 12
24.0 19.0 21.0 29.0 10.0 8.0 7.4
SD: standard deviation; APS: antiphospholipid syndrome; SLE: systemic lupus erythematosus.
b a b b b a
a a
b b a
b a
b a a
a a b
DIAPS: Damage index in patients with thrombotic antiphospholipid syndrome (APS). SLICC: Systemic Lupus International Collaborating Clinics; aPL: antiphospholipid antibodies. a Denotes items that are newly considered in the DIAPS. b Denotes items taken from SLICC/American College of Rheumatology Damage Index (ACR DI).
18% azathioprine, 29% glucocorticoids, 3% cyclophosphamide and 1% rituximab and intravenous Ig (IVIG). Health-related quality of life, evaluated with the EuroQol, showed mobility problems in 35.2%, selfcare difficulties in 11.5%, inability to perform daily living activities in 33.9%, pain in 30.4%, and anxiety or depression in 50.6%. Mean health status (reported by visual analog scale (VAS)) was 70.22 16.37 SD. The DIAPS items correlated with the EuroQol domains: peripheral vascular disease, with mobility, usual activities, and pain; cardiovascular involvement, with self-care and pain; neuropsychiatric disease, with all domains except pain; eye abnormalities, with self-care, anxiety, and depression; and cutaneous disease, with pain. Pulmonary, renal, gastrointestinal, and endocrine systems had no correlation with the EuroQol domains. The EuroQol domains mobility (r ¼ 0.441), pain/discomfort (r ¼ 0.487), health status visual analog (r ¼ –0.479), usual activities (r ¼ 0.375), and selfcare (r ¼ 0.354) reported by the patients showed a significant correlation with the global DIAPS score (p ¼ 0.000). The DIAPS had a high internal consistency (a Cronbach 0.619).
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Table 3 DIAPS items and EuroQol health status domains correlation Domain/EuroQol18 DIAPS
Mobility
Self-care
Usual activities
Pain/Discomfort
Anxiety/Depression
VAS Euro Qol health status
Peripheral vascular Pulmonary Cardiovascular Neuropsychiatric Ophthalmologic Renal Cutaneous Musculoskeletal Gastrointestinal Endocrine DIAPSa
0.360/0.000 0.063/0.437 0.146/0.072 0.162/0.045 0.023/0.784 0.021/0.805 0.150/0.077 – 0.033/0.698 0.041/0.630 0.441/0.000
0.060/0.460 0.031/0.703 0.206/0.011 0.368/0.000 0.165/0.049 0.012/0.885 0.110/0.196 – 0.062/0.468 0.035/0.683 0.354/0.000
0.225/0.005 0.52/0.524 0.155/0.056 0.229/0.004 0.148/0.077 0.084/0.321 0.042/0.623 – 0.125/0.143 0.034/0.685 0.375/0.000
0.391/0.000 0.066/0.417 0.192/0.017 0.134/0.099 0.043/0.613 0.063/0.462 0.225/0.007 – 0.048/0.578 0.099/0.244 0.487/0.000
0.078/0.332 0.090/0.268 0.147/0.070 0.159/0.049 0.189/0.023 0.022/0.793 0.032/0.705 – 0.017/0.842 0.012/0.888 0.234/0.003
0.251/0.002 0.007/0.939 0.100/0.239 0.310/0.000 0.193/0.027 0.017/0.848 0.092/0.300 – 0.021/0.811 0.072/0.420 0.479/0.000
P values (correlation is significant at the 0.05 level). DIAPS: Damage index in patients with thrombotic antiphospholipid syndrome (APS); VAS: visual analog score. a Global total score.
Discussion APS, a systemic and potentially devastating disease that occurs among young individuals, features increased morbidity, organ damage, and mortality. Thus, an instrument must be developed to determine with precision APS-related damage. We are unaware of other attempts to design and validate a damage index that is specific for APS patients. In the current study, the DIAPS demonstrated content, criterion, and construct validity. Criterion validity was evaluated as a proxy by the EuroQol, an instrument that accurately reflects patients’ and doctors’ opinions. The DIAPS showed a significant correlation with the EuroQol. Wang et al., using the SDI, evaluated the relationship between selfreported quality of life and disease activity and damage in SLE. In their study, health status as rated by the EuroQol was associated with damage and these authors considered the EuroQol a powerful instrument to measure health-related quality of life in SLE. The EuroQol has shown a significant association with chronic damage, and the findings clearly make clinical sense.20 To our knowledge, the EuroQol has not been previously used to evaluate the quality of life in APS. The high impact of APS on irreversible organ damage and survival in patients with SLE has been studied. In a longitudinal study of SLE patients with a follow-up of 9.7 years, RuizIrastorza et al. identified cumulative damage measured by the SDI. Cumulative survival at 15 years was lower in patients with APS compared with those without APS.10
APS has the potential to cause severe, irreversible damage from the very onset of the disease. We clearly recognized this issue in our patients with APS, in whom the time to diagnosis averaged 5.5 years. This finding contrasts with previous studies7,20,21 in which damage in APS appeared after many years of disease (more than 10 years). We agree that disease progression causes cumulative damage. However, thrombotic events that are considered the hallmark of APS may cause irreversible damage from the very beginning of the disease. There have been attempts to explore the damage in APS with the SDI instrument. Recently, Grika et al.7 assessed the accumulated organ damage using the SDI in a retrospective study of 135 patients with APS, of whom 89 were primary. They concluded that APS occurs among young individuals and causes increased morbidity, with one-fourth of the patients progressing to organ damage after a mean duration of 10 years from disease onset. However, the SDI they used has been designed for SLE, not for APS. Barbhaiya and Erkan21 analyzed the utility of the SDI in aPL-positive patients and/or APS, SLE or other systemic autoimmune diseases. These authors showed that the SDI score increased with additional aPL- and/or SLE-related damage. Important aPL-related organ damage was not identified. Their conclusion, in agreement with Vlachoyiannopoulos,22 was that a specific damage index for APS was needed. In the present study, we developed and validated a specific DIAPS. We are aware that the DIAPS has limitations. As Barbhaiya and Erkan concluded, key manifestations of APS such as livedo reticularis/racemosa, multiple sclerosis-like disease, or diffuse pulmonary hemorrhage, were Lupus
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not included.21 Although the DIAPS showed good content validity on initial validation, additional clinical manifestations of APS should be evaluated to determine their possible contribution to irreversible damage. Also, our study is cross-sectional, and a long-term follow-up study is required to validate our findings. Intraobserver and interobserver variability of the DIAPS need to be tested. A further limitation is that the DIAPS was not tested in related or mimicking conditions such as SLE and vasculitis. It is also necessary to determine its sensitivity to change over time. Finally, since the majority of patients in our study were Latin American Mestizo, an external validation in populations with a different genetic background should be undertaken. Finally, the items included in the DIAPS should be weighted to complete its clinimetric validation. Although the DIAPS is not intended to evaluate the obstetrical impact of chronic damage, infertility was included. Recently, at the 9th meeting of the European Forum on Obstetric APS,23 obstetric APS was considered a separate entity from thrombotic APS. The strength of the present study is that the DIAPS was developed specifically for APS. In our patients, the DIAPS appeared to be an accurate instrument to assess organ damage. In support of our findings, Ugolini Lopes et al.24 recently presented a cross-sectional analysis of 93 patients with primary APS followed at a single APS outpatient clinic in Sa˜o Paulo, Brazil. Damage was evaluated both by using the SDI and the DIAPS index herein described.15 A positive correlation between disease duration and higher SLICC/ACR DI and DIAPS scores was found (p < 0.05). In their opinion, the DIAPS appeared to be a better surrogate measure of disease severity in APS.
Conclusions This initial validation study demonstrated content and construct validity of the DIAPS, a new physician-reported instrument to assess thrombotic APS damage. The DIAPS showed a good correlation with the EuroQol. Further studies should be conducted to evaluate the reliability and clinimetric properties of this instrument in other populations. We believe that the DIAPS, used from the early stages of APS to measure the impact of this potentially devastating disease, may become a useful tool in clinical, epidemiologic and economic studies.
Funding This research received no specific grant from any funding agency in the public, commercial, or notfor-profit sectors.
Conflict of interest statement The authors have no conflicts of interest to declare.
Acknowledgments We are thankful to the following physicians for patient recruitment and clinical data collection: Esthela Loyo de Lo´pez, Dominican Republic; Salvador Sermen˜o Ca´ceres, El Salvador; Liz Caballero, Oscar Urdaneta and Ivette Montes de Oca, Venezuela; Leonor Barile, Aline Martı´ nezMartı´ nez, Claudia Mendoza Pinto, Rosa Elda Barbosa, Ana Sofı´ a Vargas and Gustavo Lugo Zamudio, Mexico. We are indebted to Dr Mario Cardiel (MC) for his methodological help during the earliest and pilot index measurements. We are also very grateful to Dr Maximiliano Garcı´ a de la Pen˜a (MGP) for his methodological support and the initial definitions. We sincerely thank Drs Doruk Erkan (DE) and Munther A. Khamashta (MAK) who helped us, as international clinical experts, in the first phase of the study. This research project would not have been possible without the support of the Pan American League of Associations for Rheumatology (PANLAR) for the creation of the APS Latin American Registry.
References 1 Miyakis S, Lockshin MD, Atsumi T, et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost 2006; 4: 295–306. 2 Cervera R, Piette JC, Font J, et al. Antiphospholipid syndrome: Clinical and immunologic manifestations and patterns of disease expression in a cohort of 1,000 patients. Arthritis Rheum 2002; 46: 1019–1027. 3 Alarco´n-Segovia D, Pe´rez-Ruiz A, Villa AR. Long-term prognosis of antiphospholipid syndrome in patients with systemic lupus erythematosus. J Autoimmun 2000; 15: 157–161. 4 Amigo MC. Prognosis in antiphospholipid syndrome. Rheum Dis Clin North Am 2001; 27: 661–669. 5 Erkan D, Yazici Y, Sobel R, Lockshin MD. Primary antiphospholipid syndrome: Functional outcome after 10 years. J Rheumatol 2000; 27: 2817–2821. 6 Amigo MC, Garcı´ a-Torres R. Kidney disease in antiphospholipid syndrome. In: Khamashta MA (ed.), Hughes syndrome: Antiphospholipid syndrome, 2nd ed. London: Springer-Verlag, 2006. pp. 99–111.
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7 7 Grika EP, Ziakas PD, Zintaras E, et al. Morbidity, mortality, and organ damage in patients with antiphospholipid syndrome. J Rheumatol 2012; 39: 516–523. 8 Tektonidou MG, Ioannidis JP, Boki KA, et al. Prognostic factors and clustering of serious clinical outcomes in antiphospholipid syndrome. QJM 2000; 93: 523–530. 9 Cervera R, Serrano R, Pons-Estel GJ, et al. Morbidity and mortality in the antiphospholipid syndrome during a 10-year period: A multicentre prospective study of 1000 patients. Ann Rheum Dis, Epub ahead of print 24 January 2014. DOI: 10.1136/annrheumdis-2013-204838. 10 Ruiz-Irastorza G, Egurbide MV, Ugalde J, Aguirre C. High impact of antiphospholipid syndrome on irreversible organ damage and survival of patients with systemic lupus erythematosus. Arch Intern Med 2004; 164: 77–82. 11 Gladman D, Ginzler E, Goldsmith C, et al. The development and initial validation of the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index for Systemic Lupus Erythematosus. Arthritis Rheum 1996; 39: 363–369. 12 Streiner DL, Norman GR. Health measurement scales: A practical guide to their development and use, 2nd ed. New York: Oxford University Press Inc, 2003. pp. 144–154. 13 Feinstein AR. Clinimetrics. London: Yale University Press, 1987. pp. 194–201, 4,5. 14 Amigo MC, Khamashta MA, Cardiel M, et al. Development and validation of an antiphospholipid damage index: A multicenter, binational project. Lupus 1998; 7(Suppl 1): 68. 15 Amigo MC, Barile LA, Barraga´n A, et al. Development and initial validation of a chronic damage index in patients with antiphospholipid syndrome (abstract). Arthritis Rheum 2011; 63(Suppl): S3–S4.
16 Gladman DD, Urowitz MB. The SLICC/ACR damage index: Progress report and experience in the field. Lupus 1999; 8: 632–637. 17 Fries JF, Hochberg C, Medsger TA Jr, Hunder GG, Bombardier C. Criteria for rheumatic disease. Different types and different functions. The American College of Rheumatology Diagnostic and Therapeutic Criteria Committee. Arthritis Rheum 1994; 37: 454–462. 18 EuroQol—A new facility for the measurement of health-related quality of life. The EuroQol Group. Health Policy 1990; 16: 199–208. 19 Da Rocha Castelar Pinheiro G, Khandker RK, Sato R, Rose A, Piercy J. Impact of rheumatoid arthritis on quality of life, work productivity and resource utilization: An observational, cross-sectional study in Brazil. Clin Exp Rheumatol 2013; 31: 334–340. 20 Wang C, Mayo NE, Fortin PR. The relationship between health related quality of life and disease activity and damage in systemic lupus erythematosus. J Rheumatol 2001; 28: 525–532. 21 Barbhaiya M, Erkan D. The optimal tool for assessment of organ damage in antiphospholipid syndrome. J Rheumatol 2013; 40: 89. 22 Vlachoyiannopoulos PG Dr. Vlachoyiannopoulos replies. J Rheumatol 2013; 40: 90. 23 Swadzba J, Sydor WJ, Kolodziejczyk J, Musial J. Summary of the 9th meeting of the European Forum on Antiphospholipid Antibodies. Lupus 2014; 23: 395–399. 24 Ugolini Lopes M, Aguila L, Tonon R, et al. SLICC and DIAPS: Potential indices for damage assessment in primary antiphospholipid syndrome (PAPS). APLA & LACA 2013 14th International Congress on Antiphospholipid Antibodies, 18–21 September 2013, Rio de Janeiro, Brazil.
Appendix Damage Index for APS. Glossary of terms
Items included in DIAPS
Definition
1 2
Peripheral vascular Deep vein thrombosis Intermittent Claudication
3 4 5
Tissue loss (minor) Tissue loss (major) Vascular venous Insufficiency
6
Pulmonary Pulmonary infarction
7
Pulmonary arterial hypertension
8
Chronic thromboembolic pulmonary hypertension
9 10
Respiratory insufficiency Cardiovascular Coronary artery bypass
11
Myocardial infarction
12
Cardiomyopathy
13
APL associated valve hearth disease: (asymptomatic, symptomatic) APL associated valve hearth disease requiring valve replacement
14
Blood clot inside the lumen of a deep vein Fatigue, cramps, pain and weakness of the legs secondary to peripheral arterial disease which begins with walking and improves with rest Absence of tissue secondary to necrosis of the affected area. Minor (pulp) Absence of tissue secondary to necrosis of the affected area. Major (digit or limb) Morphological or functional abnormalities (venous valvular incompetence) of long duration, have to be categorized and treated accordingly with CEAP Classification1 X-Ray or CAT demonstration of pulmonary opacity or wedged-shaped density as a consequence of pulmonary vessel thromboembolic occlusion Pulmonary artery pressure > 25mm Hg at rest or >30mmHg on exercise. Mild 30 49 mmHg, Moderate 50- 69 mmHg; Severe > 70 mm Hg. Obstructive lesions, in the lobar, segmentary, or the main branches of the pulmonary artery secondary to chronic thromboembolism Secondary to multiple infarctions Surgical treatment of occlusive disease of the coronary arteries that provides better blood flow in the epicardial coronary arteries leading to a decrease angina symptoms, complications of myocardial infarction and mortality. Clinical syndrome characterized by damage of the myocardial tissue caused by imbalance between oxigen myocardial input and oxygen demand Alterations in myocardial perfusion obstruction microvasculature in the presence of normal coronary arteries ECHO* detection of valve lesions and /or b) Regurgitation and/or stenosis of mitral and/ or aortic valve Valve Lesions according to Miyakis S et al 2 Progressive, symptomatic (NYHA3 functional class lll-lV) moderate or severe valve disease
(continued)
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Continued Items included in DIAPS
15
Neuropsychiatric Cognitive impairment
16
Seizures
17 18 19
Ischemic stroke with hemiparesia Ischemic stroke with hemiplegia Multinfarct dementia
20 21
Cranial Neurophaty Sudden sensorineural Hearing loss
22
Transverse myelitis
23
Optic Neuropathy
24 25
Peripheral neuropathy Abnormal movements: – Dystonia –
26 27 28 29 30 31
Chorea
– Parkinsonism Ophtalmologic Retinal vaso-occlusive disease Blindness Renal Chronic renal failure Proteinuria Renal thrombotic microangiopathy Musculoskeletal Avascular Necrosis
33
Cutaneous Chronic cutaneous Ulcers Gastrointestinal Mesenteric thrombosis
34
Budd Chiari syndrome
35 36
Cirrhosis of the liver Endocrine Suprarenal Insufficiency
37 38
Hypopituitarism Infertility
32
Definition
Memory deficit, difficulty with calculation, poor concentration, difficulty in spoken or written language, impaired performance level, documented on clinical examination or by formal neurocognitive testing. Paroxysmal electrical discharge occurring in the brain and producing characteristics physical changes including tonic and clinical movements and certain behavioral disorders. Cerebrovascular thrombotic event resulting in focal finding as paresis Cerebrovascular thrombotic event resulting in focal finding such as hemiplegia or aphasia Cognitive impairment caused by, or associated with, vascular factors confirmed by neuroimaging (MRI/CT) Damage to a cranial nerve resulting in either motor or sensory dysfunction Acute unexplained hearing loss nearly always unilateral that occurs over less than 72 hour period (demonstrated by evoked potentials) Lower-extremity weakness or sensory loss with loss of rectal and urinary bladder sphincter control Inflammatory or ischemic condition documented by MRI of the brain and orbits that causes acute visual loss Damage to a peripheral nerve resulting in either motor or sensory dysfunction. Movement disorder characterized by involuntary sustained muscle contraction that result in twisting and repetitive movements or abnormal postures Movement disorder characterized by involuntary brief, random and irregular movements of the limbs and face, emotional or abnormal postures Bradykinesia, tremor, rigidity without a good response to dopaminergic therapy Occlusion caused by arterial or venous thrombosis, conditioning severe loss of visual acuity Total visual loss caused by any of the above ocular manifestations Estimated or measured by a glomerular filtration rate less than 60ml/min/1.73m2. Regardless of dyalisis or transplantation Proteinuria 3.5g/24hrs Demonstrated by kidney biopsy. Pathologic process characterized by compromise of the bone vasculature leading to the death of bone and marrow cells, demonstrated by imaging techniques Skin ulceration secondary to thrombotic microangiopathy Thrombosis of the mesenteric arteries or veins, leading to ischemia and eventually necrosis of any intestinal segment, spleen, liver or gall bladder. Clinico-pathological entity caused by thrombotic obstruction of hepatic venous blood flow either at the level of the hepatic veins or the inferior vena cava. Chronic liver disease characterized by progressive fibrosis leading to loss of liver function Deficit in the production of suprarenal steroid hormones due to a thrombosis or hemorrhagic infarct of the suprarenal glands Pituitary gland Insufficiency caused by of thrombosis/ischemia Failure to conceive after 12 months of frequent intercourse without use of contraception in women under age 35 and after six months in women over age 35
1
Eklo¨f B, Rutherford RB, Bergan JJ et al. Revision of the CEAP classification for chronic venous disorders: consensus statement. J vasc Surg 2004;40:1248–52. 2 Miyakis S, Lockshin MD, Atsumi T et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost 2006;4:295–306. 3 The Criteria Committee of the New York Heart Association. (1994). Nomenclature and Criteria for Diagnosis of Diseases of the Heart and Great Vessels. (9th ed.). Boston: Little, Brown & Co. pp. 253–256.
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Development and initial validation of a damage index (DIAPS) in patients with thrombotic antiphospholipid syndrome (APS) M-C Amigo1, MV Goycochea-Robles2, G Espinosa-Cuervo3, G Medina4, JA Barraga´n-Garfias5, A Vargas6 and L Javier Jara7 1 ABC Medical Center, Department of Rheumatology, Mexico DF, Mexico; 2Hospital General Regional 1, IMSS, Unidad de Invesitigaci0n en Epidemiologı´ a Clı´ nica, Mexico City, Mexico; 3Unidad de Medicina Fı´ sica y Rehabilitaci0n Centro, IMSS, Consulta Externa, Mexico City, Mexico; 4 Centro Me´dico Nacional La Raza, IMSS, Unidad de Investigaci0n, Mexico City, Mexico; 5Hospital General de Zona 48, Departamento de Reumatologı´ a, Mexico City, Mexico; 6Instituto Nacional de Cardiologı´ a Ignacio Cha´vez, Departamento de Reumatologı´ a, Mexico City, Mexico; and 7Hospital de Escpecialidades Centro Me´dico La Raza, IMSS, Departamento de Ensen˜anza e Investigaci0n, Mexico City, Mexico
Introduction: In antiphospholipid syndrome (APS), certain principal manifestations are associated with a worse prognosis and organ damage. Objective: The objective of this paper is to describe the development and initial content, criterion and construct validity of a disease-specific cumulative damage index in patients with thrombotic APS (DIAPS). Methods: Through expert panel agreement, 47 items were considered to reflect damage in APS. This preliminary version of the DIAPS was submitted to four local and international clinical and research experts in APS who ranked each item according to severity. A Delphi exercise resulted in a final 37 item instrument. In the second phase, a cross-sectional study was conducted applying the DIAPS in patients included in a multicenter electronic registry of patients with APS. Quality of life related to health status was evaluated with the EuroQol for construct validation. An a Cronbach and correlation with the EuroQol scale were calculated with SPSS 20.0 (p < 0.05). Results: We evaluated the DIAPS in 156 patients, 77% female, with a mean age at diagnosis 34.7 5.5 years. A total of 69% had primary APS. Common comorbidities included obesity, depression and dyslipidemia. The most frequent manifestations resulting in sequelae were deep venous thrombosis and ischemic stroke. Blindness, retinal occlusive vessel disease, myocardial infarction, cardiac valve requiring replacement, mesenteric thrombosis, and renal insufficiency also occurred. Homogeneity: a Cronbach 0.619. DIAPS items correlated with EuroQol domains with the exception of pulmonary, renal, gastrointestinal, and endocrine systems. Conclusion: This study demonstrates content, criterion and construct validity of a new physician-reported instrument to assess the DIAPS. In addition, the DIAPS correlated with the EuroQol. Lupus (2015) 0, 1–8. Key words: Antiphospholipid syndrome; Damage index; Hughes syndrome
Introduction Antiphospholipid syndrome (APS), an autoimmune-acquired thrombophilia, is defined by the presence of thrombosis and/or pregnancy morbidity plus persistently positive assays for circulating antiphospholipid antibodies (aPL).1 While recurrent thrombosis is the hallmark of APS, recurrent
Correspondence to: Mary-Carmen Amigo, ABC Medical Center, Sur 136 # 116, Las Ame´ricas, Suite # 417, Mackenzie Tower, Mexico City, 01120 Mexico. Email: [email protected] Received 26 July 2014; accepted 12 January 2015
pregnancy loss or cytopenias may be the sole manifestation of the syndrome.2 The long-term prognosis for patients with APS is to a large extent influenced by the risk of recurrent thrombosis or damage caused by mechanisms that are only partially understood.3,4 Certain manifestations of APS carry a worse prognosis, and permanent damage may occur in various organs.5–7 Moreover, a significant impact of the disease on long-term survival has been documented in large, prospective cohort studies of patients with different clinical subsets of APS.8,9 Also, decreased survival has been shown in systemic lupus erythematosus (SLE) patients who in addition had APS.10
! The Author(s), 2015. Reprints and permissions: http://www.sagepub.co.uk/journalsPermissions.nav
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Thus, organ damage in APS needs to be quantified in the clinical setting, and an instrument that measures accumulated damage over time is required. To comply with clinimetric principles, an APS damage measurement instrument must have content validity, which is the ability to reflect the full range of cumulative or irreversible damage that APS may inflict. In addition, it must have construct validity to explain the inter-relationships between all the component items. As an example, the Systemic Lupus International Collaborating Clinics/ American College of Rheumatology (SLICC/ ACR) Damage Index (SDI),11 which was developed for SLE, misses key features of APS, a condition that only partially overlaps with SLE.12,13 An early version of a damage index for APS was previously presented by our group. In this study, 27 clinical items with potential to cause chronic damage in APS were reviewed by local (MC, MCA) and international (MAK) experts. An instrument containing these items was applied to 38 patients with primary APS, 30 patients with SLE-associated APS, and 30 patients with SLE.14 Subsequently, additional items were included, and an early validation of the instrument was performed.15 The present study represents a further improvement of the damage index for thrombotic APS (DIAPS) including the content and construct validity of our instrument.
Patients and methods Phase 1 Development of the DIAPS
Clinimetrics conceptualizes the measurement of clinical phenomena via indices or scales.12 As a first step in developing a clinimetric instrument to measure organ damage in APS, we met with clinical epidemiologists and clinicians to discuss how organ damage could be quantified in this condition. To fulfill content validity we first reviewed the SDI for SLE11 to find items that were also applicable to APS. We then included elements that were considered to reflect damage that is unique to APS. In the first round, experts identified 60 manifestations that could cause irreversible damage in APS. In the second round, an operative definition for each of these clinical manifestations was established (Appendix). Finally, after independent review by three methodology experts (MVGR, GEC, MGP) and three clinical experts in APS (MCA, LJJ, GM), a 47-item instrument was
selected by consensus.15 This preliminary version of the DIAPS was submitted to four local (MCA, LJJ) and international (MAK, DE) experts in APS who ranked the items according to severity (minimal impact, low impact, high impact). A Delphi exercise was then performed to exclude items of low specificity, resulting in a final 37-item instrument. To represent damage, the item had to be present for at least six months, or cause a permanent hearing loss or hemiplegia. The APS-specific elements that are not included in the SDI for SLE are the following: Respiratory system damage: Chronic thromboembolic pulmonary hypertension and respiratory insufficiency caused by multiple lung infarctions. Cardiovascular system damage: Heart valve damage including (a) asymptomatic valve disease (b) symptomatic valve disease, and (c) valve disease requiring valve replacement. It should be mentioned that the SDI, as initially reported, considered only a diastolic murmur or a systolic murmur >3/6. Gladman and Urowitz, in a progress report, clarified that any operation performed after the diagnosis of SLE, such as for heart valve disease, added to the burden of illness and represented additional damage.16 Central nervous system damage: Different from the SDI, which includes only ‘‘cerebrovascular accident ever,’’ the DIAPS includes ischemic stroke with hemiparesis, ischemic stroke with hemiplegia, multi-infarct dementia, sensorineural hearing loss, optic neuropathy, and abnormal movement disorders such as chorea, parkinsonism and dystonia. Eye damage: Different from the SDI, which includes only ‘‘retinal change or optic atrophy,’’ the DIAPS includes arterial/venous retinal vaso-occlusive disease and blindness. Kidney damage: Both chronic renal failure and renal thrombotic microangiopathy (TMA) documented by renal biopsy were included. TMA may manifest clinically with massive proteinuria, which adds to the risk of thrombosis, severe and persistent arterial hypertension, and chronic renal failure (CRF). The SDI includes CRF and proteinuria 3.5 g/24 hours. TMA should be included, in addition to renal insufficiency, because there are patients with TMA without renal insufficiency and cases with renal insufficiency in which a biopsy determination of TMA is critical to prognosis and treatment. Skin damage: Chronic cutaneous ulcers. Bone damage: Avascular necrosis of bone. Gastrointestinal damage: Mesenteric thrombosis, arterial or venous thrombosis involving the liver (including the Budd-Chiari syndrome), the spleen or the intestine, and cirrhosis of the liver secondary to nodular regenerative hyperplasia. Endocrine system damage: Adrenal insufficiency
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and hypopituitarism requiring lifelong treatment caused by APS. Phase 2 The second phase of the study was crosssectional and was conducted using a multicenter online electronic database, the APS Latin American Registry (2009–2012) (http://investigacion.colmexreuma.org.mx/saaf/index.html). This Mexican initiative supported by the Pan American League of Associations for Rheumatology (PANLAR) considered the following variables: general demographics, clinical manifestations at the time of diagnosis, duration of disease, concurrent diagnoses, and treatment. A DIAPS index form was completed by a physician. In addition to completing the DIAPS form, we documented every clinical manifestation of APS as follows: (0) absent, (1) present without sequelae, and (2) or present with sequelae. As an example, regarding deep vein thrombosis, (0) indicates its absence, (1) indicates its presence with symptoms resolved within six months, and (2) indicates its presence with damage, as shown by chronic leg edema. The output rating of the DIAPS considers only two score manifestations. The final score was obtained by adding the output ratings for each domain (i.e. peripheral vascular, pulmonary). This allowed us to establish a ratio (not shown) of individual clinical manifestations/sequelae. In this initial phase of the study, we decided not to weigh the items. Criterion validity requires a concurrent comparison with a gold standard. In its absence, we decided to use an instrument that measured the consequences of damage.17 To this end, we used the EuroQol, a generic, standardized measurement of health18 to determine the quality of life of the patients. The EuroQol describes and rates healthrelated quality of life by measuring five dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. These dimensions may fall short of the entire spectrum of damage that occurs in the DIAPS, but most, directly or indirectly, appear to be covered. We selected the EuroQol because it is short, multilingual, validated, and has shown consistent results in different countries and many chronic diseases including rheumatic diseases.18–20 Finally, the EuroQol is a useful surrogate index to calculate the economic impact of disability. Analysis The general demographics, clinical manifestations and the treatment of APS were analyzed with
descriptive statistics. For the DIAPS, a Spearman’s correlation with the EuroQol scale was calculated, looking for each domain of the EuroQol and the global patient assessment. The internal consistency of the DIAPS items used to assess the damage in APS patients was calculated with a Cronbach (p 0.05). We used SPSS, version 20.0. The study protocol was reviewed and accepted by the Research Committee of the Mexican College of Rheumatology.
Results The original SDI for SLE considered 12 different organ systems with a total of 37 items. The DIAPS used 22 items from SDI plus 15 new elements that were found specific of APS according to the consulted experts. Some SDI items were expanded to show the heterogeneity of some clinical manifestations that are particular to APS. A Delphi panel performed with the international experts showed a high reliability of 35/37 items. However, chronic cutaneous ulcers and retinal vaso-occlusive disease were rated differently by experts. Nevertheless, the final consensus considered that these two items have an irreversible impact in patients with APS and both were included. The DIAPS, which includes 10 organ systems and 37 items, is shown in Table 1. The DIAPS was applied to 156 patients listed in a multicenter, international electronic registry mentioned in Methods. Eleven centers participated: seven from Mexico, two from Venezuela and one each from El Salvador and the Dominican Republic. Demographic and clinical characteristics of these patients are shown in Table 2. There was a preponderance of women, and the dominant ethnic group was Mestizo. More than 60% of the patients had less than 12 years of formal education. The most frequent thrombotic manifestations were stroke and venous thrombosis. In the 156 patients, aPL were present as follows: immunoglobulin (Ig)G anticardiolipin antibodies (aCL) in 73%, IgM aCL in 51%, lupus anticoagulant (LA) in 50%, IgG anti-b2-glycoprotein 1 (ab2GP1) in 18%, and false-positive Venereal Disease Research Laboratory (VDRL) test in 15.6%. The majority of patients were on antithrombotic therapy, 79% were on permanent anticoagulation (international normalized ratio (INR) 2–2.5), 6% on permanent high anticoagulation (INR 3–3.5), and 40% were on low-dose aspirin. In addition, almost 41% of patients received antimalarials, Lupus
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Table 1
Items included in the DIAPS SLICCb damage index
1. Peripheral vascular Deep vein thrombosis Intermittent claudication Tissue loss: minor Tissue loss: major Vascular venous insufficiency 2. Pulmonary Pulmonary infarction Pulmonary arterial hypertension Chronic thromboembolic pulmonary hypertension Respiratory insufficiency 3. Cardiovascular Coronary artery bypass Myocardial infarction Cardiomyopathy aPL-associated heart valve disease: (asymptomatic, symptomatic) aPL-associated heart valve disease requiring valvular replacement 4. Neuropsychiatric Cognitive impairment Seizures Ischemic stroke with hemiparesia Ischemic stroke with hemiplegia Multi-infarct dementia Cranial neuropathy Sudden sensorineural Hearing loss Transverse myelitis Optic neuropathy Peripheral neuropathy Abnormal movements: – Dystonia – Chorea – Parkinsonism 5. Ophthalmologic Retinal vaso-occlusive disease Blindness 6. Renal Chronic renal failure Proteinuria 24 h 3.5 g OR Renal thrombotic microangiopathy 7. Musculoskeletal Avascular necrosis 8. Cutaneous Chronic cutaneous ulcers 9. Gastrointestinal Mesenteric thrombosis Budd-Chiari syndrome Cirrhosis of the liver 10. Endocrine Suprarenal insufficiency Hypopituitarism Infertility
Table 2 Baseline characteristics of 156 APS patients DIAPSa damage index Demographic characteristics Age (years) Age at diagnosis (years) Gender Ethnic group Education
b b b b
Mean SD Mean SD Female Mestizo High school
n
%
43 13.5 34.7 5.5 120 92 95
77.0 59.0 61.0
b
b b a
a
b b b b
b
b b b b a
APS Characteristics Primary APS APS associated with other immunologic disease: SLE SLE Like Sjo¨gren’s syndrome Rheumatoid arthritis Systemic vasculitis
108 48
69.0 31.0
39 3 3 1 2
25.0 1.9 1.9 0.6 1.2
Comorbidities Obesity Hypertension Anxiety/Depression Dyslipidemia Thyroid disease Diabetes mellitus Fybromyalgia
37 30 33 46 16 13 12
24.0 19.0 21.0 29.0 10.0 8.0 7.4
SD: standard deviation; APS: antiphospholipid syndrome; SLE: systemic lupus erythematosus.
b a b b b a
a a
b b a
b a
b a a
a a b
DIAPS: Damage index in patients with thrombotic antiphospholipid syndrome (APS). SLICC: Systemic Lupus International Collaborating Clinics; aPL: antiphospholipid antibodies. a Denotes items that are newly considered in the DIAPS. b Denotes items taken from SLICC/American College of Rheumatology Damage Index (ACR DI).
18% azathioprine, 29% glucocorticoids, 3% cyclophosphamide and 1% rituximab and intravenous Ig (IVIG). Health-related quality of life, evaluated with the EuroQol, showed mobility problems in 35.2%, selfcare difficulties in 11.5%, inability to perform daily living activities in 33.9%, pain in 30.4%, and anxiety or depression in 50.6%. Mean health status (reported by visual analog scale (VAS)) was 70.22 16.37 SD. The DIAPS items correlated with the EuroQol domains: peripheral vascular disease, with mobility, usual activities, and pain; cardiovascular involvement, with self-care and pain; neuropsychiatric disease, with all domains except pain; eye abnormalities, with self-care, anxiety, and depression; and cutaneous disease, with pain. Pulmonary, renal, gastrointestinal, and endocrine systems had no correlation with the EuroQol domains. The EuroQol domains mobility (r ¼ 0.441), pain/discomfort (r ¼ 0.487), health status visual analog (r ¼ –0.479), usual activities (r ¼ 0.375), and selfcare (r ¼ 0.354) reported by the patients showed a significant correlation with the global DIAPS score (p ¼ 0.000). The DIAPS had a high internal consistency (a Cronbach 0.619).
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Table 3 DIAPS items and EuroQol health status domains correlation Domain/EuroQol18 DIAPS
Mobility
Self-care
Usual activities
Pain/Discomfort
Anxiety/Depression
VAS Euro Qol health status
Peripheral vascular Pulmonary Cardiovascular Neuropsychiatric Ophthalmologic Renal Cutaneous Musculoskeletal Gastrointestinal Endocrine DIAPSa
0.360/0.000 0.063/0.437 0.146/0.072 0.162/0.045 0.023/0.784 0.021/0.805 0.150/0.077 – 0.033/0.698 0.041/0.630 0.441/0.000
0.060/0.460 0.031/0.703 0.206/0.011 0.368/0.000 0.165/0.049 0.012/0.885 0.110/0.196 – 0.062/0.468 0.035/0.683 0.354/0.000
0.225/0.005 0.52/0.524 0.155/0.056 0.229/0.004 0.148/0.077 0.084/0.321 0.042/0.623 – 0.125/0.143 0.034/0.685 0.375/0.000
0.391/0.000 0.066/0.417 0.192/0.017 0.134/0.099 0.043/0.613 0.063/0.462 0.225/0.007 – 0.048/0.578 0.099/0.244 0.487/0.000
0.078/0.332 0.090/0.268 0.147/0.070 0.159/0.049 0.189/0.023 0.022/0.793 0.032/0.705 – 0.017/0.842 0.012/0.888 0.234/0.003
0.251/0.002 0.007/0.939 0.100/0.239 0.310/0.000 0.193/0.027 0.017/0.848 0.092/0.300 – 0.021/0.811 0.072/0.420 0.479/0.000
P values (correlation is significant at the 0.05 level). DIAPS: Damage index in patients with thrombotic antiphospholipid syndrome (APS); VAS: visual analog score. a Global total score.
Discussion APS, a systemic and potentially devastating disease that occurs among young individuals, features increased morbidity, organ damage, and mortality. Thus, an instrument must be developed to determine with precision APS-related damage. We are unaware of other attempts to design and validate a damage index that is specific for APS patients. In the current study, the DIAPS demonstrated content, criterion, and construct validity. Criterion validity was evaluated as a proxy by the EuroQol, an instrument that accurately reflects patients’ and doctors’ opinions. The DIAPS showed a significant correlation with the EuroQol. Wang et al., using the SDI, evaluated the relationship between selfreported quality of life and disease activity and damage in SLE. In their study, health status as rated by the EuroQol was associated with damage and these authors considered the EuroQol a powerful instrument to measure health-related quality of life in SLE. The EuroQol has shown a significant association with chronic damage, and the findings clearly make clinical sense.20 To our knowledge, the EuroQol has not been previously used to evaluate the quality of life in APS. The high impact of APS on irreversible organ damage and survival in patients with SLE has been studied. In a longitudinal study of SLE patients with a follow-up of 9.7 years, RuizIrastorza et al. identified cumulative damage measured by the SDI. Cumulative survival at 15 years was lower in patients with APS compared with those without APS.10
APS has the potential to cause severe, irreversible damage from the very onset of the disease. We clearly recognized this issue in our patients with APS, in whom the time to diagnosis averaged 5.5 years. This finding contrasts with previous studies7,20,21 in which damage in APS appeared after many years of disease (more than 10 years). We agree that disease progression causes cumulative damage. However, thrombotic events that are considered the hallmark of APS may cause irreversible damage from the very beginning of the disease. There have been attempts to explore the damage in APS with the SDI instrument. Recently, Grika et al.7 assessed the accumulated organ damage using the SDI in a retrospective study of 135 patients with APS, of whom 89 were primary. They concluded that APS occurs among young individuals and causes increased morbidity, with one-fourth of the patients progressing to organ damage after a mean duration of 10 years from disease onset. However, the SDI they used has been designed for SLE, not for APS. Barbhaiya and Erkan21 analyzed the utility of the SDI in aPL-positive patients and/or APS, SLE or other systemic autoimmune diseases. These authors showed that the SDI score increased with additional aPL- and/or SLE-related damage. Important aPL-related organ damage was not identified. Their conclusion, in agreement with Vlachoyiannopoulos,22 was that a specific damage index for APS was needed. In the present study, we developed and validated a specific DIAPS. We are aware that the DIAPS has limitations. As Barbhaiya and Erkan concluded, key manifestations of APS such as livedo reticularis/racemosa, multiple sclerosis-like disease, or diffuse pulmonary hemorrhage, were Lupus
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not included.21 Although the DIAPS showed good content validity on initial validation, additional clinical manifestations of APS should be evaluated to determine their possible contribution to irreversible damage. Also, our study is cross-sectional, and a long-term follow-up study is required to validate our findings. Intraobserver and interobserver variability of the DIAPS need to be tested. A further limitation is that the DIAPS was not tested in related or mimicking conditions such as SLE and vasculitis. It is also necessary to determine its sensitivity to change over time. Finally, since the majority of patients in our study were Latin American Mestizo, an external validation in populations with a different genetic background should be undertaken. Finally, the items included in the DIAPS should be weighted to complete its clinimetric validation. Although the DIAPS is not intended to evaluate the obstetrical impact of chronic damage, infertility was included. Recently, at the 9th meeting of the European Forum on Obstetric APS,23 obstetric APS was considered a separate entity from thrombotic APS. The strength of the present study is that the DIAPS was developed specifically for APS. In our patients, the DIAPS appeared to be an accurate instrument to assess organ damage. In support of our findings, Ugolini Lopes et al.24 recently presented a cross-sectional analysis of 93 patients with primary APS followed at a single APS outpatient clinic in Sa˜o Paulo, Brazil. Damage was evaluated both by using the SDI and the DIAPS index herein described.15 A positive correlation between disease duration and higher SLICC/ACR DI and DIAPS scores was found (p < 0.05). In their opinion, the DIAPS appeared to be a better surrogate measure of disease severity in APS.
Conclusions This initial validation study demonstrated content and construct validity of the DIAPS, a new physician-reported instrument to assess thrombotic APS damage. The DIAPS showed a good correlation with the EuroQol. Further studies should be conducted to evaluate the reliability and clinimetric properties of this instrument in other populations. We believe that the DIAPS, used from the early stages of APS to measure the impact of this potentially devastating disease, may become a useful tool in clinical, epidemiologic and economic studies.
Funding This research received no specific grant from any funding agency in the public, commercial, or notfor-profit sectors.
Conflict of interest statement The authors have no conflicts of interest to declare.
Acknowledgments We are thankful to the following physicians for patient recruitment and clinical data collection: Esthela Loyo de Lo´pez, Dominican Republic; Salvador Sermen˜o Ca´ceres, El Salvador; Liz Caballero, Oscar Urdaneta and Ivette Montes de Oca, Venezuela; Leonor Barile, Aline Martı´ nezMartı´ nez, Claudia Mendoza Pinto, Rosa Elda Barbosa, Ana Sofı´ a Vargas and Gustavo Lugo Zamudio, Mexico. We are indebted to Dr Mario Cardiel (MC) for his methodological help during the earliest and pilot index measurements. We are also very grateful to Dr Maximiliano Garcı´ a de la Pen˜a (MGP) for his methodological support and the initial definitions. We sincerely thank Drs Doruk Erkan (DE) and Munther A. Khamashta (MAK) who helped us, as international clinical experts, in the first phase of the study. This research project would not have been possible without the support of the Pan American League of Associations for Rheumatology (PANLAR) for the creation of the APS Latin American Registry.
References 1 Miyakis S, Lockshin MD, Atsumi T, et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost 2006; 4: 295–306. 2 Cervera R, Piette JC, Font J, et al. Antiphospholipid syndrome: Clinical and immunologic manifestations and patterns of disease expression in a cohort of 1,000 patients. Arthritis Rheum 2002; 46: 1019–1027. 3 Alarco´n-Segovia D, Pe´rez-Ruiz A, Villa AR. Long-term prognosis of antiphospholipid syndrome in patients with systemic lupus erythematosus. J Autoimmun 2000; 15: 157–161. 4 Amigo MC. Prognosis in antiphospholipid syndrome. Rheum Dis Clin North Am 2001; 27: 661–669. 5 Erkan D, Yazici Y, Sobel R, Lockshin MD. Primary antiphospholipid syndrome: Functional outcome after 10 years. J Rheumatol 2000; 27: 2817–2821. 6 Amigo MC, Garcı´ a-Torres R. Kidney disease in antiphospholipid syndrome. In: Khamashta MA (ed.), Hughes syndrome: Antiphospholipid syndrome, 2nd ed. London: Springer-Verlag, 2006. pp. 99–111.
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7 7 Grika EP, Ziakas PD, Zintaras E, et al. Morbidity, mortality, and organ damage in patients with antiphospholipid syndrome. J Rheumatol 2012; 39: 516–523. 8 Tektonidou MG, Ioannidis JP, Boki KA, et al. Prognostic factors and clustering of serious clinical outcomes in antiphospholipid syndrome. QJM 2000; 93: 523–530. 9 Cervera R, Serrano R, Pons-Estel GJ, et al. Morbidity and mortality in the antiphospholipid syndrome during a 10-year period: A multicentre prospective study of 1000 patients. Ann Rheum Dis, Epub ahead of print 24 January 2014. DOI: 10.1136/annrheumdis-2013-204838. 10 Ruiz-Irastorza G, Egurbide MV, Ugalde J, Aguirre C. High impact of antiphospholipid syndrome on irreversible organ damage and survival of patients with systemic lupus erythematosus. Arch Intern Med 2004; 164: 77–82. 11 Gladman D, Ginzler E, Goldsmith C, et al. The development and initial validation of the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index for Systemic Lupus Erythematosus. Arthritis Rheum 1996; 39: 363–369. 12 Streiner DL, Norman GR. Health measurement scales: A practical guide to their development and use, 2nd ed. New York: Oxford University Press Inc, 2003. pp. 144–154. 13 Feinstein AR. Clinimetrics. London: Yale University Press, 1987. pp. 194–201, 4,5. 14 Amigo MC, Khamashta MA, Cardiel M, et al. Development and validation of an antiphospholipid damage index: A multicenter, binational project. Lupus 1998; 7(Suppl 1): 68. 15 Amigo MC, Barile LA, Barraga´n A, et al. Development and initial validation of a chronic damage index in patients with antiphospholipid syndrome (abstract). Arthritis Rheum 2011; 63(Suppl): S3–S4.
16 Gladman DD, Urowitz MB. The SLICC/ACR damage index: Progress report and experience in the field. Lupus 1999; 8: 632–637. 17 Fries JF, Hochberg C, Medsger TA Jr, Hunder GG, Bombardier C. Criteria for rheumatic disease. Different types and different functions. The American College of Rheumatology Diagnostic and Therapeutic Criteria Committee. Arthritis Rheum 1994; 37: 454–462. 18 EuroQol—A new facility for the measurement of health-related quality of life. The EuroQol Group. Health Policy 1990; 16: 199–208. 19 Da Rocha Castelar Pinheiro G, Khandker RK, Sato R, Rose A, Piercy J. Impact of rheumatoid arthritis on quality of life, work productivity and resource utilization: An observational, cross-sectional study in Brazil. Clin Exp Rheumatol 2013; 31: 334–340. 20 Wang C, Mayo NE, Fortin PR. The relationship between health related quality of life and disease activity and damage in systemic lupus erythematosus. J Rheumatol 2001; 28: 525–532. 21 Barbhaiya M, Erkan D. The optimal tool for assessment of organ damage in antiphospholipid syndrome. J Rheumatol 2013; 40: 89. 22 Vlachoyiannopoulos PG Dr. Vlachoyiannopoulos replies. J Rheumatol 2013; 40: 90. 23 Swadzba J, Sydor WJ, Kolodziejczyk J, Musial J. Summary of the 9th meeting of the European Forum on Antiphospholipid Antibodies. Lupus 2014; 23: 395–399. 24 Ugolini Lopes M, Aguila L, Tonon R, et al. SLICC and DIAPS: Potential indices for damage assessment in primary antiphospholipid syndrome (PAPS). APLA & LACA 2013 14th International Congress on Antiphospholipid Antibodies, 18–21 September 2013, Rio de Janeiro, Brazil.
Appendix Damage Index for APS. Glossary of terms
Items included in DIAPS
Definition
1 2
Peripheral vascular Deep vein thrombosis Intermittent Claudication
3 4 5
Tissue loss (minor) Tissue loss (major) Vascular venous Insufficiency
6
Pulmonary Pulmonary infarction
7
Pulmonary arterial hypertension
8
Chronic thromboembolic pulmonary hypertension
9 10
Respiratory insufficiency Cardiovascular Coronary artery bypass
11
Myocardial infarction
12
Cardiomyopathy
13
APL associated valve hearth disease: (asymptomatic, symptomatic) APL associated valve hearth disease requiring valve replacement
14
Blood clot inside the lumen of a deep vein Fatigue, cramps, pain and weakness of the legs secondary to peripheral arterial disease which begins with walking and improves with rest Absence of tissue secondary to necrosis of the affected area. Minor (pulp) Absence of tissue secondary to necrosis of the affected area. Major (digit or limb) Morphological or functional abnormalities (venous valvular incompetence) of long duration, have to be categorized and treated accordingly with CEAP Classification1 X-Ray or CAT demonstration of pulmonary opacity or wedged-shaped density as a consequence of pulmonary vessel thromboembolic occlusion Pulmonary artery pressure > 25mm Hg at rest or >30mmHg on exercise. Mild 30 49 mmHg, Moderate 50- 69 mmHg; Severe > 70 mm Hg. Obstructive lesions, in the lobar, segmentary, or the main branches of the pulmonary artery secondary to chronic thromboembolism Secondary to multiple infarctions Surgical treatment of occlusive disease of the coronary arteries that provides better blood flow in the epicardial coronary arteries leading to a decrease angina symptoms, complications of myocardial infarction and mortality. Clinical syndrome characterized by damage of the myocardial tissue caused by imbalance between oxigen myocardial input and oxygen demand Alterations in myocardial perfusion obstruction microvasculature in the presence of normal coronary arteries ECHO* detection of valve lesions and /or b) Regurgitation and/or stenosis of mitral and/ or aortic valve Valve Lesions according to Miyakis S et al 2 Progressive, symptomatic (NYHA3 functional class lll-lV) moderate or severe valve disease
(continued)
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Continued Items included in DIAPS
15
Neuropsychiatric Cognitive impairment
16
Seizures
17 18 19
Ischemic stroke with hemiparesia Ischemic stroke with hemiplegia Multinfarct dementia
20 21
Cranial Neurophaty Sudden sensorineural Hearing loss
22
Transverse myelitis
23
Optic Neuropathy
24 25
Peripheral neuropathy Abnormal movements: – Dystonia –
26 27 28 29 30 31
Chorea
– Parkinsonism Ophtalmologic Retinal vaso-occlusive disease Blindness Renal Chronic renal failure Proteinuria Renal thrombotic microangiopathy Musculoskeletal Avascular Necrosis
33
Cutaneous Chronic cutaneous Ulcers Gastrointestinal Mesenteric thrombosis
34
Budd Chiari syndrome
35 36
Cirrhosis of the liver Endocrine Suprarenal Insufficiency
37 38
Hypopituitarism Infertility
32
Definition
Memory deficit, difficulty with calculation, poor concentration, difficulty in spoken or written language, impaired performance level, documented on clinical examination or by formal neurocognitive testing. Paroxysmal electrical discharge occurring in the brain and producing characteristics physical changes including tonic and clinical movements and certain behavioral disorders. Cerebrovascular thrombotic event resulting in focal finding as paresis Cerebrovascular thrombotic event resulting in focal finding such as hemiplegia or aphasia Cognitive impairment caused by, or associated with, vascular factors confirmed by neuroimaging (MRI/CT) Damage to a cranial nerve resulting in either motor or sensory dysfunction Acute unexplained hearing loss nearly always unilateral that occurs over less than 72 hour period (demonstrated by evoked potentials) Lower-extremity weakness or sensory loss with loss of rectal and urinary bladder sphincter control Inflammatory or ischemic condition documented by MRI of the brain and orbits that causes acute visual loss Damage to a peripheral nerve resulting in either motor or sensory dysfunction. Movement disorder characterized by involuntary sustained muscle contraction that result in twisting and repetitive movements or abnormal postures Movement disorder characterized by involuntary brief, random and irregular movements of the limbs and face, emotional or abnormal postures Bradykinesia, tremor, rigidity without a good response to dopaminergic therapy Occlusion caused by arterial or venous thrombosis, conditioning severe loss of visual acuity Total visual loss caused by any of the above ocular manifestations Estimated or measured by a glomerular filtration rate less than 60ml/min/1.73m2. Regardless of dyalisis or transplantation Proteinuria 3.5g/24hrs Demonstrated by kidney biopsy. Pathologic process characterized by compromise of the bone vasculature leading to the death of bone and marrow cells, demonstrated by imaging techniques Skin ulceration secondary to thrombotic microangiopathy Thrombosis of the mesenteric arteries or veins, leading to ischemia and eventually necrosis of any intestinal segment, spleen, liver or gall bladder. Clinico-pathological entity caused by thrombotic obstruction of hepatic venous blood flow either at the level of the hepatic veins or the inferior vena cava. Chronic liver disease characterized by progressive fibrosis leading to loss of liver function Deficit in the production of suprarenal steroid hormones due to a thrombosis or hemorrhagic infarct of the suprarenal glands Pituitary gland Insufficiency caused by of thrombosis/ischemia Failure to conceive after 12 months of frequent intercourse without use of contraception in women under age 35 and after six months in women over age 35
1
Eklo¨f B, Rutherford RB, Bergan JJ et al. Revision of the CEAP classification for chronic venous disorders: consensus statement. J vasc Surg 2004;40:1248–52. 2 Miyakis S, Lockshin MD, Atsumi T et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost 2006;4:295–306. 3 The Criteria Committee of the New York Heart Association. (1994). Nomenclature and Criteria for Diagnosis of Diseases of the Heart and Great Vessels. (9th ed.). Boston: Little, Brown & Co. pp. 253–256.
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