Beyond thrombosis: a scoping review of patient-reported outcomes in antiphospholipid syndrome

Abstract

Antiphospholipid syndrome (APS) is an autoimmune disorder characterized by thrombosis and pregnancy morbidity, with heterogeneous nonthrombotic manifestations that may substantially affect daily functioning and well-being. Patient-reported outcomes (PROs) offer a direct assessment of symptom burden and quality of life but remain underutilized in APS. We performed a scoping review of PubMed from inception through July 2025 using terms related to APS and PROs (quality of life, fatigue, pain, depression, psychological well-being, and health surveys). We included eligible English-language studies that reported PROs in APS. Both qualitative and quantitative studies were included. Twelve cohort studies evaluated PROs in APS. Most studies used legacy instruments such as the 36-item short form health survey. A few recent studies have used patient-reported outcomes measurement information system (PROMIS) tools. Across studies, patients with APS reported impairments in multiple domains of health-related quality of life (HRQOL) as well as overall HRQOL compared with population norms, which are associated with comorbid systemic lupus erythematosus (secondary APS), a history of thrombosis, and greater end-organ damage. Anticoagulation monitoring and international normalized ratio lability contributed to treatment dissatisfaction and reduced HRQOL. Major gaps include the longitudinal assessment of PROs and their temporal relation to clinical events and the evaluation of PROs in obstetric APS and children and older adults with APS. No APS-specific PRO instruments have been developed. There is a need to either develop APS-specific instruments or validate generic instruments such as PROMIS measures in large representative APS cohorts. Incorporating PROs into clinical practice and research can enhance clinical care and facilitate patient-centered, personalized management of APS.

Introduction

Antiphospholipid syndrome (APS) is a multisystem autoimmune disorder defined by arterial or venous macrovascular thrombosis, obstetric morbidity, and rare microvascular manifestations associated with persistently positive antiphospholipid antibodies (aPL). The laboratory criteria for APS include positive results for the lupus anticoagulant assay, as well as moderate to high titers of anticardiolipin antibodies and anti–β₂-glycoprotein I antibodies. Expanding on the revised Sapporo criteria, originally published in 1999 and revised in 2006,^1,2 the 2023 American College of Rheumatology (ACR) and European League Against Rheumatism classification criteria³ now include a broader range of clinical entities that reflect the diverse spectrum of disease presentation and activity. These include cardiac valve vegetation or thickening, otherwise unexplained thrombocytopenia, and specific microvascular entities such as livedo racemosa/livedoid vasculopathy and aPL nephropathy. APS may manifest as a primary condition (primary APS [PAPS]) or in association with other autoimmune diseases (secondary APS [SAPS]), most commonly systemic lupus erythematosus (SLE). The management of APS spans antithrombotic therapy and immunomodulatory therapies such as hydroxychloroquine, rituximab, and complement inhibition in cases of microvascular or recurrent/refractory disease.⁴

The clinical spectrum and morbidity associated with APS are heterogeneous⁵ and range from a single thrombotic event without recurrence to recurrent vascular complications, miscarriage, or catastrophic APS,⁶ a rare and life-threatening manifestation characterized by rapidly developing thrombosis in multiple organs resulting in the death or permanent loss of organ function.⁷ Some patients may experience microvascular complications such as nephropathy and pulmonary hemorrhage or cardiac abnormalities for which there are few effective treatments. APS poses significant morbidity,⁵ lifelong treatment, frequent clinical interactions for anticoagulation monitoring, and adjustment of daily activities. These demands affect psychological well-being, social functioning, and physical health.

Although the clinician’s objective assessment is the cornerstone for clinical care and research in APS, the patient’s subjective experience and symptom burden are undermeasured. Arguably, the least understood patients are those who either develop findings not included in classification criteria (eg, chorea, myelitis, and migraine) or a constellation of patient-reported symptoms that clinicians may not have guidance on addressing such as perceived cognitive dysfunction (often reported as “brain fog”). In APS, clinicians typically implement medical therapies only after overt end-organ damage is evident. However, symptoms such as pain, fatigue, cognitive dysfunction, and emotional distress are not systematically assessed and are absent from existing APS clinical guidelines (Figure 1). For example, although cognitive dysfunction is often reported in patients with APS,^8,9 only 39% of respondents in a large international survey of APS clinicians, evaluate vascular cognitive impairment or dementia.¹⁰

Figure 1.

PROs in APS. APS affects multiple domains of HRQOL, which significantly affect the patient experience of disease but are inadequately captured by objective clinical evaluations such as imaging or laboratory studies.

Patient-reported outcomes (PROs) are valuable where objective clinical end points either do not assess the biopsychological dimensions of the patient’s lived experience of illness or do not fully capture the heterogeneity of disease activity in patients with seemingly similar clinical end points. PROs are standardized tools that capture a patient’s self-rated health status, functioning, and physical and emotional well-being.¹¹ Although PROs are increasingly used to evaluate chronic autoimmune diseases such as SLE and rheumatoid arthritis12, 13, 14, 15 and increasingly used in studies of other hematologic disorders such as sickle cell disease,^16,17 and immune thrombocytopenia,18, 19, 20 their application in APS has not been studied extensively. In a heterogeneous disease such as APS, with variable end-organ damage, integrating PROs into clinical and research settings may allow a better understanding of the impact of disease burden on the lived patient experience and guide shared decision-making in patient-centered treatment approaches.^21,22

We performed this scoping review to map the existing literature regarding PROs in patients with APS, identify the most frequently measured domains and their measurements, and identify areas for future research and clinical application.

Methods

Search strategy and eligibility criteria

We searched PubMed using Medical Subject Headings terms from database inception through July 2025 with the following keywords: antiphospholipid syndrome, patient-reported outcomes, quality of life (QOL), fatigue, pain, depression, psychological well-being, and health surveys. We also screened reference lists and used OpenEvidence to identify additional studies. Publications were eligible for inclusion if they (1) assessed PROs in individuals with APS or in populations positive for aPL and (2) were published in English. Both qualitative and quantitative studies were considered. Studies were excluded if they were not available in English, were review articles, used overlapping populations without providing new patient-level data, focused primarily on conditions other than APS where PRO data from patients with APS could not be extracted separately, or did not report PROs.

Results and discussion

We identified 12 full-length manuscripts that reported on PROs in APS (Table 1; Figure 2). Most studies identified impaired health-related quality of life (HRQOL) in patients with APS compared with the general population, with the greatest burden seen in those with SLE and a history of thrombosis. Increased organ damage, lack of social support, and treatment-related burdens have also been identified as potential predictors of reduced HRQOL as discussed below. Most published APS studies have used non–disease-specific legacy instruments such as the 36-item short form health survey (SF-36), EuroQol-5 Dimension (EQ-5D) or functional assessment of chronic illness therapy–fatigue (FACIT-F). More recently, a few studies have incorporated tools from the patient-reported outcomes measurement information system (PROMIS), which includes generic, flexible tools that provide standardized measurement of core health domains and in general, have broad applicability, efficiency, precision, and strong psychometric properties. These instruments are widely available and have been validated across multiple populations and disease settings, but they may underestimate the impact of APS-related damage and may be less suited to examine the impact of APS-specific risk factors on PROs. In view of these limitations, APS-specific damage and disease burden indices such as the damage index in APS (DIAPS) have been developed.³⁵ Although these tools are not PROs and likely not ready for routine clinical use, additional development and validation are ongoing and aim to complement existing clinical and PRO tools.

Table 1.

Summary of PRO measures and key findings in APS

Study	PRO tools used	Population	Female, %	Key findings	Association with worse PRO measures
Zuily et al23	SF-36	115 (PAPS, SAPS, and aPL)	75	HRQOL reduced particularly in association with arterial thrombosis	SAPS and arterial thrombosis
Balitsky et al24	SF-36	826 (PAPS and SAPS)	61-92	HRQOL impaired across all groups regardless of thrombosis	SLE and thrombosis
Georgopoulou et al25	SF-36 and ad hoc	270 (PAPS and SAPS)	84	SAPS associated with worse HRQOL than PAPS; main issues included pain and fatigue	SAPS, pain, and fatigue
Haladyj et al26	SF-36 and WHOQOL-BREF	112	86	SF-36 deficits in MCS and PCS; venous thrombosis worsened HRQOL	Venous thrombosis
Hernández-Molina et al27	SF-36 and LupusQoL	50 (PAPS)	86	Lower HRQOL than controls: HRQOL worse in anticoagulated APS vs controls; pain is significant	Anticoagulation and pain
Medina et al28	DIAPS and SF-36	67 (PAPS)	78	Organ damage measured by DIAPS score was associated with worse total score and PCS on SF-36	Organ damage
Gaspar et al29	DIAPS and EQ-5D	108	66	48% with organ damage; pain and psychological issues common	Organ damage and psychological issues
Weiner et al30	PROMIS PF, CF, and PI	139 (PAPS, SAPS, and aPL)	66	47% with impaired physical function; 49%, impaired cognitive function; pain average: 3/10	Physical and cognitive impairment
Bearne et al31	FACIT-F, PHQ-9, IPAAW, PSQI, and MSPSS	87 (PAPS)	91	62% with severe fatigue; 40%, depression; and 69%, poor sleep. Fatigue tied to depression	Fatigue, depression, and poor sleep
Cardwell et al32	Qualitative interviews	21 (PAPS, SAPS, and aPL)	95	High psychosocial burden: 81%, future worry and 62%, unmet information needs	Psychosocial burden
Chighizola et al33	Ad hoc and SF-12	92 (PAPS)	84	Mental QOL more impaired than physical QOL; women and patients with fatigue most affected	Fatigue
de Oliveira Vaz et al34	SF-36 and DASS	66 (PAPS)	63	HRQOL lower; psychological burden from anticoagulation; and presence of arterial thrombosis and INR lability worsened scores	Warfarin and INR lability

CF, cognitive function (PROMIS domain); IPAQ, International Physical Activity Questionnaire; MSPSS, multidimensional perceived social support scale; PF, physical function (PROMIS domain); PHQ-9, patient health questionnaire-9; PI, pain intensity (PROMIS domain); PSQI, Pittsburgh Sleep Quality Index.

Figure 2.

Preferred Reporting Items for Systematic Reviews and Meta-Analyses flow diagram of study selection. Flow diagram depicting the identification, screening, eligibility assessment, and inclusion of studies evaluating PROs among patients with APS. Studies were identified through a PubMed literature search using predefined search terms related to APS and PRO domains, including QOL, fatigue, depression, psychological well-being, and health surveys. Records were screened and excluded based on predefined eligibility criteria. Twelve studies were included in the qualitative synthesis.

Overall HRQOL in APS

Multiple studies have identified a significant impairment in HRQOL among individuals with both PAPS and SAPS compared with those of controls and population norms.23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34 The 36-item short form (SF-36), which assesses both mental and physical health, has been widely applied in APS. SF-36 comprises 8 dimensions spanning bodily pain, general health, mental health, physical function, role-emotional, role-physical, social function, and vitality. In a multicenter secondary cohort of 115 patients with a mean age of 42.7 years (36 were aPL-positive without APS, 26 were SLE-positive without APS, and 53 had APS), the results of SF-36 were reported as 2 subscales computed as weighted sums of the 8 domains: the mental component summary (MCS), which represents psychological and emotional well-being, and the physical component summary (PCS), which represents mobility and physical functioning. Patients with SLE-associated APS and arterial thrombosis performed particularly poorly, with mean PCS and MCS scores significantly lower than normative values from the French general population.²³ Arterial thrombosis was independently associated with impaired scores after controlling age and cardiovascular risk factors. This pattern is notable considering that arterial thrombosis is the most common form of thrombotic recurrence in APS.^36,37 Patients with arterial thrombosis are treated with more intensive antithrombotic regimens such as higher intensity warfarin (international normalized ratio [INR] target 3-4) or adding antiplatelet therapies to anticoagulants compared with those with venous thrombosis alone, which may add to the burden of treatment and adverse effects such as bleeding. Our findings also raise questions about whether patients with high-risk APS should undergo more rigorous screening for cumulative end-organ damage as well as deleterious effects on HRQOL. Existing risk models are largely limited to clinician-reported findings such as triple-positive aPL profiles or high global APS scores (GAPSS and adjusted GAPSS).^23,38 Overall, the study showed that patients with SLE-associated thrombotic APS have worse HRQOL compared with aPL carriers or those with SLE without thrombosis.

A large study from the University of Toronto²⁴ also applied the SF-36 in 826 patients including those with PAPS (n = 35), SAPS (n = 37), SLE and thrombosis without persistently positive aPL by the revised Sapporo criteria (n = 75), SLE with aPL without thrombosis (n = 71), and SLE without thrombosis or aPL (n = 608). All groups demonstrated impaired HRQOL compared with normative control data. In contrast to the results from Zuily et al,²³ this study found that patients with thrombosis (PAPS, SLE with thrombotic APS, and SLE with thrombosis without aPL) had similar MCS and PCS scores compared with those without thrombosis regardless of the duration of time between the thrombotic event and SF-36 administration. An exception was the subgroup of patients with SLE and thrombosis (regardless of venous or arterial), which was separately associated with the worst patient-reported QOL. Georgopoulou et al used SF-36 and evaluated 270 patients with PAPS and SAPS and similarly reported impaired HRQOL across multiple domains. Patients with SAPS reported worse HRQOL than those with PAPS, and pain, fatigue, and limited disease awareness were identified as major contributors to disease burden.

More recently, Haladyj et al²⁶ evaluated PROs in 112 Polish patients with APS (57 PAPs and 55 SAPS) using the SF-36 as well as the World Health Organization Quality-of-Life Scale (WHOQOL-BREF). The WHOQOL-BREF is a modified, shorter version of the original WHOQOL-100 scale and evaluates 4 domains: physical health, psychological well-being, social relationships, and environmental health. Questions are answered using a 5-point Likert scale, with each item conferring a score from 1 to 5. Raw scores in each domain are changed to a score of 4 to 20, and the resulting domain scores range from 0 to 100, with higher scores indicating a better QOL. Overall, patients with APS had consistently reduced scores (deficits of 10-20 points) compared with the general population. There was no significant difference between scores for PAPS and SAPS in contrast to the previously discussed studies. The association of thrombosis with HRQOL varied depending on the presence of SLE. Thrombosis was associated with more HRQOL impairment in the SAPS group but not in those with PAPS.²⁶

Correlation of HRQOL measures with measurements of APS-related damage

PROs have also been studied in association with clinician-reported measures of disease damage. In a study of 50 patients with PAPS, Hernández-Molina et al²⁷ applied the modified Systemic Lupus International Collaborating Clinics (SLICC)/ACR Damage Index for SLE, with additional points being added for livedo racemosa, adrenal infarcts, inferior vena cava filter placement, and multiple sclerosis–like disease features. This modified SLICC/ACR score was then evaluated in conjunction with the MOS-SF-36 scores as well as the Lupus Quality of Life (LupusQoL) scores,³⁹ a similar instrument evaluating 8 domains: physical health, emotional health, body image, pain, planning, fatigue, intimate relationships, and burden to others. The SF-36 and LupusQoL scores were strongly correlated. The modified SLICC/ACR scores signifying increased diseased activity were correlated with worse HRQOL scores on both instruments, with the strongest association observed for the peripheral vascular domain, which assesses symptoms and limitations related to peripheral (arterial) vascular manifestations, including pain, numbness, cold extremities, and restrictions in daily activities resulting from impaired circulation.

DIAPS is an APS-specific instrument developed for damage accrual in patients with thrombotic APS originally derived from the SLICC/ACR Damage Index for SLE.⁴⁰ The instrument incorporates 37 APS-related clinical complications to provide a composite damage index, has been applied to large international APS registry data, and correlated with worse EuroQol measures of QOL in its initial development and validation.⁴¹ In a cross-sectional analysis of 67 patients with PAPS, higher DIAPS scores at the end of follow-up (mean, 15 years) were associated with worse SF-36 scores.²⁸ External validation findings have been mixed. In a retrospective cross-sectional study of 84 patients persistently positive for aPL (including 67 with APS), patients with APS had higher DIAPS score and GAPSS than aPL carriers; however, the association of these disease activity scores with PROs was not as strong. Short form-12 (SF-12) is a validated 12-item HRQOL instrument that assesses physical (PCS) and mental (MCS) functioning across multiple domains. Neither DIAPS score nor GAPSS were significantly associated with the SF-12 physical nor mental component scores, although both SF-12 domains were lower than population norms and trended toward worse scores with increasing damage as assessed by DIAPS.⁴²

These studies demonstrate that APS is associated with persistent and significant impairment in HRQOL. Further research is needed to assess which disease features and patient groups in which these instruments are useful, such as cumulative organ damage, history and vascular subtype of thrombosis, and comorbid SLE.

Specific domains of HRQOL and domain-specific PROs

Physical function

Physical function measures are particularly relevant in APS because thrombotic events and cumulative vascular damage can directly impair mobility, endurance, and the ability to perform daily activities, even in the absence of active disease. Two studies have specifically assessed physical functioning in patients with APS.^26,30 The tools used were the PROMIS physical function short form in addition to the MOS-SF-36 PCS and the WHOQOL-BREF physical domain. HRQOL measures regarding physical functioning were significantly worse in people with APS in all reports. PROMIS physical function short form data indicated that nearly half of patients with APS had below-normal scores on physical function (T < 45), with 26% reporting moderate-to-severe impairment.³⁰ Haladyj et al²⁶ incorporated 2 measures of QOL (ie, MOS-SF-36 and WHOQOL-BREF scores) and reported that a history of venous thrombosis was associated with HRQOL impairment on the PCS of the MSO-SF-36 only in the APS/SLE group. Although the SF-36 MCS correlated with all domains of WHOQOL-BREF, the SF-36 PCS correlated only with the physical health domain of WHOQOL-BREF.²⁶ These findings show that APS impairs mobility and daily activity, often overlapping with pain, fatigue, and organ damage.

Fatigue and sleep

Bearne et al conducted a sequential explanatory mixed-methods study examining fatigue and its correlates in adults with PAPS.³¹ The quantitative phase included 103 adults with PAPS (mean age, 50.3 years; 91% female), of whom 87 were included in the final analyses. Fatigue was assessed using the FACIT-F, a validated 13-item measure of fatigue severity. Sleep quality was evaluated using the Pittsburgh Sleep Quality Index, a 19-item instrument assessing sleep quality and disturbance over the prior month. Depressive symptoms were measured using the patient health questionnaire-9. Physical activity was measured using the International Physical Activity Questionnaire. Overall, 62% of participants reported severe fatigue, and 69% demonstrated poor sleep quality. Fatigue severity was strongly correlated with depressive symptoms, physical inactivity, poor sleep quality, and lower perceived social support. In multivariate regression analyses, depressive symptoms and physical inactivity independently predicted fatigue, whereas sleep quality did not. The qualitative assessment with semistructured interviews identified the unpredictable, overwhelming nature of fatigue, its substantial impact on daily functioning and work, and the use of individualized coping strategies such as pacing. Therefore, sleep and fatigue are prevalent, multidimensional burdens in APS that are closely linked to mood and activity levels rather than disease factors alone.

Cognitive function

Objectively measured cognitive dysfunction is observed in 30% to 70% of patients with APS.^8,9 PRO-based research has shown more extensive cognitive impairments, even though ischemic stroke is the only neurologic manifestation officially covered by the APS classification criteria. In a study using the PROMIS cognitive function scale, a quarter of the cohort reported moderate-to-severe cognitive dysfunction and 26% of patients with APS had impairments based on the PROMIS cognitive function scale assessments.³⁰ Patients with APS may develop stroke or chronic cerebral small vessel disease, which have been associated with cognitive impairment in the general population and other disorders.^43,44 However, less than a third of patients in these studies had experienced stroke.^30,32 Cognitive impairment in APS occurs even in the absence of stroke and frequently co-occurs with mood disorders, pain, and exhaustion. Further research of patterns, natural history, risk factors, and mechanism of cognitive deficits in APS is needed.

Pain and symptom burden

Three studies assessed pain and overall symptom burden in patients with APS patients.^27,29,30 Gaspar et al conducted an external validation study of the DIAPS in 108 patients with thrombotic APS, assessing HRQOL using both the EQ-5D-3L and EQ-5D-5L (EQ-5D instruments with 3 or 5 levels of questions per dimension, respectively).²⁹ Pain/discomfort emerged as one of the most frequently impaired domains, with 57% of patients reporting pain and 53% reporting anxiety or depression symptoms. Worse (higher) DIAPS scores were associated with increased odds of impairment in pain/discomfort, mobility, and usual activities, although these associations lost significance in multivariable models. Hernández-Molina et al evaluated HRQOL in 50 patients with PAPS using the SF-36 and the LupusQoL instrument, comparing results with population controls.²⁷ Patients with APS reported significantly worse QOL across multiple domains, with pain-related scores mainly affected. Patients receiving long-term oral anticoagulation reported lower LupusQoL scores in pain, physical functioning, and perceived burden to others and lower SF-36 physical functioning scores. Pain burden correlated with peripheral vascular damage and the authors hypothesized that this may be due to the pain and discomfort related to postthrombotic syndrome. Weiner et al assessed pain intensity and its relationship to other PROs in a cross-sectional cohort of 139 individuals with persistently positive aPL, including patients with PAPS, SAPS, and aPL-positive individuals without clinical APS.³⁰ Greater pain burden was moderately linked to worse physical and cognitive function, with higher pain scores associated with medication use and older age.

Pain is a common, clinically meaningful component of symptom burden in APS, which independently affects physical functioning and overall QOL. Pain is only partially explained by cumulative organ damage, highlighting the need for more comprehensive, symptom-focused management.

Depression, anxiety, and psychosocial burden

Only 3 studies have evaluated mental health outcomes in APS using dedicated psychiatric assessment tools.^31,32 Psychological morbidity was a major finding across APS cohorts with ∼40% of patients meeting the criteria for moderate-to-severe depression on the patient health questionnaire-9.³¹ Qualitative interviews further revealed substantial psychosocial burden, including unmet informational needs, lifestyle disruption, family planning concerns, and pervasive worry about the future.³²

The AQUEOUS study³³ was a multicenter Italian investigation designed to assess the psychosocial impact of PAPS on young adults aged 18 to 45 years. Ninety-two patients completed a study-specific questionnaire alongside the validated SF-12, with vascular and obstetric manifestations equally represented. Compared with the general population, patients demonstrated significantly reduced QOL scores, with mental health more profoundly affected than physical health. Nearly half reported a perceived need for psychological support, with this number rising to 89% among women after pregnancy complications. Although fertility itself appeared preserved, APS diagnosis substantially affected family planning decisions due to fears of treatment side effects, heritability, and ability to care for children. The study also reported higher rates of hospitalizations and learning disabilities among children before their mothers were diagnosed with APS, suggesting potential consequences of APS with delayed diagnosis. Specific studies addressing the burdens of recurrent pregnancy loss or obstetric APS complications were not found. These findings underscore the importance of integrating mental health and reproductive counseling into APS care.

Treatment burden and anticoagulation

Anticoagulation with warfarin in thrombotic APS requires ongoing monitoring associated with significant time, and financial burden, as has been demonstrated in other medical conditions requiring anticoagulation such as stroke and atrial fibrillation.^45,46 The treatment burden associated with warfarin is also higher than with direct oral anticoagulants. For example, in a prospective study using the Duke Anticoagulation Satisfaction Scale (DASS), warfarin users had significantly higher total burden scores (51.0 vs 44.7; P < .0001), reflecting greater daily-life limitations and greater psychological impact.⁴⁷ Three studies evaluated treatment burden and anticoagulation satisfaction in patients with APS,^27,29,34 using DASS for treatment satisfaction and SF-36 and LupusQoL for QOL. Patients receiving long-term anticoagulation had lower (worse) LupusQoL scores, specifically in the domains of physical function, pain, intimate relationships, and burden to others, although it is unclear whether this effect is driven by the anticoagulant therapy or the accrual of damage secondary to APS-sequelae. A study by de Oliveira Vaz et al who administered DASS, a 25-item scale designed to explore both the negative and positive impacts of anticoagulation on 66 patients with PAPS who were on warfarin. Among patients with APS on warfarin, the most negatively affected domain on the DASS was psychological impacts, followed by limitations, and overload/tasks.³⁴ The authors attributed these psychological effects of anticoagulant therapy to concerns regarding efficacy, risk of bleeding, and anxiety related to INR control. Reduced time in therapeutic range for the INR correlated with higher psychological impact, and these effects persisted despite higher adherence to warfarin, as measured by a mean treatment measure addition score of 5.8. A mean treatment measure addition score >5 indicates adherence to treatment.³⁴ Compared with older adults who may be more accustomed to taking medications for comorbidities, younger patients had worse perceived QOL, particularly limitations related to anticoagulation.³⁴ Warfarin self-management with home INR monitoring did not change reported treatment satisfaction on DASS.³⁴ Additional studies reinforced that anticoagulation, while essential for thrombosis prevention, imposes a lasting psychological and lifestyle toll.^27,29

The likely higher burden of long-term parenteral anticoagulation or adjunctive immunomodulatory therapies given for recurrent thrombosis in patients already on warfarin therapy has not been evaluated.^4,48,49

Future directions and research priorities

APS has a significant impact on physical and psychosocial functioning, fatigue, and other aspects of QOL. However, significant gaps in research must be addressed especially in the areas of longitudinal PROs and in pediatric, transition-age and older patients.³³ Cognitive problems are reported by patients on general cognitive assessment PROs, but there are few APS-specific assessments. The impact of microvascular and neurologic manifestations of APS on QOL and cognition have never been evaluated,³⁰ even though it is plausible that neurologic manifestations are likely to affect cognition and microvascular manifestations such as alveolar hemorrhage and cutaneous ulcers for which there are limited effective treatments and high morbidity are likely to negatively affect HRQOL. Occupational productivity, caregiver burden, social isolation, and treatment burden remain undermeasured.^31,32,34 Females are overrepresented in APS cohorts (usually 65%-95%), limiting inference for men and potentially obscuring sex-specific trends in HRQOL.^24,30,32,33 Finally, the psychosocial impact, treatment burden, and HRQOL implications of obstetric APS have yet to be definitively evaluated.

Most PRO studies in APS have used widely available, easily administered tools such as SF-36 or PROMIS, which have not been specifically validated in APS populations.^50,51 Disease-specific indices such as the DIAPS score³⁵ and the recent European League Against Rheumatism Antiphospholipid Syndrome Disease Activity Score⁴⁹ have been developed and validated to address these gaps. However, these are clinician-reported rather than patient-reported instruments, representing a significant gap in comprehensively capturing the patient perspective on disease burden, symptoms, and treatment impact. There is a need to either develop APS-specific PRO measures or to validate generic instruments such as PROMIS in large APS cohorts representing the spectrum of phenotypic variability in APS, as has been done for other rheumatologic disorders such as SLE.52, 53, 54, 55, 56

Although there has been increasing attention on the patient’s lived experiences, when and how clinicians should incorporate PRO screening into clinical practice and the impact on clinical management remain to be established. There is also growing interest in using PROs in clinical trials reflected by the US Food and Drug Administration guidance on developing or repurposing PROs as clinical outcome assessments in clinical trials. Future research on PROs in APS should consider features that would make a PRO instrument “fit for purpose,” including whether it covers all important aspects of the concept (or domain) of interest, is administered appropriately, is not overly influenced by other processes/concepts, and its scores correspond with the meaningful aspect of health related to the concept.⁵⁷ With greater understanding of PROs, the management of APS could evolve from a reactive to a proactive approach that provides increasingly patient-centered care.

Conclusions

Existing studies on PROs in APS reveal significantly impaired HRQOL compared to the general population, with impacts on both physical and mental health (Figure 2). Thrombosis, particularly arterial events, comorbid lupus, and cumulative APS-related damage all contribute to worse HRQOL across multiple domains.^23,24,28,29 APS is a chronic disease and although standard management strategies are effective in preventing recurrent clinical events in most patients, the comprehensive care of patients with APS should also include HRQOL assessment, patient education, psychological support, and strategies to address the complex psychosocial burden that remains undermeasured by routine clinical assessment. Additional studies to validate existing PRO instruments in diverse cohorts of individuals with APS and to identify APS-specific and other factors affecting the patient experience are required to make this a reality. Incorporating PROs into clinical practice and research may improve patient-centered care, inform shared decision-making, and individualize treatment.

Conflict-of-interest disclosure: The authors declare no competing financial interests.