Re:Evidence in Support of the Validity of the TNF Brake Hypothesis
Response to the eLetter by Maksymowych WP, entitled ?Evidence in Support of the Validity of the TNF Brake Hypothesis"
with great interest we read the Letter by our colleague
W.Maksymowych, entitled ?Evidence in Support of the Validity of the TNF
Brake Hypothesis", which commented on our paper "Continuous increase in
the rate of new bone formation in patients with ankylosing spondylitis
(AS)" . He argues that our interpretation of the results of our study
is misleading in relation to the TNF brake hypothesis proposed by him.
Since there have been several versions of this hypothesis [2-4] we have
decided not to go into much detail and semantics but rather discuss the
recent progress in the field.
One of the major open questions related to the pathophysiology of AS is
the nature of the link between inflammation and ankylosis. Several years
ago we have reported that syndesmophyte formation after 2 years is more
probable if, at baseline, spinal inflammatory lesions as detected by
magnetic resonance imaging (MRI) using STIR sequences are present , and
this finding was confirmed later .
However, it was clear from the beginning that this couldn't be the only
influencing factor, since the majority of syndesmophytes appeared to have
grown from vertebral edges without any bone marrow edema at baseline [2,
5], and that finding was also confirmed later . In our most recent
paper  on imaging results of the EASIC cohort related to the course of
radiographic progression under TNF-blocker treatment over 5 years, MRI
examinations of AS patients at baseline and after 2 years were included.
In this larger study, the regression of inflammation alone was not predictive of new bone formation. More importantly, another MRI finding has attracted increasing interest in the last years, and that is characterized by fat signals detected in T1 sequences [7, 8]. Indeed, both our groups have shown that there are different types of spinal lesions that can be differentiated by MRI techniques in AS and that may play different role in the important sequence of events from inflammation to new bone formation [4, 7]. There are basically four types of MRI findings in the spine that may precede syndesmophyte formation: (i) signs of inflammation without any other pathologic finding in parallel, (ii) signs of inflam?mation with a concomitant fat signal, (iii) a fat signal without signs of inflammation and (iv) no lesions at all .
There are several studies that suggest that anti-TNF therapy does not
inhibit new bone formation in AS [9-11], but, in addition to the paper
discussed here , another very recent one also reported some reduction
of syndesmophyte formation . However, both studies were clearly not
performed with patients in an early stage of disease. From several long-
term studies we know that there definitely is some progression in AS
patients treated with TNF blockers and that there is no major difference
between different dosages of the anti-TNF compound . Factors that
predict radiographic progression such as gender, prevalent syndesmophytes
and smoking have been described  - and these should be controlled for
in well-powered analyses with sufficient patient numbers.
In the paper here under discussion we report on radiographic outcomes in a
small number of AS patients treated for 8 years with infliximab . The
comparison to a historical cohort suggests that syndesmophyte formation
may decelerate over longer periods of time in patients on anti-TNF
therapy. Since patients were treated with TNF blockers almost continuously
over a time period of 8 years in this study, the number of spinal
inflammatory lesions is likely to be considerably reduced in most cases
already after some months of treatment. However, in another paper we
showed that about 20% of the spinal inflammation detected at baseline is
still present after 2 years . Furthermore, it is noteworthy that
within this time period of 8 years there was a short period of treatment
discontinuation of about 4-6 months after 3 years of continuous therapy
. This may have caused some worsening of spinal inflammation in that
time period. However, this was probably again suppressed when anti-TNF
therapy was re-administered but that was not investigated.
The basis of our concluding statement in that paper was indeed that the TNF-brake hypothesis implies that the use of anti-TNF agents may accelerate the development of new bone since TNF upregulates dickkopf-1 which, in turn, downregulates Wingless (Wnt) pathway signaling for new bone formation . The background here is that proinflammatory cytokines such as TNF have been shown to stimulate expression of bone forming factors, such bone morphogenetic proteins (BMPs) and Wnt proteins. Thus, by antagonising TNF, dickkopf-1 expression will also decrease and allow signalling for new bone formation through the Wnt pathway.
A recent study on serum levels of dickkopf-1 and sclerostin in patients with AS has confirmed that this could indeed play a role . The TNF brake hypothesis has initially been put forward to explain the observation that new syndesmophytes are more likely to develop at sites where inflammation has resolved (low TNF, low dickkopf-1, high Wnt) as opposed to sites of persistent inflammation (high TNF, high dickkopf-1, low Wnt) . The finding that resolved but not persistent chronic inflammatory lesions (CILs) are associated with new syndesmophytes  led to the assumption that, once inflammation resolves, either spontaneously or through pharmacologic suppression of TNF, this allows signalling through Wnt to promote new bone formation. In that scenario, in an established inflammatory lesion, TNF may act primarily as a brake on new bone formation through Dickkopf-1. Resolution of the CIL by anti-TNF therapy may allow tissue repair to become manifest as bone, while persistence of the CIL may preclude syndesmophyte formation. . However, on the other hand, our recent data suggest , much as proposed by W.Maksymowych in his letter, that early inflammatory lesions may well resolve without sequelae (new bone formation), if effective anti-TNF therapy is instituted and inflammation does resolve prior to activation of bone formation. Whether an 'average' AS patient does really present with a mixture of different inflammatory lesions has not yet been shown to date. It seems likely that, next to the activity of the disease, age and disease duration will also have an influence on that. In this regard, it may be more important to perform analyses on the level of vertebral edges rather than on the patients? level, to be able to also study intercorrelations between vertebral edges within patients. In conclusion, our understanding of the mechanisms responsible for the process of new bone formation in patients with axial SpA with and without treatment with TNF blockers is still limited. More prospective studies including the performance of MRIs in short intervals in combination with biomarkers, clinical findings and radiographs or even more sophisticated outcome parameters providing imaging results and new scoring methods with a high sensitivity to change will hopefully shed more light and give better answers to this complicated scenario of axial spondyloarthritis.
1. Baraliakos X, Haibel H, Listing J, et al. Continuous long-term anti-TNF therapy does not lead to an increase in the rate of new bone formation over 8 years in patients with ankylosing spondylitis. Ann Rheum Dis. 2013 Mar 27.
2. Maksymowych WP, Chiowchanwisawakit P, Clare T, et al. Inflammatory lesions of the spine on magnetic resonance imaging predict the development of new syndesmophytes in ankylosing spondylitis: evidence of a relationship between inflammation and new bone formation. Arthritis Rheum 2009; 60(1):93-102.
3. Pedersen SJ, Chiowchanwisawakit P, Lambert RG, et al. Resolution of inflammation following treatment of ankylosing spondylitis is associated with new bone formation. J Rheumatol 2011; 38(7):1349-1354.
4. Maksymowych WP, Morency N, Conner-Spady B, et al. Suppression of inflammation and effects on new bone formation in ankylosing spondylitis: evidence for a window of opportunity in disease modification. Ann Rheum Dis 2012 May 5.
5. Baraliakos X, Listing J, Rudwaleit M, et al. The relationship between inflammation and new bone formation in patients with ankylosing spondylitis. Arthritis Res Ther 2008;10(5):R104.
6. van der Heijde D, Machado P, Braun J, et al. MRI inflammation at the vertebral unit only marginally predicts new syndesmophyte formation: a multilevel analysis in patients with ankylosing spondylitis. Ann Rheum Dis 2012; 71(3):369-373.
7. Baraliakos X, Heldmann F, Callhoff J, et al. Which spinal lesions are associated with new bone formation in patients with ankylosing spondylitis treated with anti-TNF agents? - a long-term observational study using magnetic resonance imaging and conventional radiography. Ann Rheum Dis 2013; accepted for publication.
8. Chiowchanwisawakit P, Lambert RG, Conner-Spady B, et al. Focal fat lesions at vertebral corners on magnetic resonance imaging predict the development of new syndesmophytes in ankylosing spondylitis. Arthritis Rheum 2011; 63(8):2215-2225.
9. van der Heijde D, Burmester G, Melo-Gomes J, et al. Inhibition of radiographic progression with combination etanercept and methotrexate in patients with moderately active rheumatoid arthritis previously treated with monotherapy. Ann Rheum Dis 2009;68(7):1113-1118.
10. van der Heijde D, Landewe R, Baraliakos X, et al. Radiographic findings following two years of infliximab therapy in patients with ankylosing spondylitis. Arthritis Rheum 2008;58(10):3063-3070.
11. van der Heijde D, Salonen D, Weissman BN, et al. Assessment of radiographic progression in the spines of patients with ankylosing spondylitis treated with adalimumab for up to 2 years. Arthritis Res Ther 2009;11(4):R127.
12. Haroon N, Inman RD, Learch TJ, et al. The Impact of TNF-inhibitors on radiographic progression in Ankylosing Spondylitis. Arthritis Rheum 2013 Jul 1.
13. Braun J, Baraliakos X, Hermann KG, et al. The effect of two golimumab doses on radiographic progression in ankylosing spondylitis: results through 4 years of the GO-RAISE trial. Ann Rheum Dis 2013 May 3.
14. Poddubnyy D, Haibel H, Listing J, et al. Baseline radiographic damage, elevated acute-phase reactant levels, and cigarette smoking status predict spinal radiographic progression in early axial spondylarthritis. Arthritis Rheum 2012;64(5):1388-1398.
15. Baraliakos X, Listing J, Haibel H, et al. The significance of vertebral erosions associated with spinal inflammation in patients with ankylosing spondylitis as identified by magnetic resonance imaging and the changes observed after 2 years of anti-TNF therapy J Rheumatol 2013; accepted for publication.
16. Baraliakos X, Listing J, Brandt J, et al. Clinical response to discontinuation of anti-TNF therapy in patients with ankylosing spondylitis after 3 years of continuous treatment with infliximab. Arthritis Res Ther 2005;7(3):R439-444.
17. Diarra D, Stolina M, Polzer K, et al. Dickkopf-1 is a master regulator of joint remodeling. Nat Med 2007;13(2):156-163.
18. Appel H, Ruiz-Heiland G, Listing J, et al. Altered skeletal expression of sclerostin and its link to radiographic progression in ankylosing spondylitis. Arthritis Rheum 2009;60(11):3257-3262.
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