Scrutinizing the Perio-Systemic Link?

After rather devastating negative conclusions made in a systematic review (SR) of the literature regarding the long claimed, possibly causal, relationship between periodontitis and atherosclerotic vascular disease by Lockhart et al. (2012), a highly alerted group of members of our specialty organizations, the Amercian Academy of Periodontology and the European Federation of Periodontology, had hastily organized a joint workshop, in the end of 2012, to fix unwelcome results of a number of large intervention studies by creating new systematic reviews on the Perio-Systemic link. The clear aim was to cement, once and forever, the claim of the number one clinical problem: periodontal disease and general health are closely related.

While the proceedings had been published, open access, in special issues of our main professional journals, the Journal of Clinical Periodontology and the Journal of Periodontology, workshop participants of the EFP presumptuously condensed the 209 pages of the 16, mostly valuable, papers in a nutshell, strangely called Manifesto.

According to Wikipedia, a manifesto is “a published verbal declaration of the intentions, motives, or views of the issuer, be it an individual, group, political party or government.”

A manifesto usually accepts a previously published opinion or public consensus or promotes a new idea with prescriptive notions for carrying out changes the author believes should be made. It often is political or artistic in nature, but may present an individual’s life stance. Manifestos relating to religious belief are generally referred to as creeds [sic].

It is, of course, the political intention which matters. Who could ever challenge our thought leaders’ Manifesto?

Well, a so far unknown dental practitioner, who seems to work in Suffolk, England, UK, at least attempted to scrutinize the link between periodontal disease and systemic conditions asking the question, “Does recent evidence continue to support the European Federation of Periodontology’s 2012 Manifesto?” According to his current employer’s web page, it seems so that Dr. Watts is not even a specialist; scroll down to find his name and credentials under Dentists. His “Guest Editorial” is published in a recent issue of the Journal of the International Academy of Periodontology. In fact, one has to scrutinize rather what Dr. Watts concluded.

Let’s start with diabetes. Dr. Watts correctly quotes the Manifesto’s line of evidence as regards intervention studies.

Randomised clinical trials consistently demonstrate that mechanical periodontal therapy associates with approximately a 0.4% reduction in HbA1C at 3-months, a clinical impact equivalent to adding a second drug to a pharmacological regime for diabetes.

There are a few questionable statements and omissions here. First, the claim is apparently based on patients with both periodontitis and diabetes. But this may not apply to patients with gingivitis or mild periodontitis when “mechanical” treatment may be indicated as well. Mechanical periodontal therapy won’t lead to anything if periodontitis had not developed to the extent of a systemic inflammatory response, one important issue of possible plausibility  as regards much of the Perio-Systemic link. This is also mentioned in the Manifesto’s first paragraph as regards diabetes mellitus. Then, as we will see below, stressing numerical values in a manifesto appears to be highly problematic as further research may easily lead to higher or lower average values. The Manifesto mentions consistent reduction of 0.4% HbA1c on average at three months which may mean an equivalent of an additional drug in a pharmacological regime. But what is more important in the prevention of diabetes and treatment of diabetics is weight loss, exercise, healthy diet. No word on that in the Manifesto. And finally, if the effect of scaling was not long-lasting, what’s the meaning of making a big issue of it?

When the EFP Manifesto was formulated, there were only a few small, mostly low quality, mainly single-center randomized controlled trials (RCTs) available which had been systematically reviewed by Engebretson and Kocher (2013). Dr. Engebretson himself and a large number of co-authors had just completed the so far largest, multicenter study on the effect of non-surgical periodontal treatment on HbA1c, an important marker for diabetic control, in which more than 500 patients had been randomized. The data were due to be published but not included in the SR by Engebretson and Kocher.

When Engebretson et al. finally published their data in 2013 in JAMA, conceding that they had been unable to achieve any effect of nonsurgical periodontal therapy on HbA1c levels in diabetic patients with periodontitis, our thought leaders’ outcry was loud and angry. Undisputed, the paper, after all the first definitive RCT, had some serious limitations. After letters to the JAMA editors had been published, all culminated in a statement and special advise by each and every editor of our professional journals, presidents of our societies and other interested celebrities, altogether 21 authors led by Dr. Wenche Borgnakke at the University of Michigan, Ann Arbor (Borgnakke et al. 2014).

Given the inconlusive nature of these data [of the study by Engebretson et al. 2013], we recommend that the existing body of evidence in which meta-analyses consistently conclude that successful periodontal therapy appears to improve glycemic control, should instruct us until results from future studies are reported. We urge all interested parties to refrain from using  this study results as a basis for future scientific texts, new research projects, guidelines, policies, and advice regarding the incorporation of necessary periodontal treatment in diabetes management.” (Emphasis added.)

A case of attempted censorship and clearly academic misconduct. I have written about the “Engebretson scandal” which has exposed the questionable political agenda of our thought leaders many times on this blog, see, for example, here and here.

Including Engebretson’s data in a new systematic review would not only drastically lower the 0.4% HbA1c reduction claim in the EFP Manifesto but also that of “consistency” of observations in the numerous small-scale and poorly designed single-center studies. Including the large-scale muticenter RCT would add significant heterogeneity with a need to downgrade the alleged evidence. A likely disaster in future debates with diabetologists who have to be convinced to spread the information among our medical colleagues that periodontal treatment of diabetic patients was of utmost importance in diabetic control. A similarly disastrous effect actually had negative conclusions of the above mentioned systematic review by Lockhart et al. (2012) on periodontal disease as a possible causal factor of atherosclerotic vascular disease after which medical professionals had obviously lost interest in periodontics.

So, the brazen but desparate attempt by Borgnakke et al. (2014) to censor unwelcome results of Dr. Engebretson’s RCT had a reason. It was in vain, though.

In November 2015, the Cochrane Collaboration published an updated systematic review on the subject (Simpson et al. 2015). I had reported on Simpson’s report here. In essence, this is the most comprehensive SR on the effects of periodontal therapy on HbA1c levels in diabetic patients with periodontitis so far. These authors discussed, in some detail, why they had included the large RCT by Engebretson et al. (2013) in their considerations. In their several meta-analyses they calculated an average 0.29% HbA1c reduction 3 months after scaling and root planing was completed (95% confidence interval -0.10; -0.48%). There was significant heterogeneity present and, after 6 months, no significant reduction of HbA1c was any longer noticeable.

But Dr. Danny Watts from Suffolk does not mention the most comprehensive systematic review so far (Simpson et al. 2015) when “scrutinizing” the link between periodontitis and diabetes in his respective Table 1 which compiles results of 6 new SRs, published after the EFP Manifesto had been formulated. In the text of his “Guest Editorial, Dr. Watts mentions that there was “[o]nly one systematic review (Wang et al. 2014a) [which] found that non-surgical periodontal treatment did not significantly improve glycaemic control in type 2 diabetics, however it included just three studies (n=143) in its meta-analysis.” He missed that Wang et al. (2014) had compared additional systemic doxycline to mechanical periodontal therapy. Wang et al. (2014) actually concluded that “adding doxycycline to periodontal therapy with SRP [scaling and root planing] does not significantly improve metabolic control in patients with T2DM and chronic periodontitis.” Conspiciously, two further systematic reviews of systematic reviews of studies on the effect of periodontal treatment on markers of diabetic control had very recently been published (Botero et al. 2016, Faggion et al. 2016). Both erroneously include Wang et al. (2014). Had Dr. Watts been inspired by these two reports?

Two systematic reviews (Li et al. 2015, Wang et al. 2014b) listed by Dr. Watts in his Table 1 had actually included Engebretson’s results which, not surprisingly, increased dramatically the “sample sizes”. Their point estimates of HbA1c in respective meta-analyses were considerably smaller than the EFP Manifesto’s claim of 0.4% HbA1c reduction. However, the Cochrane review (Simpson et al. 2015) included altogether 14 RCTs (1499 participants) in the respective meta-analysis making it the most comprehensive SR so far. Their point estimate was a 0.29% reduction (-0.10; 0.48%) of HbA1c 3 months after non-surgical periodontal therapy. Albeit significant, considerable heterogeneity and high risk of bias led to downgrading the quality of the evidence to low. So, “further research is very likely to have an important impact on the confidence in the estimate of effect and is likely to change the estimate.”

Dr. Watts concludes his section on the EFP’s Manifesto’s claim on diabetes,

The improvement in glycaemic control is consistently reported after three months. After six months, the results from systematic reviews are inconclusive, … . On the whole, the merits of the EFP manifesto relating to diabetes mellitus remain well supported by the recent systematic reviews.

That may well be questioned. As seen, the estimate of the latest thorough Cochrane review (not even mentioned in Dr. Watts’ “Guest Editorial”), is 27% lower than the claimed 0.4% HbA1c reduction. Furthermore, the observations are not consistent as heterogeneity of studies was significant. And, there is high risk of bias, all of which led to low quality evidence only.

So, if the whole idea of a “Manifesto” is not being abandoned, it needs an update in this regards.

It would have been mandatory for Dr. Watts to adopt or at least discuss the conclusion of the most recent, largest SR of the Cochrane Collaboration, rather than to parrot what has been reported in a surge of questionable SRs on the issue, mainly with considerable overlap of RCTs considered. It would have been appropriate for the Editor of the Journal of the International Academy of Periodontology, Professor Mark R. Patters, to honestly guide his young practitioner colleague when asking him for a “Guest Editorial” in his journal.

A few remarks as regards Dr. Watts’ further conclusions. Next, he addresses another claim of the EFP Manifesto:

There is moderate evidence that periodontal treatment reduces systemic inflammation as evidenced by reductions in C-reactive protein (CRP) and oxidative stress, and leads to improvements of clinical and biochemical measures of vasuclar endothelial function.”

Apart from inconsistency of these results, what has so far mostly been ignored is the observation made in some intervention studies. They were pointed out by Lockhart et al. (2012):

Available data indicate a general trend toward a periodontal treatment–induced suppression of systemic inflammation and improvement of noninvasive markers of ASVD [atherosclerotic vascular disease] and endothelial function. The effects of PD [periodontal disease] 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. [Emphasis added.]

Well, when one considers longstanding bacteremia in periodontitis patients as utmost important in the development of atherosclerotic lesions (as has been suggested for a couple of years as a plausible reason for the observed association),  “intensive therapy” of periodontal disease, meaning subgingival scaling and root planing, would put any patient at further risk for having cardiovascular problems. As far as I know, respective undesired side effects of periodontal treatment have never been systematically examined.

In Table 2 of his “Guest Editorial”, where six “systematic studies” examining the association of periodontal disease, or the effect of non-surgical treatment, on the biomarkers of cardiovascular disease are listed, Dr. Watts, in his “Guest Editorial” confuses his readers by reporting the results of a recent meta-analysis of cross-sectional studies by Zeng et al (2016), who calculate, after adjustment for smoking and diabetes, a slightly positive (irrelevant) association between periodontal disease and carotid atherosclerosis (odds ratio 1.08; 95% confidence interval 1.00; 1.18). Dr. Watts erroneously reports this finding as if it was observed after non-surgical periodontal therapy. He stresses that so far only biomarkers are chosen as endpoints in intervention studies and that no definitive study had been performed to assess the effect of periodontal therapy on cardiovascular events. In fact, there exists a notorious pilot study by Offenbacher et al. (2009), the PAVE study, with severe design problems and inconclusive results. According to Dr. Watts, the EFP Manifesto’s claim for biomarkers and endothelial function therefore still holds. However, given the inconsistency of observations (heterogeneity) and high risk of bias, the quality of the evidence should rather be regarded low. And, it is high time to start studying adverse effects of periodontal therapy (“transient proinflammation and deranged endothelial function”) more seriously.

An honest update of the EFP Manifesto would include these issues.

The next topic in Dr. Watts’ “Guest Editorial” addresses adverse pregnancy outcomes. The EFP manifesto states:

Results from clinical trials have shown that, in general, scaling and root planning [sic] carried out during the second trimester of pregnancy, with or without antibiotic therapy, does not significantly improve adverse pregnancy outcomes, such as preterm birth and low birth weight. However, some clinical trials did report a favourable effect overall and it is possible that certain populations of pregnant women may benefit from periodontal therapy, even though others will not. One reason for negative study results may be that the interaction between periodontitis and pregnancy outcomes is more complex than our current understanding and the study results may have been affected by the type and timing of treatment employed and by the types of patients selected.

Dr. Watts concludes, after referring to mainly two recent SRs by Lopez et al. (2015) and Schwendicke et al. (2015), that the first part of the above statement still holds (“does not significantly improve adverse pregnancy outcomes”) but that evidence is lacking for the second part (“it is possible that certain populations of pregnant women may benefit from periodontal therapy”). Very recently, a Cochrane review had been published on the issue (Iheozor-Eijofor et al. 2017) which again highlights that

[i]t is not clear if periodontal treatment during pregnancy has an impact on preterm birth (low-quality evidence). There is low-quality evidence that periodontal treatment may reduce low birth weight (<2500 g), however, our confidence in the effect estimate is limited. There is insufficient evidence to determine which periodontal treatment is better in preventing adverse obstetric outcomes. Future research should aim to report periodontal outcomes alongside obstetric outcomes.

So, it might be considered questionable to keep anything in this regard in an update of the Manifesto.

Dr. Watts also addresses, and provides new data since 2012 for, a couple of “other diseases” such as chronic obstructive pulmonary disease, chronic kidney disease, obesity and metabolic syndrome, cognitive impairment, even obstructive sleep apnoea, which was not mentioned in the EFP Manifesto. All of these had been associated with periodontitis. What is missing is an update on the meanwhile well-established association of periodontal disease with all kinds of (smoking-related) cancer, in particular lung cancer, pancreas cancer, and breast cancer; be it real or due to incomplete confounder adjustment. It remains highly unlikely that cancer can be prevented by periodontal therapy, though.

In conclusion, careful reading this “Guest Editorial” comes to a much more sober conclusion. Having been a simple message for couple of years, mainly for political reasons and, in particular, for practitioners, the Manifesto’s authors should honestly assess whether certain claims, if made cautiously, that periodontal treatment may actually result in better general health still hold. The picture is far more complicated than previously believed.

3 August 2017 @ 11:14 am.

Last modified August 4, 2017.

 

 

 

 

 

 

 

 

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