This is an intriguing question for which no clear-cut answer is ever found in clinical practice in any case of spondyloarthritis (SpA) except in reactive arthritis, where specific infectious agents (Shigella, Salmonella, Yersinia, Campylobactor and Chlamydia) are known to be the initiating agents. The two most widely studied environmental factors implicated in the development of spondyloarthritis in genetically susceptible hosts, are trauma and infection. Enthesitis, the characteristic pathological process in spondyloarthritis, is thought to have its origins in trauma—the high mechanical stress of large contracting muscles on a small footprint of bone. With very elegant experiments using clinical imaging studies and animal models of spondyloarthritis, Dennis McGonagle and his group have shown that the ‘synovio-entheseal complex’ is susceptible to mechanical stress-induced microdamage. This microdamage may lead to inflammation-related pathway dysregulation and perpetuation of enthesitis and subsequently synovitis (recently reviewed in Jacques P, McGonagle D. Best Pract Res Clin Rheumatol. 2014;28(5):703–710). Trauma also provides the mechanistic links to skin and nail Koebner phenomenon seen in psoriasis and psoriatic arthritis (PsA) patients. In murine models of IL-23 overexpression, a disease primarily presenting as enthesitis is shown to involve joint structures, the aortic root and uvea (Sherlock JP, et al. Nat Med. 2012;18(7):1069–1076). It is well recognized that specific infectious agents act as initiating factors in reactive arthritis, and more recently, the human microbiome has come under increasing scrutiny for playing an important role in the pathogenesis of spondyloarthritis (see more explanation in answers to the following questions #2 & #3).

The answer to which subtype of SpA a person will progress to, probably lies in the specific genetic background of the host plus the environmental factors the host is exposed to. Genetic predisposition to psoriasis and psoriatic arthritis differs from that of axial spondyloarthritis. Prominent genes identified via GWAS for psoriasis and PsA susceptibility include HLA-Cw6, IL12B, IL23R, IL23A, TNIP1, TNFAIP3, LCE3B-LCE3C, TRAF3IP2, NFkBIA, FBXL19, TYK2, IFIH1, REL, and ERAP1; and genes implicated in the pathogenesis of AS include HLA-B27 (especially the allele B*27:05), HLA-B60 (B*40:01), IL-1A, ERAP1, IL-23R, IL-1R2, ANTXR2, STAT3, and Kinesin family 21B (For excellent reviews of genetics of SpA (see O’Rielly D. Rahman P. Best Pract Res Clin Rheumatol. 2014;28(5):673–685, and Reveille J. Ann Rheum Dis. 2011;70[Suppl 1]:i44–i50). A person inheriting the right mix of genetic material is predisposed to develop the specific type of SpA.

In addition to the genetics, the human microbiome is now thought to play a very important role in the development of a specific type of SpA. A recent on-line publication described a “discrete microbial signature” of gut microbial communities, profiled by sequencing and qPCR amplification of the 16S rRNA gene on terminal ileum biopsies of AS patients (Costello ME et al. Arthritis Rheum DOI: 10.1002/art.38967 Epub ahead of print). They found significantly higher levels of specific bacteria lachnospiracea, ruminococcaceae, rikenellaceae, porphyromonadaceae, and bacteroidaceae in the AS patients’ gut compared to healthy controls. It is interesting that two of these five species (lachnospiraceae and prevotellaceae) have also been strongly associated with colitis and Crohn’s disease. These and other similar observations support a hypothesis previously put forward by my university colleagues that genes associated with AS act at least in part through their effects on the gut microbiome (Rosenbaum JT, Davey M. Arthritis Rheum. 2011;63:3195–198).

While genetics has been shown to play a major role in the disease severity in AS (Hamersma J. Arthritis Rheum. 2001;44(6):1396–1400), whether gut microbiome play any role in disease progression remains to be seen.

The answer to this question is not known except that only a minority of juvenile SpA patients develops a persistent disease lasting in to adulthood. A recent systematic literature review on the subject of predictors of prognosis in JIA analyzed 3679 articles and selected 40 of them for further scrutiny (van Dijkhuizen EH et al. Ann Rheum Dis. 2014 Jun 24. doi: 10.1136/2014-205265. Epub ahead of print). Polyarticular onset predicted a worse prognosis for all outcomes, except quality of life; and a diagnostic delay and the systemic onset predicted continuation of active disease. They could not find any particular factors predicting progression of JIA to arthritis in adulthood. A previous study found that early presence of ankle and/or wrist disease, symmetric joint involvement, and an elevated ESR were indicators of the likelihood of disease progression in a child with oligoarticular JIA (Al-Matar MJ et al. Arthritis Rheum. 2002;46[10]:2708).

The role of microbiome in disease development among children with enthesitis related arthritis (ERA), a subtype of JIA thought to be the pediatric equivalent to axSpA in adults, was recently investigated. The researchers found significantly lower levels of Faecalibacterium genus bacteria in the gut of children with ERA compared to controls (Stoll ML, et al. Arthr Res Ther. 2014;16:486 doi:10.1186/s13075-014-0486-0, Epub ahead of print). These organisms exert anti-inflammatory effects through production of butyrate, and hence their deficiency may have an etiopathogenic role in juvenile SpA. However, the role of microbiome in disease perpetuation in adulthood is not known.

Early diagnosis is critical in axial spondyloarthritis patients for two main reasons. Firstly, studies on cohorts have shown that the disease burden is comparable in nr-axSpA patients and AS patients (Kiltz U, et al. Arthritis Care Res. 2012;64:1415–1422). Early diagnosis and appropriate treatment would reduce this disease burden on our patients. Secondly, several clinical trials have shown that TNF inhibitors are not only effective in treating the early axSpA, but that the same biologic agents may be more effective when used early than in late established disease (see answer to the following question #5). It is unlikely that different cytokines would be implicated in different clinical stages of axial spondyloarthritis, though this has not been formally tested to my knowledge.

Evidence is emerging that treating axial SpA patients in early stages can have better outcome compared to treating AS patients with established disease. There are at least four studies, which have shown that treating nr-axSpA patients in the early stage increase their chances of ‘partial remission’ when compared to results in established AS patients. Haibel et al. treated active nr-axSpA patients (n=46) with placebo or adalimumab for 12 weeks. The rate of ASAS partial remission was 53% in patients with disease duration less than 3 years compared to 16% in patients with disease duration more than 3 years (Haibel H et al. Arthritis Rheum. 2008;58(7):1981–1991). In two other similar studies on nr-axSpA patients using infliximab and etanercept, the rates of ASAS partial remission were 55.6% and 50%, respectively (Barkham N et al. Arthritis Rheum. 2009;60(4):946–954, and Song et al. Ann Rheum Dis 2011;70(4):590–596) whereas the ASAS partial remission rates are about 25–30% in established AS patients (Landewe R et al. Ann Rheum Dis. 2014;73:39–47). In the INFAST study (Sieper J et al. Ann Rheum Dis. 2014;73(1):101–107), nr-axSpA patients treated with infliximab plus naproxen had a 62% ASAS partial remission rate at 28 weeks.

The distinct pattern of joint involvement in adult versus juvenile forms of SpA (predominantly axial versus largely peripheral, respectively) is probably related to the differences in the biomechanical forces experienced by human skeleton at different stages of life. Juvenile SpA typically starts in a lower-limb predominant oligoarticular fashion and then migrates to the sacroiliac joints (SIJ) and spine, whereas the adult SpA starting in the 20s–30s age group involves SIJ first with inflammatory low back pain as the presenting symptom. One can hypothesize that different areas of the skeleton experience major biomechanical forces during adulthood compared to childhood. The biomechanical forces experienced by the synovio-entheseal complexes at the SIJ and spine in bending/twisting/turning in adulthood may be more compared to those in children, and a similar case can be made about the lower extremity joints in children. This may explain the phenotypic differences observed in SpA presentation in adults versus children.

While the final pathway of osteoblastic differentiation and new bone formation may be similar in DISH and AS, the underlying pathogenic mechanisms are likely to be very different. AS is an inflammatory rheumatic disorder where as DISH is a noninflammatory, degenerative disorder of the skeleton. The pathogenesis of AS includes a complex interplay between the genetic, immunological and environmental factors, and the exuberant healing response to the inflammatory lesions is thought to underlie the new bone formation. The pathogenic mechanisms of new bone formation in DISH are not yet fully elucidated, though mechanical factors are thought to play an important role.

At the last ACR annual meeting held in Boston in November 2014, data were presented from two clinical trials on secukinumab (IL-17A monoclonal antibody) in the treatment of ankylosing spondylitis. In two phase III studies, secukinumab used with and without IV bolus doses showed good efficacy in controlling the signs and symptoms of patients with AS (ASAS20 responses of 61% compared to placebo rate of 29% at week 16) and also improving patient reported outcomes (mean changes from baseline exceeded the minimum clinically important difference for SF-36 PCS, SF-36 MCS, ASQoL and FACIT-Fatigue at all-time points up to week 16 in secukinumab but not in placebo group) (Baeten et al. and Deodhar et al. presentations at the ACR 2014 annual meeting). It therefore appears that the IL-23/IL-17 axis manipulation is especially effective in treating patients with PsA and axial SpA. A word of caution here: IL-17 blocking agents may exacerbate inflammatory bowel disease (Zhang SJ et al. Eur Rev Med Pharmacol Sci. 2013;17(24):3291–3295), hence one cannot conclude that blocking IL-17 would be useful in “all” spondyloarthritides.

I do not think that high CRP in an HLA-B27 positive individual would be sufficient to constitute a “preclinical SpA” stage. Strong family history of SpA in first-degree relatives, along with an appropriate genetic background, plus “as yet not well characterized” constituents of the gut microbiome may describe such a stage, but we are not close to defining it yet.

The “window of opportunity” for effective treatment is a different question. The INFAST trial has shown that we may have a window of opportunity to treat axSpA effectively so that a percentage of patients could be maintained in a drug-free remission state (Sieper J et al. Ann Rheum Dis. 2014;73(1):101–107). As noted in the answer to question #5 above, nr-axSpA patients naïve to any pharmacologic therapy were treated aggressively using infliximab and naproxen. Patients in partial remission at 28 weeks were randomized to no treatment or treatment with naproxen alone. At 1 year, 40% and 48% of patients could be maintained in partial remission without a biologic. These results are similar to recent “withdrawal trials” done in rheumatoid arthritis and indicate that early aggressive treatment (“window of opportunity”) may put axSpA patients in drug-free remission state.

A few years ago I would have answered this question differently, and would have said that HLA-B27 positive “normal and healthy” individuals continue to lead “normal and healthy” life. However, new data are emerging to suggest that HLA-B27 positive individuals may have reduced life span compared to those without this genotype. In the National Health & Nutritional Examination Survey (NHANES) study, it was found that for adults 50–69 years of age the prevalence of HLA-B27 was 3.6% (95% CI 2.2–5.8%), compared to 8% for adults 20–29 years of age (Reveille et al. Arthritis Rheum. 2012;64(5):1407–1411). This drop in the prevalence of HLA-B27 with advancing age suggests increased mortality in people with this genetic background. While the exact cause of the increased mortality is not clear, it may be at least partly related to an old observation that HLA-B27 positive individuals have increased prevalence of cardiac conduction abnormalities (Bergfeldt L et al. Acta Med Scand. 1987;222(4):293–299).