Visions, Illusions, Animations

It is remarkable that the prestigious Journal of Clinical Periodontology, founded by Hans Mühlemann and edited for decades by Jan Lindhe, is going to publish a commercial for a Quintessence Publishing and Sunstar production, part of a Quintpub series of DVDs (all called Cell-to-Cell Communication) of short (each runs for about 15 minutes) animated (“3D”) movies. The first installations in this series had been about inflammatory reactions in the periodontium (I had critically reported on its educational value here), periodontal regeneration and osseointegration.

The “Guest Editorial [in JCP] Science transfer” advertising the upcoming release of a new movie on “Oral Health and General Health – the Links between Periodontitis, Atherosclerosis, and Diabetes” by Søren Jepsen, Bernd Stadlinger, Hendrik Terheyden and Mariano Sanz just went online. Still, the movie, which had its “world premiere” at EuroPerio 8 in London, is not available. Its trailer can be found on the EFP webpage, though. Its “storyboard” (the publisher apparently likes to emulate credits in Hollywood movies as “actors” cells, hormones and cytokines are listed) had been published in the German Dental Association’s Zahnärztliche Mitteilungen. For the majority of rather uncritical dentists, even the trailer (the full movie is to be published early next year) might suggest that periodontitis is causally implicated in myocardial infarction, a fearmongering and irresponsible claim as long as established risk factors for cardiovascular disease as high blood pressure, high cholesterol, smoking, unhealthy diet, obesity, lack of physical activity, and diabetes, are just ignored.

No evidence for causal relationship between periodontal disease and atherosclerotic vascular disease

Let’s limit the following to the above claim. In April 2012, a scientific statement of the American Heart Association was published in Circulation. The question was, “Periodontal Disease and Atherosclerotic Vascular Disease: Does the Evidence Support an Independent Association?” Lockhart et al. (2012) summarize their 25 printed pages article as follows.

The relation between PD [periodontal disease] and ASVD [atherosclerotic vascular disease] is potentially of great public health importance because of their high prevalence. Extensive review of the literature indicates that PD is associated with ASVD independent of known confounders. This information comes mostly from observational studies, however, and therefore does not demonstrate that PD is a cause of ASVD, nor does it confirm the contention that therapeutic periodontal interventions prevent heart disease or stroke or modify the clinical course of ASVD. Although a contribution of PD to ASVD is biologically plausible, periodontal and cardiovascular diseases share multiple risk factors that are prevalent and powerful promoters of disease, including tobacco use, diabetes mellitus, and age.

[…]

Available data indicate a general trend toward a periodontal treatment-induced suppression of systemic inflammation and improvement of noninvasive markers of ASVD and endothelial function. The effects of PD therapy on specific inflammatory markers are not consistent across studies, and their sustainability over time has not been established convincingly, however, and determinants of variability in these responses remain poorly understood. In addition, transient proinflammation and deranged endothelial functions are observed after intensive therapy for PD.

This review highlights significant gaps in our scientific understanding of the interaction of oral health and ASVD. Identification of clinically relevant aspects of their association or therapeutic strategies that might improve the recognition or therapy of ASVD in patients with PD would require further study in well-designed controlled interventional studies. Such investigations should reflect the longitudinal effectiveness of different approaches to managing periodontal health, given the possibility of PD recurrence after therapy and the extended time course of evolution of ASVD and its manifestations. Uniform criteria for PD case definitions, extent, and severity; standardized treatment protocols; and consideration of time course, important confounders, and effect modifiers on the association of PD and ASVD would also improve future studies. Finally, the implications of the observed transient detrimental effects of PD therapy on markers of inflammation and endothelial function should be clarified. In the meantime, statements that imply a causative association between PD and specific ASVD events or claim that therapeutic interventions may be useful on the basis of that assumption are unwarranted. (Emphasis added.)

In particular the last sentence is enlightening as the medical profession appears to have finally reacted to unwarranted claims made by the periodontal community for, say, 25 years. The statement was made on behalf of the American Heart Association (AHA) Rheumatic Fever, Endocarditis, and Kawasaki Disease Committee of the Council on Cardiovascular Disease in the Young, Council on Epidemiology and Prevention, Council on Peripheral Vascular Disease, and Council on Clinical Cardiology. The World Heart Federation endorsed it and the American Dental Association Council on Scientific Affairs explicitly concurred with conclusions of this report.

Nevertheless, an outcry among American and European periodontists indicated that the above conclusions were not really welcome. I have reported about that on this blog, see here. Two authors of the statement, Panos Papapanou and Maurizio Trevisan, were even asked by the Journal of the American Dental Association for an editorial in which they apparently downplayed the last sentence of the above quote. The EFP and AAP immediately decided to hold a joint workshop later in 2012, certainly in an attempt to challenge and amend Lockhart’s conclusions with an even broader perspective about periodontal disease and systemic health in general. A close look at the numerous systematic reviews which had been produced ahead of the workshop reveals, however, that there was not so much new. Yes, there is evidence from various research endeavors, but rather small effects may not be relevant. And, what has never been addressed: despite the fact that periodontal treatment might improve vascular functions in the long run, there are detrimental if transient effects in this regard short-term.

After having had read Lockhart’s review, I had forecast that cardiologists would finally lose any interest in periodontal disease. It had been dampened already in 2009 when the US Preventive Services Task Force had recommended not to screen asymptomatic subjects with no history of coronary heart disease for non-traditional risk factors such as periodontitis to prevent respective events.

On animating an obsessive claim despite lack of evidence for causality

Back to the advertising guest editorial in JCP. Jepsen et al. open their editorial with,

The transfer of knowledge from research and academic communities to clinical practice presents an enormous challenge. This is particularly true for when attempting to convey the clinical relevance and implications of laboratory-based research.

It is even more important to inform the interested public about the low level of evidence emerging from laboratory-based research, so-called mechanistic knowledge. Evidence-based medicine is mainly based on randomized clinical trials and prospective cohort studies, and whatever has been found in cell cultures and animals, however enthralling, may only serve for the formulation of new hypotheses, not more. Jepsen et al. claim that one of the November 2012 “landmark” consensus workshop’s purposes was to pay attention to “the biological mechanisms underpinning the proven epidemiological associations between oral and systemic diseases.” But when these associations are in fact moderate at best, and intervention (i.e. treatment of periodontitis) does not result in beneficial effects of a magnitude which can be regarded clinically relevant, then well-formulated hypotheses based on laboratory and animal research may be meaningless. And not worth of being touted to an ultimately bored public.

Despite of having been quoted 312 times (according to Google Scholar) since 2012, the American Heart Association’s assessment (see above) on the relationship between periodontitis and atherosclerotic vascular disease by Lockhart et al. (“statements that imply a causative association between PD and specific ASVD events or claim that therapeutic interventions may be useful on the basis of that assumption are unwarranted”) has either largely been ignored by our rather patronizing periodontal scientific leadership or reconstrued by two of its very authors, periodontists of course. It seems as if there was a similar clandestine agreement among our “thought leaders” not to mention undesired opinions, however well-founded on sound evidence, and results anymore as in the recent Engebretson case.

Recently, Papapanou (2015) tried again to abrogate Lockhart’s conclusions with which he, a coauthor of the statement, was apparently uncomfortable.

Viewed collectively, the preponderance of evidence from both mechanistic studies and human epidemiological data corroborate the view that periodontitis acts as a biologically plausible risk factor. Indeed, after reviewing the available evidence, the scientific statement of the American Heart Association clearly stated that ‘observational studies to date support an association between periodontitis and ASVD independent of known confounders’[48]. Although the possibility that so far unrecognised confounders (for example, genetic predispositions that affect both periodontitis and ASVD) cannot be ruled out, the current interpretation is that periodontitis constitutes a systemic inflammatory stressor that contributes to increased risk for ASVD. Unfortunately, instead of concentrating on this important message, disproportionate attention of the public and the press focussed on a subsequent statement of the same publication [by Lockhart et al.] that read ‘They do not, however, support a causal relationship’, which is a less meaningful proposition for the reasons explained above.

But that’s it all about. Papapanou argues that there is no single cause for any disease (with one notable exception, genetically conferred Mendelian diseases), which is of course true; and that systemic inflammation, to which periodontitis might contribute, in fact increases the risk for atherosclerotic vascular disease. He further stresses that “the quoted lack of evidence [for a causal relationship] reflects the fact that the appropriate studies (i.e. RCTs examining the effect of periodontal interventions on ASVD-related clinical events) have not been conducted. It does not imply that there is evidence demonstrating that periodontal interventions are ineffective in preventing/ameliorating ASVD.” But the PAVE pilot study had revealed inconclusive results which led to termination of funding, and for good reason. One must not design intervention studies with however desired but unlikely outcomes, when hundreds if not thousands of periodontitis patients have to be randomized and half of them proper periodontal treatment withheld for prolonged periods of time. And furthermore, one has to see these studies critical as long as it seems to be unclear whether the intervention itself may comprise risks, short-term or longer, for undesired effects on vascular function, see above.

When Papapanou (2015) concludes,

It would be unfortunate if the misinterpretations of the current state of evidence discussed above, in combination with the understandable reluctance of funding agencies in the aftermath of expensive negative trials[57, 74, 76, 83], would result in abandoning this challenging, but utterly important, research topic before it is fully and adequately investigated. Risk is a continuous, not a dichotomous, concept [sic]; periodontitis is an inflammatory stressor with potential impact on several body systems; and a plethora of interesting questions remain unanswered,

his reasoning may be utterly circular and contains misinterpretations as well. The observed, if at all moderate, increase of risk for cardiovascular events in periodontitis patients which may or may not be due to still unknown confounders should, and largely negative outcomes of expensive intervention studies must, end the story, at least for the time being, however fascinating laboratory research and that in experimental animals would be for scientists. In this connection, the upcoming JCP commercial editorial by Jepsen et al., which ignores sober conclusions of the AHA paper (Lockhart et al. 2012) but carries the idea further based on an older and more enthusiastic review (as assumed from the title which seemingly quotes a Motown pop song by Martha Reeves) by Kebschull (2010), explains what might be an illusion.

Jepsen et al. by quoting, among others, systematic reviews prepared on the occasion of the joint EFP/AAP workshop in 2012 emphasize that periodontal bacteria inevitably enter the circulation during normal oral function. They refer to in vitro observations which may suggest that periodontal bacteria can invade the endothelial lining cells of blood vessels, can induce atherosclerosis in animal models of disease, and also that the host’s inflammatory-immune response favors atheroma formation, maturation and exacerbation. Recent comprehensive studies of metagenomes from human atherosclerotic plaque samples yield a very complex picture, though. Contrary to common believes, the most abundant species in both asymptomatic (i.e. stable) control and symptomatic atherosclerotic plaque samples was Lactobacillus rhamnosus, a probiotic. While Helicobacter pylori (having long, and probably erroneously, been implicated in cardiovascular disease) ranked fourth in abundance of symptomatic samples, a typical periodontal pathogen, Porphyromonas gingivalis, was not among the 25 most abundant species but was present mainly in asymptomatic atheromas. As Mitra et al. write, “asymptomatic atherosclerotic plaques have more abundance of host microbiome-associated microbial families such as Porphyromonadaceae, Bacteroidaceae, Micrococcaceae, and Streptococcaceae” than symptomatic atherosclerotic plaques.

This result suggests that these host microbiome-associated microbial families are one of the first colonizers of the arteries. These early colonizers might support the growth of sulfur-consuming families such as sulfur-oxidizing symbionts and Thiotrichaceae [13] and pathogens such as Helicobacteraceae and Neisseriaceae, which were found to be abundant in the symptomatic atherosclerotic plaques.

[…]

Some of the infectious agents that are most prevalent in our symptomatic atherosclerotic samples, e.g., Acinetobacter, Acidovorax, and N[eisseria] polysaccharea have not been reported previously. FISH [fluorescence in situ hybridization] observation validated the presence of biofilm-like structures of these pathogens in the symptomatic atherosclerotic plague [sic] samples (Fig. 7).

Fig. 7 FISH images of Acidovorax spp. and H. pylori in atherosclerotic plaque samples. Representative results of plaque samples after applying the Acidovorax spp.-specific probe (a), H. pylori-specific probe (b), as well as two negative control probes, i.e., Candidate division TM7 (c), and Paracoccus spp. (d), on atherosclerotic plaque material from several different patients. We observed morphogically distinct clusters of Acidovorax spp. and H. pylori cells surrounded by atherosclerotic tissue material (Mitra et al. 2015)

Fig. 7
FISH images of Acidovorax spp. and H. pylori in atherosclerotic plaque samples. Representative results of plaque samples after applying the Acidovorax spp.-specific probe (a), H. pylori-specific probe (b), as well as two negative control probes, i.e., Candidate division TM7 (c), and Paracoccus spp. (d), on atherosclerotic plaque material from several different patients. We observed morphogically distinct clusters of Acidovorax spp. and H. pylori cells surrounded by atherosclerotic tissue material (Mitra et al. 2015)

Mitra et al. indeed found certain periodontal pathogens, for instance, P. gingivalis (mainly in asymptomatic atheromas), but in low abundance. In particular when compared to the abundance of organisms which have not been probed so far. Obviously, speculating, based on a very much limited number of selected probes, about the possible roles of P. gingivalis and other periodontal pathogens in atherogenesis or the destabilization of atheromas strongly resembles entertaining a house of cards.

In their advertorial, Jepsen et al. claim “potential benefits of periodontal treatment on systemic health.” In the absence of respective definitive studies, they have to refer to surrogate markers of systemic inflammation, such as hsCRP, not atherosclerotic events. As surrogate markers have been shown to actually deteriorate after periodontal treatment (before improving later-on), and as the circulation is in fact flooded by periodontal bacteria during subgingival scaling, a key point is apparently missing here: Are there any serious adverse effects of periodontal treatment as regards cardiovascular disease? So far, they have not been reported. But has anybody looked at the possibility?

Finally, one has to carefully consider the wording of the “Conflict of interest and Source of Funding” statement by Jepsen et al. 2015) as well.

The authors do not declare [sic] any conflict of interest with regard to the promotion of the scientific content of the joint EFP/AAP workshop on “Periodontal and Systemic Diseases” by this project. Funds for the production of the educational film and its dissemination were provided by educational grants from Quintessence and Sunstar.

Well, they might not be able to declare that there were no conflicts of interest as regards the promotion of a commercial DVD by Quintessence/Sunstar. The authors thank, among many others, Dr. Alexander Ammann, CEO at QuintPub, for his vision.

See a very usefull glossary of causality in public health science by Mervyn Susser here.

28 December 2015 @ 10:16 am.

Last modified January 5, 2016.

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