Dear Editor,

With interest we read the article by Allanore et al. on three patients with polymyositis (PM) and one with dermatomyositis (DM) in whom myocarditis was diagnosed and the therapeutic effect of immunosuppressants monitored by contrast enhanced cardiac MRI (cMRI) [1]. The report raises the following questions and concerns: Cardiac involvement in DM/PM has been repeatedly described and usually remains asymptomatic [2,3,4]. The most frequent symptomatic manifestations are arrhythmias, myocarditis, or arteritis [3,5,6,7]. Rare cardiac manifestations are heart failure [2], pericarditis [4], pericardial tamponade [6], restrictive cardiomyopathy [8], or pulmonary hypertension [3].

Did the authors observe cardiac manifestations other than myocarditis in their four patients? Was ST-segment elevation and septal hypokinesia in patient 2 and mitral insufficiency in patient 3 attributable to DM/PM? Diagnosis of myocarditis is a challenge and relies on the determination of CK, CK-MB, gallium citrate or indium labeled anti-myosin antibodies, ECG, AECG, echocardiography, and myocardial biopsy. A further possible tool may be myocardial scintigraphy [9]. Which is the evidence that the described abnormalities indeed represent myocarditis due to DM/PM? The references given only refer to viral myocarditis but not to DM/PM. Was the cMRI diagnosis confirmed by any of the conventional diagnostic techniques? Were CK-MB values elevated in any of the 4 patients? Was coronary angiography carried out in any patient to confirm possible vasculitis? Was endomyocardial biopsy carried out in any of the four patients?

How to explain that all four patients had evidence of myocarditis although myocarditis can be found in only 30% of the DM/PM patients at autopsy [10]? According to the results, two patients reported cardiac symptoms. In table 1, however, all four patients are mentioned to have had cardiac symptoms. It has been also reported that the cardiac BMIPP SPECT may be positive in myocarditis in DM/PM [11].

Regions with reduced tracer uptake relate to wall motion abnormalities. Were such investigations carried out in any of the four patients to confirm the cMRI findings? How to explain that patient four, who had the largest myocardial area affected in the anteroseptal wall on cMRI did not show any abnormality on echocardiography or ECG. Did he have elevated CK-MB or troponin T levels? Did all patients undergo muscle biopsy, to which degree were patients affected neurologically, and were the neurological abnormalities related tot the cardiac abnormalities? DM/PM is frequently associated with malignancy [12].

Was DM/PM in any of the four patients a paraneoplastic phenomenon? Regarding figure 1 it seems that both images represent different image planes and are thus not comparable with regard to the therapeutic effect of corticosteroids. Although contrast cMRI may have a potential to support the diagnosis of myocarditis in DM/PM this technique has to be compared with a golden standard for diagnosing myocarditis, like endomyocardial biopsy, before finally assessing its value in the diagnosis of myocarditis in DM/PM. As long as the sensitivity and specificity remains unknown, cMRI can not be recommended as a tool for diagnosing or or monitoring treatment of myocarditis in DM/PM.

References

1 Allanore Y, Vignaux O, Arnaud L, Puechal X, Pavy S, Duboc D, Legmann P, Kahan A. Effects of corticosteroids and immunosuppressors on idiopathic inflammatory myopathy related myocarditis evaluated by magnetic resonance imaging. Ann Rheum Dis 2006;65:249-52.

2 Cuny C, Eicher JC, Collet E, Chatard C, Chauffert B, Lorcerie B, Martin F, Wolf JE, Louis P. Dilated cardiomyopathy disclosing dermatopolymyositis. Management. Ann Cardiol Angeiol (Paris) 1993;42:155- 8.

3 Lundberg IE. Cardiac involvement in autoimmune myositis and mixed connective tissue disease. Lupus 2005;14:708-12.

4 Tami LF, Bhasin S. Polymorphism of the cardiac manifestations in dermatomyositis. Clin Cardiol 1993;16:260-4.

5 Alyan O, Ozdemir O, Geyik B, Demirkan D. Polymyositis complicated with complete atrioventricular block - a case report and review of the literature. Angiology 2003;54:729-31.

6 Pereira RM, Lerner S, Maeda WT, Goldenstein-Schainberg C, Cossermelli W. Pericardial tamponade in juvenile dermatomyositis. Clin Cardiol 1992;15:301-3.

7 Vinsonneau U, Delluc A, Bergez C, Caumes D, Talarmin F. Second degree atrioventricular block in mixed connective tissue disease. Rev Med Interne 2005;26:656-60.

8 Finsterer J, Stöllberger C, Avanzini M, Rauschka H: Restrictive cardiomyopathy in dermatomyositis. Scand J Rheumatol 2006;(in press)

9 Buchpiguel CA, Roizemblatt S, Pastor EH, Hironaka FH, Cossermelli W. Cardiac and skeletal muscle scintigraphy in dermato- and polymyositis: clinical implications. Eur J Nucl Med 1996;23:199-203.

10 Lie JT. Cardiac manifestations in polymyositis/dermatomyositis: how to get to the heart of the matter? J Rheumatol 1995;22:809-11.

11 Ito K, Sugihara H, Zen K, Hikosaka T, Adachi Y, Tanabe T, Yoneyama S, Katoh S, Nakamura T, Azuma A. Clinical usefulness of 123I-BMIPP myocardial SPECT in collagen disease. Kaku Igaku 2000;37:327-32.

12 Dalakas MC, Hohlfeld R. Polymyositis and dermatomyositis. Lancet 2003;362:971-82.

Dear Editor,

I read with immense interest the e-letter on the analgesic effect of pamidronate.In fact I have been observing this effect with alendronate for past couple of years. When I prescribe weeky alendronate for my patients who also have rheumatoid arthritis, they come back requesting for the weekly dose to be prescribed daily. The symptom relief however lasts only for the day the dose is administered. In other words even though the effect of weekly alendronate on osteoporosis may last a whole week, the pain relief as well as a feeling of well being and improvement in appetite lasts only for the day it is given.

Dear Editor,

Re: 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. Baraliakos X, Haibel H, Listing J, Sieper J,Braun J. 1doi:10.1136/annrheumdis-2012-202698

I read with interest the findings of an observational cohort study in which patients with ankylosing spondylitis (AS) receiving infliximab (IFX) (n = 22) were compared for radiographic progression over 8 years with a historical cohort (n = 34) naive to anti-tumor necrosis factor alpha therapy (anti-TNF). After adjusting for baseline damage there was no difference between treatment groups over the 0-4 year time frame but a significantly greater rate of progression was evident in the 4-8 year time frame in the historical cohort. The authors then conclude that since there was less bone formation in the IFX treated group, these data argue against a major role for the TNF-brake hypothesis.

The basis for this concluding statement is that the authors interpret the TNF brake hypothesis as implying that the use of anti-TNF agents will accelerate the development of new bone since TNF upregulates dickkopf-1 which, in turn, downregulates Wingless (Wnt) pathway signaling for new bone formation [1]. So by removing TNF, dickkopf-1 also decreases which then allows signaling for new bone formation through the Wnt pathway [2]. This hypothesis was 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) [3].

But what Baraliakos et al misinterpret about the TNF brake hypothesis is that this mechanism was proposed to explain the sequence of events in an established inflammatory lesion where bone formation pathways have already been triggered. Proinflammatory cytokines such as TNF have been shown to stimulate expression of bone forming factors, such bone morphogenetic proteins (BMPs) and Wnt proteins [4]. In a more detailed elaboration of the hypothesis, it was proposed that early inflammatory lesions resolve without sequelae, such as new bone, if effective therapy is instituted and inflammation resolves prior to activation of bone formation pathways by triggers such as TNF [5,6]. If the lesion is advanced and bone formation pathways are entrenched, TNF may well act as a brake on new bone formation acting through dickkopf-1.

We have reported prospective data to support this hypothesis demonstrating that lesions demonstrating inflammation at vertebral corners using short tau inversion recovery (STIR) MRI resolve completely with anti -TNF therapy while more complicated inflammatory lesions, marked by fat metaplasia using T1-weighted MRI, are predisposed to development of new bone even if the inflammation resolves [7]. The average patient with AS recruited to clinical trials of anti-TNF agents will have a mixture of early inflammatory and more advanced inflammatory lesions so the net effect of using an anti-TNF will be no impact on new bone formation when assessed over time frames as short as 2 years. This would explain the lack of impact of anti-TNF therapies on radiographic progression over 2 year time frames [8]. But it was predicted by the TNF brake hypothesis that over longer time frames anti-TNF should reduce new bone formation because treatment will prevent the ongoing development of new anti-inflammatory lesions. Following institution of treatment, all the advanced lesions resolve and then develop new bone. But since new inflammatory lesions are prevented by ongoing anti-TNF therapy, the hypothesis predicts that over longer time frames there should be a divergence in radiographic progression between anti-TNF treated and control patients. This is what Baraliakos et al have now shown.

Consequently, rather than arguing against a role for the TNF brake hypothesis, the data presented by Baraliakos et al actually reinforce its validity. Furthermore, recent data further reinforces its validity by demonstrating that new bone formation is indeed inhibited by anti-TNF therapy provided it is used early in the disease course [9].

References

1. Diarra D, Stolina M, Polzer K, et al. Dickkopf-1 is a master regulator of joint remodeling. Nat Med 2007;13:156-63.

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;60:93-102.

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;38:1349-54.

4. Lories RJ, Luyten FP. Bone morphogenetic proteins in destructive and remodeling arthritis. Arthritis Res Ther 2007;9:207-15.

5. Maksymowych WP. What do biomarkers tell us about the pathogenesis of ankylosing spondylitis? Arthritis Res Ther 2009;11:101-2.

6. Maksymowych WP. Advances in pathogenesis through animal models and imaging. Nature Rev Rheumatol 2013;9:72-74.

7. Maksymowych WP, Morency N, Conner-Spady B, Lambert RG. Suppession of inflammation and effects on new bone formation in ankylosing spondylitis: evidence for a window of opportunity in disease modification. Ann Rheum Dis 2013;72:23-28.

8. 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:R127.

9. Haroon N, Inman RD, Learch TJ, Weisman MH, Lee MJ, Rahbar MH, et al. The impact of TNF-inhibitors on radiographic progression in ankylosing spondylitis. Arthritis Rheum published online DOI 10.1002/art.38070

Conflict of Interest:

None declared

Response to the eLetter by Maksymowych WP, entitled ?Evidence in Support of the Validity of the TNF Brake Hypothesis"

Dear Editor,

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)" [1]. 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 [5], and this finding was confirmed later [2]. 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 [6]. In our most recent paper [7] 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 [7].

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 [1], another very recent one also reported some reduction of syndesmophyte formation [12]. 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 [13]. Factors that predict radiographic progression such as gender, prevalent syndesmophytes and smoking have been described [14] - 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 [1]. 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 [15]. 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 [16]. 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 [17]. 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 [18]. 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) [13]. The finding that resolved but not persistent chronic inflammatory lesions (CILs) are associated with new syndesmophytes [3] 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. [3]. However, on the other hand, our recent data suggest [7], 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.

References

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.

Conflict of Interest:

None declared