Factors predicting axial spondyloarthritis among first-degree relatives of probands with ankylosing spondylitis: a family study spanning 35 years

Abstract

ObjectiveFactors predicting axial spondyloarthritis (axSpA) among first-degree relatives (FDRs) of ankylosing spondylitis (AS) patients need to be defined. We investigated the predictive value of the probands’ HLA-B27 and radiographic sacroiliitis status on disease occurrence among their FDR. We also assessed the predictive value of features of the clinical history, including chronic inflammatory back pain (CIBP) and acute anterior uveitis (AAU), among the FDR and how they can be used to improve classification and diagnosis of axSpA.MethodsIn 1985, we studied 363 AS probands and 806 FDR who underwent rheumatologic examination, completed questionnaires, provided blood samples for HLA-typing and underwent radiography of sacroiliac joints. At follow-up in 2018–2019, 125 patients and 360 FDR were available for study, and completed a postal questionnaire about axSpA features. FDRs were asked to report whether after 1985 they had been diagnosed by Swiss rheumatologists as having axSpA.ResultsAmong HLA-B27(+) FDR, axSpA occurred in 25.4%–26.3%, independent of the radiographic sacroiliitis status of the proband. AAU occurred in 13/34 (38.2%) FDR with axSpA vs 29/251 (11.6%) FDR without axSpA (p=0.00004, OR=4.74 95% CI 2.15 to 10.47). The presence of CIBP at baseline did not predict later occurrence of axSpA but combining CIBP and pain/discomfort at the thoracic spine and at anterior (ventral) chest wall ever, assessed at follow-up in 2018–2019, provided 83.1% sensitivity and 87.2% specificity for current axSpA.ConclusionOccurrence of AAU among FDR of axSpA probands should prompt screening for axSpA. Moreover, co-occurrence of CIBP and pain/discomfort in the thoracic spine and at anterior chest wall as a three-question tool may further enhance clinical suspicion of axSpA among these FDR.

Heterogeneity of axial spondyloarthritis: genetics, sex and structural damage matter

“…We report on heterogeneity among probands due to genetics (HLA-B27 status and PRS), sex and severity, defined as structural damage to the SI joints (by the mNY criteria). Occurrence of axSpA among FDR is reported elsewhere 21. The mean age of the 249 male and 114 female probands was 44.19±11.1 years.…”

“…The observed genetic differences (PRS and association with HLA-B27) are also certainly relevant regarding differences in heredity. Recurrence of the disease is high among the offspring of HLA-B27(+) parents with AS, but rare in HLA-B27(−) families 8 21 25. In particular, disease recurrence among the offspring of female HLA-B27(+) probands is substantial 25.…”

The challenge of new classification criteria for axial spondyloarthritis

“…requires the clinical history of the presence of inflammatory spinal pain at at-least 2 of these 3 regions, and it has 83.1% sensitivity and 87.2% specificity, with a positive likelihood ratio (LR + ) of 6.5; this contrasts with a LR + of only 2.9 for chronic IBP (based on 80% sensitivity and 72% specificity). 8 It is important to note that good performing classification criteria should not only clearly define the full 'Gestalt' of a heterogeneous disease such as axSpA, but also should allow proper interpretation of clinical and epidemiologic studies, therapeutic trials, and research on etiopathogenesis. This requirement is challenging as the current criteria fall short regarding this requirement.…”

“…This requirement is challenging as the current criteria fall short regarding this requirement. For example, women with nr‐axSpA, as a group have a disease that is clinically and genetically distinct from nr‐axSpA in men 8–10 . The parents (especially mothers) with human leukocyte antigen (HLA)‐B27(+) AS strongly affect likelihood of recurrence/occurrence of axSpA among their HLA‐B27(+) offspring 8 .…”

“…For example, women with nr-axSpA, as a group have a disease that is clinically and genetically distinct from nr-axSpA in men. [8][9][10] The parents (especially mothers) with human leukocyte antigen (HLA)-B27(+) AS strongly affect likelihood of recurrence/occurrence of axSpA among their HLA-B27(+) offspring. 8 The disease recurrence is much lower if the proband has nr-axSpA, and its recurrence is very uncommon in HLA-B27(−) families.…”