With the growing awareness of the impact of chronic back pain and axial spondyloarthritis and recent breakthroughs in genetics and the development of novel treatments which may impact best on early ...disease, the need for markers that can facilitate early diagnosis and profiling those individuals at the highest risk for a bad outcome has never been greater. The genetic basis of ankylosing spondylitis has been considerably advanced, and HLA-B27 testing has a role in the diagnosis. Knowledge is still incomplete of the rest of the genetic contribution to disease susceptibility, and it is likely premature to use extensive genetic testing (other than HLA-B27) for diagnosis. Serum and plasma biomarkers have been examined extensively in assessing disease activity, treatment response, and as predictors or radiographic severity. For assessing disease activity, other than C-reactive protein and erythrocyte sedimentation rate, the most work has been in examining cytokines (particularly interleukin 17 and 23), matrix metalloproteinase (MMP) markers (particularly MMP3). For assessing those at the highest risk for radiographic progression, biomarkers of bony metabolism, cartilage and connective tissue degradation products, and adipokines have been most extensively assessed. The problem is that no individual biomarkers has been reproducibly shown to assess disease activity or predict outcome, and this area still remains an unmet need, of relevance to industry stakeholders, to regulatory bodies, to the healthcare system, to academic investigators, and finally to patients and providers.
The spectrum of axial spondyloarthritis (AxSpA) (including both non-radiographic and radiographic AxSpA), also known as ankylosing spondylitis AS, has achieved growing recognition. With the ...development of treatments not only effective in controlling disease activity but also in slowing radiographic progression, and given the cost and risk profiles of these novel treatments and the limitations of current clinical criteria, imaging and peripheral blood biomarkers (C-reactive protein, HLA-B27 testing), the need for better biomarkers has never been greater. The purpose of this review is to present up-to-date information on the biomarkers for the diagnosis for assessing disease diagnosis, activity, treatment response, and radiographic progression of AxSpA, and entails multiple search strings used to identify articles of interest published in PubMed and the Cochrane database up to May 1, 2021. We present the current status of research in serologic biomarkers such as cytokines, adipokines, matrix metalloproteinases, calprotectin, CD74, antibodies, bone turnover markers, and circulating protein fragments of cartilage and connective tissue degradation and other biomarkers. Despite a great deal of work, most serologic results have been disappointing and to date none perform better than CRP. Recent promising preliminary data for some has been published, but require further confirmation. Transcriptomic biomarkers such as micro-RNAs and genetic biomarkers also show promise to assist in diagnosis and possibly for radiographic severity, including a recently developed panel of genetic risk markers used in a polygenic risk score instrument in AS diagnosis. These need further confirmation and application in AS as well as in nr-AxSpA.
Key Points
• With innovations in diagnosis and treatment, and with the poor performance of currently utilized biomarkers in axial spondyloarthritis, the need for better serologic biomarkers for diagnosis for diagnosis, disease activity, and predicting disease progression never been greater.
• A great deal of effort has been put into examining cytokines, matrix metalloproteinases, calprotectin, CD74, bone turnover makers, circulating protein fragments of cartilage and connective tissue degradation as well as varied other biomarkers. Despite some recent promising findings that need further confirmation, none have been identified that outperform C-reactive protein.
• Recent studies examining micro-RNA in peripheral blood, as well as DNA markers involved in generating a polygenic risk score look promising, but need further confirmation.
Ankylosing spondylitis (AS), psoriasis and inflammatory bowel disease (IBD) often coexist in the same patient and in their families. In AS, genes within the MHC region, in particular HLA-B27, account ...for nearly 25% of disease hereditability, with additional small contributions from genes outside of the MHC locus, including those involved in intracellular antigen processing (that is, ERAP1, which interacts with HLA-B27) and cytokine genes such as those involved in the IL-17-IL-23 pathway. Similar to AS, the strongest genetic signal of susceptibility to psoriasis and psoriatic arthritis also emanates from the MHC region (attributable mostly to HLA-C(*)06:02 although other genes have been implicated), and gene-gene interaction of HLA-C with ERAP1. The remaining hereditary load is from genes involved in cytokine production, specifically genes in the IL-17-IL-23 pathway, the NFκB pathway and the type 2 T-helper pathway. In IBD, similar genetic influences are operative. Indeed, genes important in the regulation of the IL-17-IL-23 pathway and, in Crohn's disease, genes important for autophagy (that is, NOD2 and ATG16L1 and IRGM) have a role in conferring susceptibility of individuals to these diseases. Thus, AS, psoriasis and IBD seem to share similar pathogenic mechanisms of aberrant intracellular antigen processing or elimination of intracellular bacteria and cytokine production, especially in the IL-17-IL-23 pathway.
Many challenges have made it difficult to determine the prevalence of spondyloarthritis (SpA) in North America. They include the ethnic heterogeneity of the population, the lack of feasibility of ...applying current criteria (such as requirements for human leukocyte antigen-B27 testing and imaging studies such as pelvic radiographs and magnetic resonance imaging scanning) and the transient nature of some SpA symptoms (ie, peripheral arthritis and enthesitis). Current estimates of the prevalence of SpA in the United States range between 0.2% and 0.5% for ankylosing spondylitis, 0.1% for psoriatic arthritis, 0.065% for enteropathic peripheral arthritis, between 0.05% and 0.25% for enteropathic axial arthritis and an overall prevalence of SpA as high as >1%. With newer population-based instruments becoming available, the availability of the widely validated European Spondyloarthropathy Study Group criteria and the lower cost and greater feasibility of genetic testing, opportunities for true population-based studies of SpA are possible and will likely soon ensue.
Radiographic axial spondyloarthritis (also known as ankylosing spondylitis AS) is a chronic immune-mediated arthritis characterized by inflammation of the axial skeleton, peripheral joints, and ...entheses. It is estimated that 1 in every 200 people are affected by AS, making it an important healthcare and socioeconomic issue. In this review, we aim to explore the current understanding of AS risk factors and provide a comprehensive update. Multiple search strings were used to identify articles of interest published in PubMed between January 1, 2013, and February 1, 2021. On the basis of the literature review and analysis, we present up-to-date information on the risk factors of developing AS and our viewpoints on disease onset and progression. Multiple genetic and nongenetic risk factors have been suggested in the onset of AS. HLA-B27 is known to have a strong association with the disease, but other genes have been implicated in disease development. Aside from genetics, other factors are thought to be involved; up to 70% of patients with AS have subclinical intestinal inflammation, suggesting that the origin of the disease may be in the gut. The exact mechanism by which AS onset begins is most likely complex and multifactorial.
Key Points
• It remains unclear how interactions between genes
,
microbes
,
mechanical stress
,
gender
,
and other environmental and lifestyle factors predispose patients to the development of ankylosing spondylitis (AS).
• The exact mechanisms of AS are complex and multifactorial which will require much future research
• Recognizing the risk factors
,
as well as understanding gene-environment interactions
,
may offer valuable insights into the etiology of AS and have important implications for diagnosis and treatment strategies
Objective
The US national prevalence of spondylarthritis (SpA) was estimated for 2 published sets of classification criteria: the Amor criteria and the European Spondylarthropathy Study Group (ESSG) ...criteria. These 2 SpA criteria sets have been the most widely utilized in previous population‐based studies of SpA.
Methods
The US SpA prevalence estimates were based on a representative sample of 5,013 US adults ages 20–69 years who were examined in the US National Health and Nutrition Examination Survey (NHANES) 2009–2010.
Results
The overall age‐adjusted prevalence of definite and probable SpA by the Amor criteria was 0.9% (95% confidence interval 95% CI 0.7–1.1%), corresponding to an estimated 1.7 million persons (95% CI 1.4–2.1 million persons). The age‐adjusted prevalence of SpA by the ESSG criteria was 1.4% (95% CI 1.0–1.9%), corresponding to an estimated 2.7 million persons (95% CI 1.9–3.7 million persons). There were no statistically significant sex differences in SpA prevalence. The SpA prevalence among non‐Hispanic white persons was 1.0% (95% CI 0.7–1.5%) by the Amor criteria and 1.5% (95% CI 1.0–2.3%) by the ESSG criteria. SpA prevalence could not be reliably estimated in other race/ethnicity subgroups due to sample size imitations.
Conclusion
The SpA prevalence estimates are in the range of SpA prevalence estimates reported elsewhere in population‐based surveys and it is likely that SpA may affect up to 1% of US adults, a prevalence similar to that reported for rheumatoid arthritis. The current US SpA prevalence estimates may be lower than the true value because the NHANES 2009–2010 data collection did not capture a complete set of the elements specified in the 2 SpA criteria sets.
The concept of inflammatory back pain (IBP) evolved in the 1970s, coincident with the discovery of the HLA-B27 association with ankylosing spondylitis (AS), leading to the development of criteria to ...determine the presence of IBP. The concept of IBP and it relationship with AS and axial spondyloarthritis (AxSpA) has further evolved, and an instrument developed (the Spondylitis Association of America Back Pain Tool), which was further modified and field tested for use in the 2009 to 2010 National Health and Nutrition Examination Survey (NHANES). This has shown the frequency of chronic back pain to have risen to 19.4%, with nearly one third having IBP. The prevalence of AxSpA has been defined at 1.0% to 1.4% and AS at 0.52% to 0.55%. The national prevalence of HLA-B27 in the United States is 6.1%, and intriguing data from NHANES 2009 suggest a decreasing frequency with increasing age. From this arise new questions and a work agenda ahead.
The 40-year-old association of HLA-B27 with ankylosing spondylitis is one of the best examples of disease association with a hereditary marker. Genomewide association and family studies suggest that ...other important major histocompatibility complex (MHC) influences are operative in ankylosing spondylitis (AS) susceptibility. HLA-B27 positive hepatitis C individuals are immunologically more efficient in combating viral infections such as HIV-1, hepatitis C, and influenza and less efficient in combating against certain bacteria (and perhaps other organisms) capable of surviving intracellularly. A recent representative population survey of the frequency of HLA-B27 in the USA found a lower frequency of HLA-B27 in older US adults, perhaps reflecting this. Other HLA class I and class II alleles have been implicated in AS susceptibility, the most consistent being HLA-B*40/B60 (B*40:01) but also B14, B15, A*0201, DRB1*04:04, and certain DPA1 and DPB1 alleles. Non-HLA MHC alleles have also been implicated, although many such studies have been inconsistent, likely due to power issues related to the low number of HLA-B27-negative AS patients examined. The best evidence is for major histocompatibility complex class I chain-related gene A (MICA) whose recognition by intestinal epithelial T cells expressing different V-delta-1 gamma/delta TCR further implicates the gut in AS pathogenesis. The HLA class I and class II and other non-HLA allelic associations underscore the importance of T cells in AS pathogenesis.
Modern technological innovations have advanced our understanding of the genetic basis of spondyloarthritis. In ankylosing spondylitis (AS), where the major histocompatibility complex (MHC) accounts ...for nearly half of the predisposition, most comes from HLA-B27, for which 65 subtypes are now recognised, although other genes are also at work including HLA-B60 (B*40:01). Other genes have been identified, including those involved in peptide editing for loading onto class I MHC molecules (ERAP1) and cytokine genes such as interleukin 1A (IL-1A) and those involved in the Th17 network (IL-23R, an association seen primarily in Caucasians) and others. In acute anterior uveitis, these associations are also seen as well as a region on chromosome 9p and genes whose confirmation is under way. Psoriasis and psoriatic arthritis fall into this disease spectrum, with the largest region of susceptibility coming from the MHC (most likely HLA-C, ie, C*06:02 although additional influences are also being implicated), and most of the other genetic susceptibility coming from genes involved in cytokine production, specifically genes in the Th17 pathway (IL-12B, IL-23A and IL-23R, the latter, like in AS, not seen in Asians), genes in the nuclear factor κB pathway (TNFAIP3 and TNIP1) and genes in the Th2 pathway (IL-4 and IL-13). Given that more than half of patients with AS have evidence on colonoscopy of at least occult inflammatory bowel disease (IBD), it is not surprising that shared genetic influences are operative. In IBD, genes important in the innate immune response (NOD2), autophagy (ATG6L1) and regulation of the IL-23 pathway (IL-23R) play a role in disease susceptibility.
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