INTRODUCTION

Nearly everyone will experience low-back pain (LBP) at some point in their lives.¹ LBP is the second leading cause of disability among adults in USA² accounting for 149 million days of work lost and costing 100–200 billion dollars annually.³ Inflammatory back pain (IBP) was first described as a clinical entity by Calin et al,⁴ revised in the European Spondyloarthropathy Study Group (ESSG) criteria for spondyloarthritis (SpA) in 1991,⁵ further by Rudwaleit et al in 2006⁶ and finally as part of the Assessments in Spondyloarthritis International Society Classification Criteria for Axial Spondyloarthritis in 2009.⁷

Given that ankylosing spondylitis (AS) is highly heritable,first-degree relatives (FDRs) of AS patients may represent a group at high risk of disease, particularly in HLA-B27 positive FDRs.^{8 9} HLA-B27 is more prevalent in familial than sporadic AS. The frequency of other non-major histocompatibility complex susceptibility loci is not markedly different between sporadic and familial AS.¹⁰

This study aims to examine clinical features of SpA, HLA-B27 allele and persistence of back pain in FDRs of AS patients with chronic IBP (CIBP), non-inflammatory chronic back pain (NICBP) and no chronic back pain (CBP) as well as to compare clinical features of SpA in FDRs of AS patients with CBP with participants in the National Health and Nutrition Examination Survey (NHANES) 2009–2010 with CBP.^{11 12}

RESULTS

In all, 546 FDRs of AS patients participated in this evaluation, of which 399 were divided into three groups after excluding FDRs with an AS or axial SpA diagnosis at baseline visit. The group without CBP included 162 FDRs who never experienced CBP and were at least 40 years of age (FDRs younger than 40 years were excluded from this group, and CIBP is classically expected to have commenced by age 40 years.⁴) FDRs who could not recall their age of onset of CBP were not included.

FDRs of AS patients who exhibited CIBP (N=155) had earlier onset of CBP than FDRs with NICBP (N=82) (table 1). They were also more likely to be male, in comparison to those with NICBP, and a nonsignificant trend was seen comparing those with CIBP with those without. Overall, those with CBP were more likely to be white than those without CBP (84.6%-p=0.01 overall). HLA-B27 was more frequent in those with CIBP (56.8%) compared to those without CBP, and a similar, although nonsignificant trend was seen comparing those with CIBP to those with NICBP.

FDRs with CIBP reported heel pain more frequently compared to those without CBP. Again, a similar, although nonsignificant trend was seen comparing those with CIBP to those with NICBP. Other features associated with SpA (psoriasis, uveitis, Crohn’s disease, ulcerative colitis) did not show statistically significant variations between the CIBP vs the NICBP groups.

Comparing 206 unrelated white FDRs with 772 white participants in NHANES 2009–2010 with CBP, there were no significant differences in features of IBP (where there might have been two FDRs from the same family included in table 1, one in the CIBP and one in the CIBP group, only the eldest FDR was included in this analysis). In fact, some features (AM stiffness, pain improving as the day progresses, awakening the second half of the night) were less common in FDRs with CBP compared with the general population (table 2). However, other features of SpA (earlier age at CBP onset, uveitis, psoriasis) were more frequent in FDRs of AS patients. These findings from univariable models remained very similar after adjusting for age and gender in multivariable models.

Of 23 patients with CIBP at baseline seen again 67.04±31.02 months later, 16 (73%) still had CIBP, whereas only four of 13 NICBP patients (31%) seen 61.23±31.84 months later were still symptomatic (p=0.038, OR =5.1 [C.I. 1.2, 22.5]). Of the remaining nine with NICBP, three (23%) developed CIBP and six (46%) had symptoms resolve. Of the 13 without CBP at baseline seen 75.5±29.9 months later, 11(85%) remained asymptomatic (p=0.0045, OR =12.6 [C.I. 2.2, 72.3]), two (15%) developed CIBP and none developed NICBP (15.4% vs 69.7% of those with CIBP at baseline, p=0.0045, OR =12.6 [C.I. 2.2, 72.3]).

DISCUSSION

The study demonstrated that FDRs of AS patients with CIBP have a younger age at onset, a higher frequency of heel pain, and higher frequency of HLA-B27 than those FDRs who do not develop CBP and a younger age of onset and higher frequencies of heel pain, iritis and psoriasis compared to the general US population with CBP (though other features of CIBP were not more frequently seen).

In the NHANES 2009–2010 study, one-third of population with CBP had CIBP.¹¹ One-quarter of CIBP patients in NHANES 2009–2010 met ESSG classification criteria for axial SpA.¹²

Few studies have investigated FDRs of AS patients. One study of two cohorts of families of HLA-B27 positive probands with AS found relatives who did not show radiologic abnormalities of the sacroiliac joints or the spine but had symptoms of CIBP were more likely to be B27-positive compared to asymptomatic relatives.⁸ Another study involving 51 FDRs of HLA-B27 positive AS probands found that several FDRs exhibited clinical and/or radiographic abnormalities suggestive of SpA, with one-third of the FDRs fulfiling either ESSG or ASAS criteria for SpA.⁹

Another concern, raised by the US Food and Drug Administration in its initial consideration of approving biologics for the treatment of AS in 2013, was whether the phenotype of AxSpA or CIBP remitted spontaneously.¹³ Our data, despite that relatively few returned for a second visit, suggest that the CIBP phenotype is stable and does not remit over time.

Shortcomings of this study include not being able to compare HLA-B27 typing between AS FDRs and NHANES participants with CBP due to information classification in the latter. Also, our study included mainly Caucasian subjects. Since other ethnicities were underrepresented, the findings of this study may not be generalisable to all ethnicities. Finally, potential participation bias may have occurred in patients who came back later, since patients with persistent CBP are more likely to follow up as compared to those with remitted pain, although we do not believe there would have been any difference in participation among symptomatic patients in the three groups. Nevertheless, the majority of those recontacted with CIBP had the phenotype persist over time.

Thus, CIBP in FDRs of AS patients is associated with younger age onset and a higher frequency of SpA features such as heel pain, and CBP in FDRs of AS patients is associated with HLA-B27. CIBP in FDRs of AS patients appears to persist over time in most, creating a possible need for further longitudinal studies in this group for long-term diagnostic and treatment approaches.