The 5-year results of patients treated for degenerative sacroiliitis and/or SI joint disruptions with MIS SI joint fusion using a series of triangular TPS coated implants presented herein demonstrate the long-term durability of positive outcomes regarding pain relief, return to function, and satisfaction with surgery.

Though pre-operative ODI scores were unavailable for the current case series, the published range for patients with SI joint disorders is 52.6-61.8 [23, 24, 31].

Our mean 5-year postoperative ODI score (21.5) indicates minimal to moderate impact on functional capacity, and is commensurate with results from other published studies.

Long-term complications of MIS SI joint fusion were rare.

No subject underwent revision of SI joint arthrodesis.

Similar to other reports, a large portion (47%) of patients in the present cohort had a history of previous lumbar spinal fusion.

In contrast to a report describing the use of hollow modular anchorage screws, the degree of pain improvement for patients in the current study was not affected by a history of prior lumbar spinal fusion [19].

As with all studies, we observed variations in patient outcomes.

In the current cohort, the number of pain generators, either single or multiple, influenced patient perception of improvement in pain and function after surgery.

Amongst subjects who did not respond, multiple pain generators (PG) were apparent.

Determination of primary versus secondary pain generators is critical in patients that present with multiple PGs.

Imaging studies at 5 years postoperatively revealed no evidence of implant loosening, confirmed by a consistent observation of increased bone density immediately adjacent to all walls of all implants, suggestive of biological fixation in bone.

The cause of the sclerotic bony margin often observed on the upper wall of the most cranial implant is unknown, but may be the result of a) impaction from broaching step of the procedure, b) micromotion after initial implant placement, or c) as a result of Wolff’s law in response to higher loading conditions.

Further investigation is needed to fully understand the mechanism.

After close evaluation of the appearance of the implants on plain film radiographs and CT imaging, we have come to appreciate the difference between lucency along an implant wall and actual loosening of the device.

An observation of apparent linear lucency along the wall, nose or shoulder of the implant on x-ray did not correlate with true lucency on CT in the present study, but rather with an artifact generated by the titanium implant.

In our experience, true loosening of the implant will result in the appearance of an enlarged gap between the implant and a sclerotic margin on both x-ray and CT (Fig. 7).

If implant loosening is suspected, it is vital to correlate clinical symptoms with 3 views on CT to differentiate artifact, lucency and loosening.


Multiple non-surgical and surgical treatments for SI joint disorders are available.

When non-surgical management fails to provide adequate relief of symptoms, surgical arthrodesis is an option.

Published case series of various arthrodesis techniques (both open and MIS) report variable degrees of improvement in pain and function, with more invasive approaches reporting moderately high complications and non-unions [22].

MIS techniques overall report significant improvements in pain and function, but results vary with surgical technique and patient selection.

Positive clinical outcomes are based on accurate diagnosis and assessment of all potential pain generators in the lumbar spine, SI joint and hip.

Correctly diagnosing SI joint disorders requires a rigorous approach to arrive at an accurate diagnosis.

A detailed history, comprehensive physical examination, and an index of suspicion are required to formulate a differential diagnosis.

The practitioner utilizes imaging and diagnostic testing for the process of inclusion/exclusion of the different diagnostic possibilities.

Several pathophysiologic conditions that affect the lumbar spine-SI joint-hip axis can present similarly and typically low back pain patients have multiple pain generators.

Biomechanical studies clearly show an interdependent kinematic relationship within the lumbopelvic hip complex, with changes in one structure affecting degree of motion and load within the entire complex [32].

Therefore, the SI joint should be evaluated as a potential pain generator in patients who fail to improve or experience late non-mechanical failures after lumbar arthrodesis.

Pain and degeneration in the SI joint after lumbar arthrodesis has been reported to range between 43 and 75% [6, 30, 33, 34].

The relatively low success rate of spinal fusion, combined with the high incidence of diagnosable SI joint disorders in patients presenting with low back pain strongly suggests that the SI joint is often overlooked as a PG in this population [3].

An accurate diagnosis requires not only a ruling out or downgrading of other conditions, but also a thorough evaluation of the lumbar spine and hip, as well as a physical exam that includes maneuvers that stress the SI joint and a series of image-guided intra-articular diagnostic injections.

For patients with multiple pain generators, the most bothersome should be treated first to assess the true impact of the secondary pain generator(s).

Surgical treatment of the primary PG alone may effectuate adequate pain control in certain patients, while for others sequential treatment of secondary PGs may be indicated to achieve a satisfactory final outcome.

Patients with multiple pain generators, regardless of treatment, may not experience a high degree of improvement as the sensory region of the cortical homunculus governing the low back and hip is relatively small, making it difficult for the brain to distinguish discrete pain generators in this area [35].

Functional improvement relies on the interdependent relationship of the lumbar spine, pelvis and hip axis.

Pain or loss of function in one component can overshadow improvement in another.

Identification and sequential treatment of secondary pain generators in this axis may be needed to achieve the best possible outcome.

Although the study sample size is relatively small and represents the experience of a single surgeon, this cohort represents the first patients to have received this implant.

ODI was available only at the 5-year time point; a comparison to baseline could not be performed.

It should be noted, however, that all pain and functional outcomes were self-reported by study subjects.

Larger cohort and multi-center long-term studies are needed to better understand how to formulate a surgical strategy and set realistic outcome expectations in the patient with multiple pain generators within the lumbar spine-SI joint-hip axis.


Long-term (5-year) clinical and radiographic outcomes after MIS SIJ fusion for degenerative sacroiliitis and/or SI joint disruptions are favorable.

Clinical improvements observed at 12 months postoperatively were maintained at 5years.

There was no evidence of long-term complications, implant migration or loosening.

Increased bone density was observed circumferentially in 100% of the implants.

Most (87%) scans showed intra-articular osseous bridging.

Patients who did not do well were affected by multiple severe degenerative conditions of the spine, pelvis, and/or hip.


Ten RCTs were eligible.

Formal meta-analysis was not undertaken due to concerns about methodological quality of identified studies.

Compared with medical therapy, remission rates with GMAA were generally higher, and corticosteroid- sparing effects were observed.

Compared with sham procedure, GMAA did not achieve significantly higher remission rates. " Intensive" GMAA regimens demonstrated generally higher remission rates, and time to remission was shorter compared with "conventional" regimens.

Only two RCTs were at low risk of bias.

Six were conducted in Japanese patients, which may limit generalisability.


GMAA appears of some benefit in UC.

High-quality RCTs comparing GMAA with conventional medical therapy or sham procedure in Western populations, with disease activity confirmed endoscopically, are required.


Rationale 3 Describe the rationale for the review in the context of what is already known.


A search of the medical literature was conducted using MEDLINE (1950 to August 2010), EMBASE (1946 to August 2010), and the Cochrane central register of controlled trials.

Randomised controlled trials examining the efficacy of GMAA in adult patients (> 90% over 16 years of age) with active or corticosteroid-dependent UC were eligible for inclusion.

The control arms of these trials were required to receive any of conventional medical therapy, sham apheresis procedure, or an alternative regimen using an active GMAA column.

Trials that permitted other concomitant therapies were eligible, as long as these were administered to both the intervention and control arms.

The primary outcome studied was remission of disease activity.

Secondary outcomes, where reported, included response to therapy, if remission rates were not described, effect of GMAA on endoscopic healing and quality of life, evidence of any corticosteroid-sparing effects, and adverse events arising as a result of GMAA.


Studies of GMAA in UC were identified with the terms ulcerative colitis, inflammatory bowel disease, proctitis, or colitis (both as medical subject headings (MeSH) and free text terms).

These were combined using the set operator AND with studies identified with the terms: blood component removal, leukapheresis, monocytes, or granulocytes (both as MeSH and free text terms), or granulocyte apheresis, monocyte apheresis, or adacolumn (as free text terms).


Abstracts of the papers identified by the initial search were evaluated by the lead investigator for appropriateness to the study question.

All potentially relevant papers were obtained and evaluated in detail.

The bibliographies of all identified Alimentary Pharmacology & Therapeutic F o r P e e r R e v i e w relevant studies were used to perform a recursive search of the literature.

Articles were assessed independently by two investigators using pre-designed eligibility forms, according to the eligibility criteria stated previously.

Any disagreement between investigators was resolved by discussion with a third investigator.


All data were extracted independently by two investigators on to a Microsoft Excel spreadsheet (XP professional edition; Microsoft Corp, Redmond, WA, USA) as dichotomous outcomes (i.e. remission / response or failure of remission / response).

In addition, the following clinical data were extracted for each trial, where available: number of centres, country of origin, geographical region, UC characteristics (severity of UC activity, presence of corticosteroid-dependence or resistance), schedule of GMAA used, duration of therapy, primary outcome measure used to define remission or response following therapy, and duration of follow-up.


This was performed independently by two investigators, with disagreements resolved by discussion with a third investigator.

Risk of bias was assessed as described in the Cochrane handbook, 23 by recording the method used to generate the randomization schedule, the method used to conceal allocation, whether blinding was implemented, what proportion of patients completed follow-up, whether an intention- to-treat analysis was extractable, and whether there was evidence of selective reporting of outcomes.


The search strategy identified a total of 1729 citations, 16 of which appeared to be relevant to the study question, and were therefore retrieved and evaluated in more detail (Figure 1).

Nine articles, 24-32 reporting the results of ten separate RCTs, were eligible for inclusion in the systematic review.

We did not perform a formal meta- analysis due to concerns about the high risk of bias among the RCTs we identified.


Individual trial characteristics are provided in Table 1.

Four trials compared GMAA with conventional medical therapy, 24, 25, 31, 32 two separate trials (reported in a single article) compared GMAA with sham apheresis, 26 and four trials compared "intensive" versus "conventional" GMAA regimens.

27-30 Only two trials were at low- risk of bias according to our assessment.

26 Six studies were conducted entirely in Japan, 24, 25, 27, 28, 31, 32 two in Europe, 29, 30 one in the USA and Canada, 26 and one in both Europe and Japan.

26 Eight of the trials reported remission rates, 24-30 while the remaining two reported response rates to therapy.

31, 32 Six RCTs performed a true intention-to-treat analysis, with dropouts assumed to be treatment failures.

24-26, 28, 31


We identified four trials making this comparison, all of which were conducted in Japanese centres.

24, 25, 31, 32 The first, 32 published in 1999, randomised 120 patients with UC in equal numbers to receive either five GMAA sessions over 5 weeks or standard medical therapy with corticosteroids.

Follow-up was for 7 weeks and 105 patients completed the trial.

The authors reported that 31 (58.5%) of 53 patients assigned to GMAA column responded, compared with 23 (44.2%) of 52 allocated to Alimentary Pharmacology & Therapeutic F o r P e e r R e v i e w standard medical therapy (P = 0.045).

Corticosteroid-sparing effects and adverse events data were not reported.


In a smaller study, Hanai and colleagues recruited 69 patients with corticosteroid-dependent UC.

24 The active intervention was 11 sessions of GMAA given over 10 weeks, while the control arm received a mean dose of 30mg/day of oral prednisolone.

The primary outcome reported by the authors was clinical remission, defined using a clinical activity index of ≤ 4 and a visible mucosal vascular pattern at endoscopy.

Data were also collected concerning any corticosteroid-sparing effects of GMAA therapy, cumulative corticosteroid doses, and mean corticosteroid dose at last point of follow-up of the trial, which was 24 weeks.

Remission occurred in 39 (84.8%) of 46 allocated to GMAA, compared with 16 (69.6%) of 23 randomised to corticosteroids (P = not significant).


Overall, 10 (21.7%) of the apheresis patients were corticosteroid-free at 24 weeks, compared with 3 (13.0%) of those receiving prednisolone (P = not significant).

Cumulative corticosteroid doses were significantly lower at the end of treatment in the GMAA patients (P = 0.001), and mean corticosteroid dose was also significantly lower (P = 0.003).

Adverse events were reported by 10 patients receiving GMAA, with flushing in six patients.

Adverse events among those assigned to corticosteroids were not reported.


Nakamura and colleagues recruited 20 patients with active UC, 31 all of whom were receiving corticosteroids at study commencement, and randomised them in equal numbers to either GMAA or conventional medical therapy with corticosteroids.

They used a combination of clinical symptoms, endoscopic appearance, and inflammatory markers to define response to therapy.

There was a response rate of 80.0% in the GMAA arm of the trial, compared with 20.0% in the conventional treatment patients (P < 0.05), and the proportion of patients reporting blood in the stools after Alimentary Pharmacology & Therapeutic F o r P e e r R e v i e w completion of therapy was significantly lower in those receiving GMAA (10.0% versus 70.0%, P < 0.01).

Corticosteroid-sparing effects and adverse event rates were not reported by the authors.


The most recent RCT making this comparison was conducted at 5 centres in Japan.

25 The investigators randomised 70 patients with severely active UC, most of whom were receiving 5-ASAs in combination with low-dose prednisolone, to receive either twice-weekly GMAA for weeks followed by weekly GMAA, up to a maximum of 11 sessions in total, or intravenous prednisolone at a dose of 40 to 60mg/day for 5 to 10 days, followed by tapered oral prednisolone.

Corticosteroid- dependent patients in both treatment arms also received mercaptopurine.

Follow-up was at 12 weeks, and the primary outcome measure was clinical remission, defined using a clinical activity index of ≤ 4.

The authors also reported the numbers of patients achieving a corticosteroid-free remission, and adverse events rates.

Overall, 26 (74.3%) of 35 in the GMAA arm achieved remission, compared with 16 (48.6%) of 35 receiving prednisolone (P = 0.02).

In addition, 27 (77.1%) of the GMAA patients were corticosteroid-free at 12 weeks, compared with 5 (14.3%) of the patients receiving prednisolone (P = 0.008).

Finally, only 5 (14.3%) GMAA patients reported adverse events, compared with 29 (64.4%) of those receiving corticosteroids.


There were two RCTs comparing GMAA with a sham apheresis procedure, reported in a single article.


The larger of these two trials was conducted in the USA and Canada, and recruited 168 patients with moderate to severely active UC who were already receiving treatment with at least one of 5-ASA, corticosteroids, azathioprine, or mercaptopurine.

Participants were treated for 9 weeks, and the primary outcome of Alimentary Pharmacology & Therapeutic F o r P e e r R e v i e w interest was the number of individuals achieving clinical remission, defined using a Mayo score of or less, at weeks post-randomisation.

Secondary outcome measures included endoscopic remission, and change in quality of life from baseline.

Overall, 19 (17.0%) of 112 patients were in clinical remission at 12 weeks with GMAA compared with 6 (10.7%) of 56 receiving the sham apheresis procedure (P = 0.36).

The proportion of patients achieving endoscopic remission was very similar in both treatment arms (12% versus 11%, P = 1.0).


The smaller trial was of identical design, and recruited 47 UC patients from 11 European and 1 Japanese centre.

Clinical remission occurred in 5 (16.1%) of 31 and 3 (18.8%) of 16 in the GMAA and sham apheresis arms respectively.

Changes in quality of life scores from baseline were not reported in detail, but were said to be comparable between active intervention and control patients in both trials.

Serious adverse events were reported in 14% of all GMAA and 11% of all sham apheresis patients.


Given the perhaps unexpected finding that GMAA was not significantly superior to sham apheresis in achieving clinical remission in active UC, the authors conducted a subgroup analysis, which included only the 63 patients with histological evidence of mucosal erosions or ulceration at baseline.

Clinical remission was achieved in 11 (24%) of the 46 of these individuals who received GMAA versus 0 (0%) of the 17 randomised to sham apheresis (P = 0.03).

These data suggest that GMAA is of benefit in patients with confirmed endoscopically active disease, and that the treatment effect may have been diluted by the inclusion of patients with much milder disease, or perhaps even functional symptoms.


There were four RCTs that compared "intensive" GMAA regimens with "conventional" regimens.

27-30 Ricart et al. randomised 20 UC patients with moderately active disease, all of whom were corticosteroid-dependent, to either 10 apheresis sessions over 10 weeks, or five sessions over 5 weeks.

29 The primary outcome was clinical remission, according to a clinical activity index of ≤ 4, at week 17.

Corticosteroid requirements and quality of life were also recorded.


In total, 19 patients completed the study.

In the "intensive" arm, 5 (45.5%) of 11 were in remission, compared with 3 (37.5%) of 8 in the "conventional" arm.

All those who achieved clinical remission were also in endoscopic remission, and all but one of these patients were corticosteroid-free at week 17.

Quality of life scores improved from baseline in both groups, but these differences were not statistically significant.

There were no serious adverse events observed in either arm of the trial.


In a small Japanese RCT conducted at a single centre, 28 30 patients with moderately active UC, 50% of whom were corticosteroid-dependent, were randomised to "intensive" GMAA, consisting of three sessions per week for 2 weeks followed by one session for 4 weeks, or "conventional" GMAA with 10 weekly sessions.

The primary endpoint was remission 1 week after the end of therapy (7 weeks follow-up for the "intensive" arm, versus 11 weeks for the "conventional"), defined using a clinical activity index of ≤ 4, as well as time (in days) to remission.

Changes in quality of life, corticosteroid dose, and endoscopic scores were also reported.

Overall, 12 (80.0%) of 15 in the "intensive" GMAA arm were in remission, compared with 10 (66.7%) of 15 in the "conventional" GMAA arm, but this difference was not statistically significant (P = 0.25).

However, time to remission was Alimentary Pharmacology & Therapeutic F o r P e e r R e v i e w significantly lower in those in the "intensive arm" (10.7 days versus 27.2 days, P = 0.04).

Again, there was no significant difference observed in quality of life scores, and there were no significant differences in endoscopic scores between the two arms.

Corticosteroid doses were significantly lower at the end of treatment, compared with baseline, in both arms (P = 0.03 for both).

There were four adverse events observed, two in each group.


A multi-centre Japanese RCT compared twice-weekly with weekly GMAA, up to a maximum of 10 sessions, in 163 UC patients with mildly to moderately active disease.

27 The primary outcome measure was clinical remission, again defined using a clinical activity index of ≤ 4, at 5 weeks in the "intensive" arm and 10 weeks in the "conventional" arm.

Time to remission was also compared between the two treatment regimens.

In total, 149 patients provided analysable data at study end.

The remission rate was higher in the "intensive" therapy arm of the trial, 71.2% (52 of 73) versus 54.0% (41 of 76) in the "conventional" arm (P = 0.03), and time to remission was significantly lower in the "intensive" therapy arm (14.9 days versus 28.1 days, P < 0.001).

Adverse events occurred in similar numbers of patients in each arm of the trial (17 in "intensive" versus 14 in "conventional"), but none were serious.


The largest RCT, to date, to compare "intensive" with "conventional" GMAA was conducted in 42 centres in Europe and recruited 186 patients with moderately to severely active corticosteroid-dependent or resistant UC.

30 The "intensive" arm received twice-weekly apheresis for 2 weeks followed by a further six sessions over 6 weeks.

In the "conventional" arm GMAA was administered weekly for 5 weeks.

All patients were already receiving treatment with one or more of 5-ASA, corticosteroids, azathioprine, or mercaptopurine, unless previous intolerance or non-response to these drugs had been demonstrated.

The primary outcome of interest was clinical remission Alimentary Pharmacology & Therapeutic F o r P e e r R e v i e w at 12 weeks, according to a clinical activity index ≤ 4, with 162 patients providing data for this analysis.

Time to remission and endoscopic activity were also reported.

Remission rates in the two arms were almost identical (43.9% (36 of 82 patients) with "intensive" versus 40.0% (32 of 80 patients) with "conventional"), and there was no statistically significant difference observed in terms of time to remission (39.9 days versus 46.8 days) or in endoscopic activity.

Overall, 6% of the "intensive" therapy arm and 9% of the "conventional" arm experienced a serious adverse event.


This systematic review has collected all available published RCT evidence examining the effects of GMAA in both active and corticosteroid-dependent or resistant UC.

Compared with conventional medical therapy, in the form of corticosteroids, GMAA appeared superior in several respects.

Remission rates in excess of 70% were achieved with GMAA in patients with severely active UC, 25 which were significantly higher than those achieved with conventional medical therapy.


In corticosteroid-dependent UC, rates of remission with GMAA were as high as 85%.

24 There was also evidence for corticosteroid-sparing effects with GMAA, with significantly lower cumulative doses of corticosteroid, 24 and significantly higher rates of corticosteroid-free remission in patients allocated to GMAA.

25 In addition, adverse event rates were significantly higher in patients assigned to conventional medical therapy.


Compared with a sham apheresis procedure in patients with moderately to severely active UC, 26 GMAA did not achieve significantly higher rates of clinical or endoscopic remission, and adverse events rates were comparable.

However, when only individuals with evidence of mucosal erosions or ulceration at baseline histological examination were considered in the analysis, significantly higher remission rates were observed with GMAA.


In terms of "intensive" GMAA regimens versus "conventional" regimens, available data were conflicting.

Three trials suggested that "intensive" regimens were associated with generally higher rates of remission, 27-29 and time to achievement of remission was significantly shorter in two RCTs recruiting patients with mildly to moderately active UC.

27, 28 However, the largest RCT to date demonstrated almost identical remission rates with "intensive" and "conventional" regimens in corticosteroid-dependent patients with moderately to Alimentary Pharmacology & Therapeutic F o r P e e r R e v i e w severely active disease, and no statistically significant difference in the time to remission.


The effect of GMAA on quality of life was not studied in many of the eligible RCTs but, where reported, there appeared to be no significant benefit of GMAA over conventional medical therapy, sham apheresis procedure, or between the various "intensive" and "conventional" regimens.


Strengths of our study include our rigorous methodology.

We described our search strategy, eligibility criteria, and data extraction processes in detail.

In addition, independent data extraction was undertaken by two reviewers, and discrepancies were checked and resolved.

Finally, the majority of the trials we identified used a validated definition of remission as a clinical endpoint, rather than response to therapy, which we believe is a more clinically useful outcome to the physician who is considering GMAA as a treatment option in a patient with chronic active or corticosteroid- dependent UC who is unsuitable for, or refuses, surgery.


Limitations of the present study, as with any systematic review and meta- analysis, arise from the quality of the trials included.

Only two of the ten eligible and included RCTs were at low risk of bias, 26 and most trials did not report either the method used to generate the randomisation list, or whether allocation to treatment was concealed.

In addition, only three trials reported that investigators were blinded to the assigned therapy.

25, 26 It has been well-described in the systematic review literature that RCTs that do not adhere to such reporting of their methodology, and trials that are not blinded, tend to overestimate the treatment effect associated with the active intervention.

33 Only six trials reported data using a true intention-to-treat analysis.

24- 26, 28, 31 Again, this may have led to an overestimation of the success rates with active therapy.

A final limitation is the fact that six of the ten RCTs were conducted in Japan, meaning that their results may not be generalisable to a Western population, Alimentary Pharmacology & Therapeutic F o r P e e r R e v i e w due to potential underlying differences in patient characteristics, genetics, or environment.


There has been one previous systematic review to our knowledge, to date, that has examined the efficacy of GMAA in UC.

34 In contrast to the current study, the authors felt it appropriate to perform a meta-analysis.

They reported a statistically significant benefit of GMAA over control therapy, defined using either response to therapy or clinical remission, with a number needed to treat of 5, and concluded that homogeneous evidence from seven RCTs uniformly indicated that GMAA was more successful than drug therapy in achieving response and remission.

There are some limitations of this meta-analysis that we have discussed elsewhere, 35 including pooling of data from RCTs regardless of the control intervention, and the inclusion of a pseudo-randomised study in the analysis, 37 a type of study design that is liable to selection bias.

In addition, the largest RCT that they identified showed no significant effect of GMAA on remission or response.

26 There was also statistically significant heterogeneity between studies, 36 perhaps due to underlying differences in the GMAA regimens used in the various trials.


Data from the current study demonstrate some evidence for a benefit of GMAA over conventional medical therapy, in patients with either active or corticosteroid-dependent UC, in terms of clinical remission, corticosteroid-sparing effects, and reduced adverse events rates, but no trial to date making this comparison has been conducted in a Western population.

The only study to compare GMAA with a sham apheresis procedure, conducted in both Western and Japanese patients, failed to demonstrate any significant increase in remission rates with GMAA.

The authors speculated that their patient population may have differed from those in previous trials in terms of disease activity, and that GMAA may only be effective in patients with Alimentary Pharmacology & Therapeutic F o r P e e r R e v i e w severe histological activity, an assertion supported by their post hoc analysis discussed in detail earlier.

There seems to be little to choose between various GMAA regimens in terms of clinical remission rates, though time to remission may be shorter with a more "intensive" regimen.

Adverse events were no higher with GMAA in most studies, and serious adverse events were rare, suggesting it is a safe treatment option.

Finally, data to support any beneficial effect of GMAA on quality of life are sparse.


Taken together these data tell us that, rather than designing future RCTs to examine the potential benefit of one GMAA regimen over another, what is actually required are convincing high-quality data that GMAA is effective in Western patients with UC.

Trials comparing GMAA with conventional medical therapy in corticosteroid-dependent patients are needed to demonstrate that the results from Japanese trials are reproducible.

In addition, further rigorous RCTs, of similar design to that of Sands et al., 26 should compare GMAA with sham apheresis in patients with histological evidence of active disease.

One potential niche for GMAA is in patients with chronic subacute UC refractory to, or intolerant of, 5-ASAs or immunomodulators, who are corticosteroid-dependent, but who do not have acute severe disease, and who are therefore unsuitable for either infliximab or ciclosporin.


The only other treatment option at present for this type of patient is surgery, which may not be suitable, or desirable, for all individuals.

Therefore studies that compare quality of life in patients in this situation who receive GMAA or panproctocolectomy, followed by either end ileostomy or IPAA, would also be of great interest to both patients and physicians.


In summary, this systematic review has demonstrated some evidence for a beneficial effect of GMAA in active or corticosteroid-dependent UC, in terms of both clinical remission rates and corticosteroid-sparing effects, but more data from trials Alimentary Pharmacology & Therapeutic F o r P e e r R e v i e w conducted in Western patients with endoscopic evidence of active disease are required before its true place in the management of UC is known.


Sangeetha Thanaraj: none declared.

P. John Hamlin: has participated in an advisory board for Otsuka Pharmaceuticals.

Alexander C. Ford: none declared.


10 Describe method of data extraction from reports (e.g., piloted forms, independently, in duplicate) and any processes for obtaining and confirming data from investigators.


17 Give numbers of studies screened, assessed for eligibility, and included in the review, with reasons for exclusions at each stage, ideally with a flow diagram.


For each study, present characteristics for which data were extracted (e.g., study size, PICOS, follow-up period) and provide the citations.


19 Present data on risk of bias of each study and, if available, any outcome level assessment (see item 12).


For all outcomes considered (benefits or harms), present, for each study: (a) simple summary data for each intervention group (b) effect estimates and confidence intervals, ideally with a forest plot.


21 Present results of each meta-analysis done, including confidence intervals and measures of consistency.


Again, we were confused by the reviewer's comment.

We did not reject any studies from the systematic review, but reported the results of each faithfully in the text (and Table 1) of the article.


5. The Sands study (2) itself may be underestimating the true effect of GMAA since only 63/168 (36%) had histological evidence of mucosal inflammation.

If a large number of non-inflammed "colitis" patients were recruited this would dilute the effect of an anti-inflammatory intervention.

If the Japanese studies were overstating the case for GMAA, it could be argued that the Sands study is equally flawed in the opposite direction.

This is where a meta-analysis would be useful in estimating "true" effect size.


We agreed with the reviewer.

The editor also asked us to address this issue.

Please see our response to the editor's comments above.


SIRS, We read with interest the systematic review: granulocyte ⁄ monocyte adsorptive apheresis for ulcerative colitis by Thanaraj et al. [ 1].

It would appear that a majority of patients included in the reviewed studies were on corticosteroids.

The authors found that compared with medical therapy, remission rates with granulocyte ⁄ monocyte adsorptive apheresis (GMAA) were higher, and the treatment had significant corticosteroid-sparing effect.


However, several uncontrolled studies [2], [3] reported that GMAA was effective for steroid-naïve patients or patients with the first episode of ulcerative colitis (UC).

Recently, we completed a prospective trial aimed at identifying factors affecting clinical and endoscopic efficacies of GMAA in patients with active UC [4].

The dose of corticosteroids at entry and the cumulative dose of corticosteroids administered before entry were independent significant factors for both clinical and endoscopic remission, negatively impacting the efficacy of GMAA.

Such findings suggest that GMAA might have the effect of first-line therapy for steroid-naïve patients or patients with the first UC episode [2]–[4].


Up to now, the most common medication for UC has been corticosteroids.

Most patients experience adverse side effects while on high-dose and long-term corticosteroids, adding to the disease complications and poor quality of life.

In contrast, GMAA is favoured by patients for its safety, and patients with active UC can successfully be treated with GMAA without adding corticosteroids.

In addition to the reported efficacy outcomes [2]–[5], I feel that the safety profile of GMAA is an attractive feature of this non-drug-based therapeutic intervention because adverse effects often compromise patients’ compliance with the treatment.


Another factor, which must be considered when selecting a treatment option, is the treatment cost.

When compared with corticosteroids, GMAA is expensive; one treatment session costs approximately €800.

With this in mind, if GMAA can spare patients from corticosteroids, hospitalisation and surgery, it should be cost-effective.


SIRS, We thank Dr. Yamamoto for his interest in our article [1], and for his letter regarding the role of granulocyte ⁄ monocyte adsorptive apheresis in the management of ulcerative colitis [2]. Although we agree with his general points regarding the possible benefit of granulocyte ⁄ monocyte adsorptive apheresis in ulcerative colitis, in terms of remission rates and corticosteroid-sparing effects, most of these were observed in Japanese patients.

The only sham-controlled study conducted in a Western population, to date, failed to demonstrate any clear benefit of therapy [3].

We therefore feel that it is a little premature to speculate on the cost-effectiveness of this therapy in ulcerative colitis.

As we stated in our article, what is actually required are convincing high-quality data that granulocyte ⁄ monocyte adsorptive apheresis is effective in Western patients with ulcerative colitis.


This was a randomized, controlled, nonblinded interventional animal study, the protocol for which was approved by the Karadeniz Technical University Animal Care and Ethics Committee.


Thirty mature male Wistar rats (10 weeks old, weighing 240 g to 250 g) were used.

The animals were kept in steel cages until the day of the study at a room temperature of 22 C and were given water and standard rat chow.

For the last 12 hours before the study they were given only water.


The study was performed on 30 male rats randomized into six individuals in each experimental group.

During allocation into randomized groups, 30 rats of the same weight were numbered from 1 to 30.

Rats were allocated ran- domly into each group chosen one by one, resulting in five groups of six rats each.

To maintain uniformity through the study, interventions were con- ducted on each rat in each group at the same time.

Intramuscular injection of 50 mg/kg of xylazine was used for general anesthesia.


Torsion was performed by rotating the left testis 720 degrees clockwise and maintained by fixing the testis.

The wound was closed with 4-0 catgut sutur- ing.

Bilateral castrations were performed 2 and 4 hours after torsion for the torsion groups (groups II and IV, respectively), and blood samples were taken with use of laparotomy.

Control group rats were subjected to the same surgi- cal procedures as the other rats except for the TT.

The control groups were as follows: sham group (received no treatment, only scrotal incision); scrotal incision and dissection of testes were performed without any torsion and then the skin closure in groups I and III.

The blood samples were obtained immediately from the sham group and 2 and 4 hours after the intervention for the other control groups (groups I and III), respectively.

Testicular tissue samples from torsioned and contralateral testes were stored frozen until analyzed.


Ischemia-modified albumin levels were measured.

Myeloperoxidase and MDA levels also were measured at the same time for comparison with ischemia-modified albumin values by a biochemist blinded to which groups the animals came from.


Blood samples were taken on admission.

Serum and plasma samples were prepared with 15 minutes of centrifugation at 1,800 Â g. The specimens were pipetted into Eppendorf tubes and stored at À80 C.


Reduced cobalt to albumin binding capacity (ischemia-modified albumin level) was analyzed with use of the rapid and colorimetric method of Bar-Or et al. ( 8, 9).

The results were reported as absorbance units.


Levels of rat MPO were deter- mined with use of an ELISA kit (Hycult Biotech, Uden, the Netherlands), ac- cording to the manufacturer's instructions.

The absorbance of samples was measured at 450 nm with use of a VersaMax tunable microplate reader (de- signed by the Molecular Devices Corporation, Sunnyvale, CA).

The results were expressed as nanograms per milliliter.


Malondialdehyde levels in plasma samples for determining MDA levels were established with use of the thiobarbituric acid reactive substance (TBARS) method developed by Yagi in 1984 (10).


A piece of testis tissue was used to measure MDA levels.

The sample was minced and homogenized in an ice-cold 1.15% KCl solution containing 0.05% Triton X-100 with use of an Ultra-Turrax T25 homogenizer (Janke and Kunkel IKA, Staufen, Germany).

Tissue MDA levels were determined with use of the method described by Mihara and Uchiyama (11).

Tetramethoxypropane was used as a standard, and MDA levels were calculated as nanomoles per gram of wet tissue.


Testicular tissue samples were fixed immediately in Bouin's solution, dehydrated, cleared, and embedded in paraffin.

Tissue sections (4-5 mm) were stained with hematoxylin-eosin and examined under a light microscope (Olympus BX-51; Olympus Co, Tokyo, Japan) by a histologist, in a blind, randomly numbered fashion, with no knowledge of which testis was being studied.

A four-level grading scale, similar to that described by Cosentino et al., was used to quantify histologic injury (12).

Histopathologic grading criteria were as follows: Grade 1 showed normal testicular architecture with an orderly arrangement of germinal cells.

Grade 2 injury showed less orderly noncohesive germinal cells and closely packed seminiferous tubules.

Grade 3 injury exhibited disordered sloughed germinal cells with shrunken pyknotic nuclei and less distinct seminiferous tubule borders.

Grade 4 injury defined seminiferous tubules closely packed with coagulative necrosis of the germinal cells.


Analysis of the ischemia-modified albumin, MPO, and MDA levels of the same-time control and torsion groups was performed with use of the Mann-Whitney U test.

Time-dependent changes in parameters were analyzed with use of Kruskal-Wallis analysis of variance (Mann-Whit- ney U test with corrected Bonferroni test).

The histopathologic comparison between contralateral testes was performed with the Mann-Whitney U test.

Spearman's correlation analysis was used to assess relationship between bio- chemical parameters and histopathologic scores.

Statistical significance was assumed at a level of P<.05.


Chronologic changes in biochemical parameters among the groups are given in Table 1.

Time-dependent change in serum ischemia- modified albumin levels, the only biochemical parameter in which we determined a significant change in torsion-related blood levels, is shown in Figure 1.

No correlation was determined between ischemia-modified albumin levels and blood and tissue MDA and MPO levels (P>.05 for all correlations).


Macroscopic evaluation of testes revealed no color change or pathol- ogy in the sham and control groups.

The normal pinkish color of the testes changed in groups II and IV.

Sham group testicular tissue ex- hibited a normal microscopic structure.


Significant structural differ- ences were observed between the sham groups and groups II and IV.

There were occasional pyknotic nuclei in the germinal cells, irregu- larity in the seminiferous tubules, and distinct tubular damage in 1334 Kutlu et al. Ischemia-modified albumin in testicular torsion Vol. 95, No. 4, March 15, 2011 tubular epithelial cells in group II.

Distinct tubular damage was ob- served in group IV in both testes.

Lesions in the seminiferous tubule epithelial cells were quite distinct.

There were widespread pyknotic nuclei and atrophy in the germinal epithelial cells.

The mean micro- scopic lesion scores of the groups were determined and are shown in Table 2.


There was a positive correlation between histopathologic scores of torsioned and contralateral testes (r ¼ 0.54, P¼.002).

The results emerging from analysis of the correlation between histopathologic scores and biochemical parameters are shown in Table 3.

There was a significant correlation between histopathologic score and blood and tissue MPO levels only.

There was significantly greater histopathologic damage in the 4-hour torsion group compared with all others, and the serum ischemia-modified albumin levels in this group were also signifi- cantly higher than those of the other groups.

Malondialdehyde and MPO levels exhibited no other significant differences in terms of the values determined in the other groups.


Evident histopathologic damage was greater in the 2-hour torsion group (group II) compared with the control group, though no signif- icant difference was observed in biochemical parameters compared with any of the other groups.


According to available databases, this study is the first to examine ischemia-modified albumin as a biochemical parameter of TT.

Ac- cording to our findings, ischemia-modified albumin levels in blood specimens taken after 4 hours of torsion were significantly higher than those in other groups.

Although the highest level of histopath- ologic damage in both torsioned and contralateral testes and the highest ischemia-modified albumin levels were determined in group IV, there was no significant correlation between ischemia-modified albumin levels and histopathologic damage.


Delay in the diagnosis of TT may result in the loss of a testis.

Therefore, TT is without doubt the most important of all those con- ditions responsible for an acute scrotum.

The torsion must be treated promptly to avoid loss of function of the ipsilateral and contralateral testis (13).

In experimental TT there is a consensus that an ischemic period >4 to 6 hours will result in permanent tissue damage.

If this emergency condition is not treated within 4 to 6 hours, testicular necrosis will occur.

Mammalian testes are extremely sensitive to oxidative free radical damage.

Spermatic cord torsion is characterized by tissue hypoxia and eventually by necrosis of germinal cells that give rise to subfertility or infertility 14).

The main pathology of TT is ischemia followed by reperfu- sion injury of the testis.

This injury is associated with overproduc- tion of reactive oxygen species and can cause tissue damage through cell membrane lipid peroxidation, protein denaturation, and DNA damage (15).


Previous studies with a rat model of TT have demonstrated that a 720-degree rotation of the testis for 2 hours followed by reperfu- sion causes a significant increase in testicular MDA and MPO levels (16, 17).

In an experimental study of testis torsion performed on rats, Cay et al. ( 18) determined that tissue MDA levels were significantly higher in both the torsion and torsion-detorsion groups compared with the control group.

In a recent study by Aktas x et al. ( 19), MDA levels were significantly higher in the testicular torsion group, but, although MPO levels were higher in the torsion group compared with the control group, the difference was not statistically signifi- cant.

We determined a significant correlation between histopatho- logic score and blood and tissue MPO levels.

However, there was no significant difference between the torsion and control groups in terms of blood and tissue MDA or MPO.


Ischemia-modified albumin is a new and sensitive biomarker of ischemia and oxidative stress.

The U.S. Food and Drug Administra- tion recently licensed ischemia-modified albumin for diagnostic use in suspected myocardial ischemia (20).

However, high ischemia- modified albumin concentrations do not seem to depend purely on myocardial involvement, and other organs appear to be respon- sible for the increase in ischemia-modified albumin levels.

Ischemia-modified albumin levels may rise during ischemia- reperfusion, affecting any organ, and cannot be considered together with oxidative stress.

Studies have demonstrated that many condi- tions may elevate ischemia-modified albumin levels (21-24).

The present study is the first to evaluate ischemia-modified albumin levels in TT, in which ischemic and oxidative stress conditions that affect the formation of ischemia-modified albumin are particu- larly evident.

Although no significant correlation between histo- pathologic damage and serum ischemia-modified albumin levels was determined in our study, significantly high histopathologic damage was present in the 4-hour torsion group, and, although not significant, prominently high levels in the contralateral testes (within the critical first 4-6 hours for early diagnosis of TT) (group IV) compared with the other groups and serum ischemia-modified albumin levels also were significantly higher in this group com- pared with the others.

In addition, because of a positive correlation between histopathologic scores of torsioned testes and contralateral testes, ischemia-modified albumin may be important as a prognostic factor for the status of the testes.


In conclusion, despite some limitations, the results from this pio- neering study established a high level of ischemia-modified albumin in TT, indicating a potential value for TT diagnosis.

Considering the rapid result availability and sensitivity of ischemia-modified albu- min, with respect to the ischemia, it definitely has value as adjunc- tive to available diagnostic tools.

This may have even higher importance when high-resolution ultrasound with color-flow Dopp- ler and radionuclide imaging are not available.

This study is novel with respect to establishing increased levels of ischemia-modified albumin in TT, and there is a potential for ischemia-modified albu- min levels in prediction of prognosis, which should be addressed in further studies.


There are some limitations to this study.

The first limiting feature is that the effect on ischemia-modified albumin levels of other causes of acute scrotal pain, such as acute epididymitis and orchitis, which should be considered during differential diagnosis for mesen- teric ischemia, is as yet unknown.


There was a clear increase in ischemia-modified albumin levels after TT in this study, and this may serve as evidence to avoid unnecessary surgery. But considering the experimental nature of the evidence, there is a need for additional evidence including from clinical cases for the sensitivity of ischemia-modified albu- min in TT, as possible normal ischemia-modified albumin levels would cause a delayed surgery and consequences.

The study also had some limitations in terms of the model used because experimental TT may not mimic typical TT cases seen in practice.


To the Editor:


We read with great interest the recently published article by Kutlu et al. [ 1].

In the article, the authors showed that rats that had been operated to produce testicular torsion had a higher level of ischemia-modified albumin 4 hours after the onset of the disorder.

The authors highlighted that although the blood and tissue MDA and MPO levels showed no difference between groups, the ischemia-modified albumin levels showed significant a difference in 4-hour torsion group compared with other groups.

The results derived from the animal study showed a high level of ischemia-modified albumin in testicular torsion (TT), indicating a potential value for TT diagnosis, and the value of ischemia-modified albumin level in TT should be investigated with respect to prognosis.


However we would point out the chemical specificity of ischemia-modified albumin.

Ischemia-modified albumin was first reported by Bar-Or et al., who found the new protein, with an altered metal-binding site of human serum albumin, after the onset of cardiac ischemia [2].

Human serum albumin is a peptide consisting of 585 amino acids with a unique amino acid sequence at its amino terminus-N-terminus, which serves as the primary binding site for the transitional metals cobalt, copper, and nickel ions.

Bar-Or also emphasized that the unique structure of serum albumin was found only in humans, and was not in other species.

Rat serum albumin has 608 amino acids, including the signal and pro-peptide sequences at the N-terminus, is of a different size than of its homolog-human.

Comparison of the amino acid composition of rat serum albumin with that of human albumin shows rat albumin to contain relatively more tyrosine and relatively less lysine, cystine, and leucine [3].


Based on previous research, Bar-Or et al. postulated that significant molecular changes to or loss of portions of the N-terminus of HSA could reduce the in vivo transitional metal binding capacity of HSA either during myocardial ischemia or during reperfusion immediately after the ischemia event [2].

The following research was also about myocardial ischemia, especially in patients following coronary artery bypass operation and percutaneous coronary intervention surgery.

However, there was no animal study on ischemia-modified albumin of myocardial ischemia.

Specific portions that are highly conserved often correspond to important sites, such as metal ion binding sites, in the final protein or are important to the final configuration of the protein.

The human metal ion binding site is not conserved, because it is not found in any other species.

So we do not think an animal model is suitable for monitoring the ischemia-modified albumin level changes in any disease before examining the binding capability of rat serum albumin for transitional metal ions, as well as identifying the binding site itself.


Additional research shows that ischemia-modified albumin is affected in skeletal muscle ischemia, mesenteric ischemia, intermittent claudication, stroke, end-stage renal disease, metabolic syndrome, preeclampsia and other vascular ischemia diseases.

Summarizing the results, we can conclude that ischemia-modified albumin is sensitive to ischemia, but its lack of specificity for organs or diseases limits its diagnostic value.

Therefore we question the clinical applicability of using ischemia-modified albumin to diagnose TT.


First of all, we would like to thank Zheng et al. for their interest [1] in our study and also to the editor for giving us the chance to share this information.

Ischemia modified albumin (IMA) has recently been investigated in many studies and has largely been validated for the early detection of ischemia [2].

The reduced cobalt binding capacity of albumin (IMA level) was first investigated with a colorimetric assay developed by Bar-Or et al. [ 3].

We used this method described by Bar-Or et al. [ 3] to determine serum IMA levels in rats and rabbits in our research because of the homology of the cobalt binding site between rat, rabbit and human serum albumin.


As Zheng et al. state in their letter, Peters et al. showed that rat serum albumin differs from human serum albumin in terms of amino acid levels [4].

However, Appleton et al. showed that bovine serum albumin, human serum albumin and rat serum albumin exhibit a characteristic preferential binding of one copper (II) ion [5].

The amino acid sequence in the N-terminal binding site for rat and rabbit serum albumin is N-Glu-Ala-His-Lys (GenBank accession number: NM_134326.2, NM_001082344.1) and for human serum albumin, N-Asp-Ala-His-Lys (GenBank accession number: NM_000477.5).

The mechanism that causes the modification of albumin during ischemia was explained by Bar-Or et al. [ 3].

They demonstrated that this modification was an alteration in the Asp-Ala-His-Lys sequences in the albumin N terminus [3, 6–9].


Transient metals including cobalt, nickel and copper binding regions consisting of aspartic acid, alanine, histidine and lysine are the first 4 amino acids of the N terminus indicated by Bar-Or et al. [ 7].

The third residue, histidine, has the major role of binding copper [10, 11].

Rat and rabbit serum albumin exhibit homology to human serum albumin in the amino acid sequence.

Rat and rabbit albumin has 608 and human 609 amino acids, including a signal peptide at the N terminus [12–14].

Although Zheng et al. mentioned the difference between the amino acid sequence and size of the peptides, human, rat and rabbit albumin consists of 585, 584, 584 amino acids, respectively, excluding the signal peptides.

Metal binding domains differ by one residue, an aspartic acid and glutamic acid.

These amino acids are similar structurally and chemically, and both are acidic amino acids.

In the binding domain, histidine assumes the major role and this residue is a common one.


Our presented results showed that IMA levels can be an important marker in the diagnosis of testicular torsion (TT) [15].

The literature contains many studies, similar to our own, investigating IMA levels in rats and rabbits [16, 17, 18].

These studies, which enjoy wide acceptance in the literature and have attracted wide interest are in fact of the nature of preliminary studies.

In the light of all this information, we think that our research method is valid and widely accepted in the literature and that it can serve as a guide on such an important subject as TT.


Noncommunicable diseases (NCDs) are responsible for the largest share of total health- related burden in the European Union (EU): they account for approximately 9 out of every 10 deaths and disability adjusted life years (DALYs) [1].

The four major NCDs, cardiovascular disease, cancer, chronic respiratory disease and diabetes mellitus, are responsible for at least 25% of the total healthcare spending, which is equivalent to an economic cost of 2% of the EU gross domestic product [2].

Among the avoidable risk factors, energy-dense diets high in fat, sugars and salt and low in fibre are one of the key risk factors for NCDs, thus contributing to the high health and economic burden linked to them [3,4].


Many national programs and strategies, both voluntary and mandatory, are in place to regulate marketing of front-of-pack labelling of such products.

In addition, efforts to improve the nutritional quality of the food offerings are underway at the EU level through voluntary policies (Frameworks for National Salt Initiatives (2008) [5], National Initiatives on selected nutrients (2011) [6], the Annexes on Saturated Fat (2012) [7] and Added Sugars (2015) [8] and the roadmap for Action on Food Product Improvement (2016) [9]), and mandatory targets, standards and restrictions on nutrient content of industrially processed foods (i.e., Directive for the prohibition of added sugars in fruit juices (2012) [10] and the Regulation on trans fats (2019) [11]).

More recently, the importance of healthy diets is also highlighted by the Farm to Fork Strategy [12] and Europe's Beating Cancer Plan [13].

Beyond promoting a common European approach towards salt, sugars and fat intake reductions, these initiatives aim at encouraging a participatory engagement with public authorities and the food-processing sector, holding them accountable for food reformulation progress.

Independent of the type of action undertaken at national and regional levels, mon- itoring and surveillance are crucial to understand the progress towards achieving the reformulation initiatives' targets [14,15].

The comparison between food and nutritional data across Europe is often hampered by the lack of standardisation and harmonisation between national food classifications, nomenclatures or sources of data [16].

In this sense, one of the objectives of the Joint Action on Implementation of Validated Best Practices in Nutrition (Best-ReMaP) [17] is to work towards developing a European Standardised Monitoring system for the reformulation of processed foods for countries without existing systems, based on already available tools and expertise.

However, given that this initiative started at the end of 2020, results will take time to materialise.


In the absence of an existing and consolidated system to monitor Europe-wide refor- mulation efforts, this paper aims to assess progress on the existing commitments across European countries between 2015 and 2018.

For that, we combine detailed market share and sales data with nutrition composition data from Euromonitor International to calcu- late market-share weighted averages of salt, total sugars, saturated fat and fibre content in selected food groups-most of them prioritised in several European frameworks.

By integrating changes in nutritional composition of the food offer with changes in sales, this approach also provides insights into the 'true' average nutrient contents sold to consumers through different packaged food and soft drinks categories.

Despite not measuring exactly what individuals have consumed, market data can be used by researchers and policymak- ers to keep track of the overall nutritional quality of the packaged food and drinks offered to and purchased by citizens [18-24].


The limited availability of food supply and composition data poses several challenges on assessing reformulation initiatives, which may explain why empirical peer-reviewed studies in this area have been relatively sparse.

Studies reporting de facto changes have mainly taken advantage of nationally representative cross-sectional surveys to analyse the nutritional quality of the food supply over time.

Most of these studies have mainly focused on evaluating the trends of a specific nutrient in selected food groups [19,21,23,25,26], or intended to compare the nutritional quality of similar food products across different countries at a specific point in time [16,18].

Compared to national dietary surveys and food composition tables, a third-party can offer more granular, frequent and standardised information on food sales and composition data disaggregated by type of product and brands, also avoiding reliance on individual recall [24].

Therefore, through the use of detailed and up-to-date commercially supplied food sales and composition data for many European countries, we attempt to reduce the literature gap by assessing the nutritional quality of packaged food and soft drinks sold through the retail sector, looking at several nutrients and food groups.

By directly comparing the recent trends among many European countries, our findings allow the identification of food groups and nutrients that have presented progress as well as those that require more attention from policymakers, industry and consumers.


Euromonitor International [27] is a commercial global market research company providing data on the Packaged Food and Soft Drinks industries.

Their Packaged Food and Soft Drinks databases include market-sized data of food/drink subcategories in value and volume terms, in addition to product/brand and company shares-which are available in volume and value terms for Soft Drinks, but only in value for the Packaged Food industry.

In addition, the Nutrition database displays nutrient market sales volumes, and brand volumes on retails sales as well as back-of-pack labelling information on nutrient content (energy, carbohydrates, sugars, fibre, fat, saturated fat, protein and salt) per 100 g (or 100 mL) for the Soft Drinks and Packaged Food industries.

Packaged Food/Soft Drinks and Nutrition data have been available since 2005 and 2014 respectively, until 2019, covering 5 subcategories of Soft Drinks and 16 subcategories of Packaged Food.

Both datasets are frequently updated with five years of back-trended historic data and five years of forecasts.


Euromonitor employs a research methodology of sourcing nutrition data predom- inantly online through brand/retailer websites, with store checks carried out when the information cannot be found online.

The Nutrition database only tracks products sold through retail outlets (excluding, for example, restaurants, cafés/bars and vending ma- chines).

Therefore, only retail sales are considered in this analysis.

The company relies on: (i) the regular updates of the relevant retailer's websites, and (ii) the accuracy of the data provided on the label-so it is assumed that manufacturers provide accurate and up-to-date information in line with EU regulations.


Within Europe, the company researches nutrition data for 19 of the EU27 countries (Belgium, Bulgaria, Czech Republic, Denmark, Germany, Ireland, Greece, Spain, France, Italy, Hungary, Netherlands, Austria, Poland, Portugal, Romania, Slovakia, Finland and Sweden), the United Kingdom and 2 countries that are part of the European Free Trade Association (EFTA), Norway and Switzerland.

Market data is available for 28 European countries.

As for all countries for which nutrition data is available market data also is, our study focuses on the 22 European countries listed above.


As there is no pre-existing integration of Packaged Food/Soft Drinks and Nutrition databases available in the company's platform, we created a key variable with the lowest level of product disaggregation (product/brand), which enabled the matching between both databases.

For this analysis, we focused on 14 categories and 152 subcategories (see Table A1, Appendix A) of packaged foods and soft drinks that commonly represent major sources of added sugars, salt, saturated fat and fibre across different European countries.

Moreover, these were also targeted in several national priorities and plans as well as in regional initiatives, such as the 2011 EU Framework for National Initiatives on Selected Nutrients [6].


After compiling and extracting market and nutrition data at the product/brand level, we removed those entries with: (i) missing market share, (ii) zero market share, (iii) missing/zero market value/volume and (iv) missing sugars, saturated fat, salt and fibre content data.

For each remaining product/brand, we calculated the annual volume sold (in litres for Soft Drinks and tonnes for all other products) by multiplying the market share (in %) and the annual volume sold of the corresponding subcategory.

Given that the market share data in volume terms is available only for Soft Drinks in Euromonitor, we used the value share to calculate total volume sold for all other categories, which may overestimate the volume sold of products that are more expensive per unit volume.


We later estimated the market coverage for each category/subcategory based on the sum of total volumes of products in each category and the total volume of the category directly extracted from Euromonitor.

In 2020, Euromonitor modified the 2019 Nutrition edition data structure from a product/brand level to a stock-keeping unit (or SKU) approach, which no longer allows the direct integration of market and nutrition data at the product/brand level.

Thus, to ensure consistency, repeatability and reproducibility of our analysis, we used sales data from 2015 and 2018, which corresponds to data released by Euromonitor in 2016 and 2019.


Table 1 presents the final list of packaged food and beverages categories assessed in this paper, and the number of products/brands contained in each category and the respective market coverage by country in 2018.

Overall, more than 23,000 products/brands were analysed across 14 packaged food and soft drinks categories, covering, on average, 72% of the market for these categories.


It is also possible to notice that some categories such as Dairy, Soft Drinks, Sauces, Dressings and Condiments (S, D & C), Confectionary and Sweet Biscuits, present many product variants.

Data for 2015 covers approximately 22,400 products/brands that jointly represent 68% of the market (Table A2, Appendix A), which suggests that the total number of products by category and their respective market coverage remained relatively constant over the 2015-2018 period.


Despite the high number of products/brands, some categories (such as Rice, Pasta and Noodles (R, P & N) and Baked Goods) present a relatively lower market coverage, while others contained few products that jointly represent a significant part of the total market in some countries (e.g., three products/brands represented 66% of the Greek market for soups), which justifies the focus of the analysis of the nutrient contents at the category level.


To evaluate the broader nutrient profile of the food offer in Europe, we took into account the market dynamics of each product category/subcategory by adopting a market- share weighted average approach [18,19,21].

For this, we calculated the total annual retail volume (in grams/millilitres) of product/brand i (V i ) and their respective category V (V = ∑ i V i ).

If N i represents the salt, sugars, saturated fat or fibre content of each product/brand i (in grams per 100 g/100 mL) and M i indicates their corresponding market share (in % volume for Soft Drinks and in % value for all other categories), we can calculate the weighted mean nutrient content (N) at the category level as follows:


Based on these estimates, we later calculated per capita nutrient sales values (g/pc/day) using mid-year population data for 2015 and 2018 from the European Health for all Database (HFA-DB) [28] and scaled these estimates according to the respective market coverage (as presented in Table 1) to represent 100% of the retail market.

Therefore, while we are able to identify the contribution of specific products/brands to the overall quantity of nutrients sold within major packaged food and soft drinks categories in the EU, we followed [20,22] and assumed that the remainder of the market presents the same characteristics and evolution as our sample.

This assumption minimizes data distortion given that many categories present a relatively high market coverage, and its magnitude remained stable across the analysed years [22].

Additionally, this assumption is founded on the fact that small and local companies represented by the remainder of the market are less likely to have the capacity for reformulation [20].


Data are reported as weighted mean, arithmetic mean, standard deviation, median, minimum and maximum.

Linear regressions were used to generate two-tailed, homoscedas- tic Student's t-tests to identify if there was a significant change in the weighted and arith- metic mean nutrient content of packaged food and soft drinks categories between 2015 and 2018.

All data were analysed using the STATA/SE version 15.1, and R.


Figure 1 presents our estimates of the daily per capita sales of total sugars, saturated fat, salt and fibre of all packaged food and soft drinks categories.

These estimates were pro- portionally scaled by the respective market coverage (as presented in Table 1) to represent 100% of the retail market in Europe.

For sugars, it is possible to observe that sales from Soft Drinks, Confectionary, Dairy and Baked Goods represent approximately 80% of per capita daily sugars sales across the 9 packaged food and soft drinks categories considered in this analysis in both years.

Dairy, Processed M & S, Baked Goods and Sweet Biscuits account for the largest per capita daily sales of saturated fat.

The largest volumes of salt per day were sold through Processed M & S, Baked Goods and S, D & C; for fibre, only one category (Baked Goods) accounted for approximately 45% of total per capita sales.

The per capita amount of nutrients being sold every day through the analysed categories totalled almost 70 g for sugars, 8 g for saturated fat, 3 g for salt and 7 g for fibre.

As a reference, the total amount of calories sold together with these nutrients corresponded to approximately 600, 622, 595 and 600 kcal/pc/day, respectively.


sales.

The per capita amount of nutrients being sold every day through the analysed cat- egories totalled almost 70 g for sugars, 8 g for saturated fat, 3 g for salt and 7 g for fibre.

As a reference, the total amount of calories sold together with these nutrients corre- sponded to approximately 600, 622, 595 and 600 kcal/pc/day, respectively.


We also evaluated the absolute changes in daily per capita sales of total sugars, satu- rated fat, salt and fibre between 2015 and 2018 for all packaged food and soft drinks cate- gories analysed in this paper (Figure 2).

This can provide insights into the progress to- wards reducing sugars, saturated fat and salt as well as increasing fibre intakes in the population.

Observed trends can be a result of innovation in the food offer, of changes in market share and volumes of products with certain nutrient profiles, or a combination of both.


At the European level, we observed increases in sales of sugars for 6 out of the 9 categories analysed: Sweet Biscuits (0.69 g/pc/day), Confectionary (0.44 g/pc/day), S, D & C and Sweet Spreads (0.18 g/pc/day), Baked Goods (0.17 g/pc/day)and Dairy (0.07 g/pc/day).

Soft Drinks and Breakfast Cereals presented a decrease of 0.63 and 0.06 g/pc/day, respectively.

For saturated fat, a notable reduction was estimated for Processed M & S (−0.17 g/pc/day), and increases of 0.05 g/pc/day were observed for Ready Meals and Savoury Snacks, as well as for Dairy (0.02 g/pc/day).

Breakfast Cereals and S, D & C presented variations of less than 0.01 g/pc/day.

In addition, more salt was sold through Baked Goods (0.05 g/pc/day), S, D & C (0.03 g/pc/day) and Savoury Snacks (0.01 g/pc/day) between 2015 and 2018, while for Processed M & S and Processed F & V, we estimated reductions of 0.06 and 0.01 g/pc/day.

Less fibre was also sold through Baked Goods (−0.15 g/pc/day), Processed F & V (−0.10 g/pc/day) and Ready Meals (−0.03 g/pc/day); conversely, more fibre was present in sales of Savoury Snacks (0.04 g/pc/day) and Breakfast Cereals (0.03 g/pc/day).


We also evaluated the absolute changes in daily per capita sales of total sugars, saturated fat, salt and fibre between 2015 and 2018 for all packaged food and soft drinks categories analysed in this paper (Figure 2).

This can provide insights into the progress towards reducing sugars, saturated fat and salt as well as increasing fibre intakes in the population.


We also found heterogeneous patterns when scrutinizing the changes in the amount of nutrients sold in packaged foods and soft drinks per country.

By focusing only on the categories which presented the largest variations in the analysed period, Figures 3-10 compare, in detail, the 2018 levels of daily per capita nutrients sold through se- lected categories with the respective estimated variation between 2015 and 2018 for all coun- tries.

Figures A1-A10 (Appendix A) present the results for other packaged food categories.


For Soft Drinks, despite the regional decrease in the per capita sugars sales attributable to this product category, 6 countries (Hungary, Romania, Bulgaria, Czech Republic, Slovakia and Finland) had their respective sales increased between 2015 and 2018.

In the case of Hungary and Bulgaria, this was equivalent to an additional more than 3 g/pc/day of sugars sold to consumers.

Mixed results are also found for Sweet Biscuits: notably, while few countries with large per capita levels of total sugars sales (e.g., the Netherlands, Belgium, France and Ireland) had their sales reduced, countries with relatively lower sales of sugars (such as Romania, Greece and Bulgaria) increased their per capita sugar sales attributable to these products between 2015 and 2018.

Conversely, for Confectionary, relatively large rises in daily per capita volumes of total sugars sales observed in Ireland, UK, Austria, Finland and Sweden might explain the overall increase at the European level.


Similar patterns are also visualised for Sweet Spreads and the estimated increase in sugars sold as Sweet Spreads in Norway, Germany, Austria, Switzerland and the Netherlands.

Figures 3 and 4 summarize our estimates of total sugars sold through Soft Drinks, Sweet Biscuits, Confectionary and Sweet Spreads in the analysed period, in which red and green colours show respective increases and decreases in our daily per capita estimates.

Figures 5 and 6 show that there is also a lot of variability in the amount of saturated fat sold through Processed M & S, Savoury Snacks, Ready Meals and Baked Goods across Europe.

With relatively high levels of sales, Germany, Hungary and France presented reductions of approximately 0.3 g/pc/day on the respective daily per capita volumes of saturated fat sold as Processed M & S. However, with the exception of Germany, the Netherlands, Denmark, Italy and France, all countries presented an increase in the per capita levels of saturated fat sold as Savoury Snacks.

Similar patterns were also observed for Baked Goods and Ready Meals.


As shown in Figure 7, daily per capita volumes of salt sold as Baked Goods have mainly increased in countries with relatively higher levels of sales (e.g., Germany, Czech Republic, Norway and Bulgaria).

For Processed M & S (Figure 7) and S, D & C (Figure 8), results are more heterogeneous across countries: while notable decreases were observed for Germany, Slovakia, Czech Republic and the Netherlands for the former and Slovakia, Czech Republic and Denmark for the latter, proportional increases were also estimated for Romania and the UK, as well as the UK and Portugal, respectively.

However, the per capita volumes of salt sold as Savoury Snacks appeared to have consistently increased in all countries, with the exception of Belgium, Denmark, France and Bulgaria.


By focusing only on the categories which presented the largest variations in the analysed period, Figures 3-10 compare, in detail, the 2018 levels of daily per capita nutrients sold through selected cat- egories with the respective estimated variation between 2015 and 2018 for all countries.

ductions of approximately 0.3 g/pc/day on the respective daily per capita volumes of sat urated fat sold as Processed M & S. However, with the exception of Germany, the Neth erlands, Denmark, Italy and France, all countries presented an increase in the per capita levels of saturated fat sold as Savoury Snacks.

However, the per Figure 9 examines the overall changes in daily per capita sales of fibre attributable to Baked Goods and Breakfast Cereals.

For the first category, the reductions observed at the European level reflect the decreases estimated for countries with relatively high levels of fibre sales (e.g., the Netherlands, Denmark and Finland).

Similarly, countries such as Ire- land, the UK, Finland and Norway have presented increases of more than 0.2 g/pc/day in their respective per capita fibre sales of Breakfast Cereals; at the same time, almost no expressive variation was observed for countries with relatively low levels per capita of fibre sales coming from Breakfast Cereals.

Conversely, more heterogeneous results were


Table 2 presents the overall results as distributions of total sugars in grams per 100 mL for Soft Drinks and grams per 100 g for all other packaged food categories (Breakfast Cereals, S, D & C, Sweet Biscuits, Baked Goods, Processed Fruits, Dairy, Soft Drinks, Confectionary and Sweet Spreads) across Europe in 2015 and 2018.

Confectionary, Sweet Spreads and Sweet Biscuits are the categories with the highest levels of weighted mean sugars content.

With the exception of Sweet Spreads, the sales-weighted mean sugars are lower than the arithmetic mean for all categories, which indicates that more sales came from the low-sugar products in 2015 and 2018.


The statistics related to the extremes of the distribution (maximum and minimum) suggest that outliers-that is, products with highest and lowest sugars content-might have remained in the market, and the relatively high standard deviations across all categories disclose a large heterogeneity of nutrient profiles at the product/brand level.

As an example, for Breakfast Cereals, there were specific types of Hot Cereals and Flakes with sugars content of 0.5 and 68 g/100 g, respectively.

Similarly, under Confectionary, it is possible to identify medicated confectionery with sugar-free formulations and standard mints, with respective sugars content of 0 and 99.2 g/100 g. The differences between the arithmetic mean and median point to the fact that, with the exception of Breakfast Cereals, Confectionary and Sweet Spreads, all categories present more products with lower-than-the average sugars content.


Sweet Biscuits, Baked Goods, Processed Fruits and Vegetables (F & V) and S, D & C faced increases in the overall sugars content between 2015 and 2018 for both analysed means.

However, for Confectionary, an estimated decrease was only observed for the weighted mean sugars content.

However, the differences between weighted means were statistically significant only for Soft Drinks (p < 0.05), Sweet Biscuits (p < 0.05) and Breakfast Cereals (p < 0.10).

Given that the arithmetic means of sugars content did not present a significant variation, these changes can be mainly explained by increases/decreases in sales volume of products with lower/higher sugar content, in the case of Soft Drinks and Breakfast Cereals, and increases/decreases in sales volume of products with higher/lower sugar content, particularly for Sweet Biscuits.


These statistically significant variations are also aligned with the estimated variations in per capita nutrient sales, reported in the previous sections.

Table A3 (Appendix A) shows the variations (in g/100 and in %) of the market share weighted mean sugars content across countries.

Mirroring the aggregated results at the European level, decreases in the weighted mean sugars content for Breakfast Cereals, Soft Drinks, Confectionary, Sweet Spreads and Dairy were observed for more than 70% of the countries-with notable exceptions of increases in Bulgaria (4% or 0.4 g/100 mL), Czech Republic (6% or 0.5 g/100 mL) and Portugal (16% or 1.3 g/100 mL) in the case of Soft Drinks, and Czech Republic (5% or 0.5 g/100 g), Greece (5% or 0.4 g/100 g), Portugal (6% or 0.6 g/100 g), Poland (3% or 0.3 g/100 g) and Spain (9% or 0.9 g/100 g) for Dairy products.


Some reductions in the weighted mean of Processed F & V were also estimated for most of the countries, with ranges from −1.7 g/100 g (or −26%) for Romania to −0.1 g/100 g (or −2%) for Italy.

Similarly, substantial differences in the weighted mean sugars content were found for S, D & C and Baked Goods.

For Sweet Biscuits, the majority of the countries presented either an increase or have maintained the same levels of sugars in the products belonging to this category.


Overall, our results indicate that the weighted mean sugars content estimated for different European countries was reduced, on average, in only 2 out of the 9 analysed categories.

However, in some countries, such as Denmark, Ireland and the Netherlands, declines in the weighted sugars content can be extended to 8 out of the 9 analysed categories.

Nonetheless, the magnitude of these changes was rather small throughout all categories analysed: as an example, the weighted mean sugars content in Soft Drinks and in Processed F & V decreased by more than 5% in only 6 countries; for Confectionary, this was identified only in 4 countries.


The statistics presented in Table 3 show that Sweet Biscuits, Processed M & S and Savoury Snacks have consistently presented the highest values of weighted mean saturated fat content.

Except for Processed M & S, the weighted mean saturated fat content is lower than the respective arithmetic means for all categories in both analysed years, pointing out that products high in saturated fat were responsible for a comparatively smaller proportion of total sales.

The variability of data-represented by the standard deviation-remained virtually unchanged in the period, underpinning the large heterogeneity of saturated fat content in categories such as Sweet Biscuits, Savoury Snacks, Dairy and Baked Goods.

Since the arithmetic mean is higher than the median for all categories, the largest part of the products belonging to the analysed categories presented saturated fat content higher than the average.


Reductions in the market-weighted and arithmetic means of saturated fat were ob- served for Breakfast Cereals, S, D & C, Sweet Biscuits, Processed M & S, Soup and Savoury Snacks, while opposite trends were found for Dairy and Baked Goods.


However, the hypothesis tests for differences between means unveiled a statistically significant (p < 0.05) reduction in the market-weighted mean only for Sweet Biscuits (−8.3% or −0.7 g/100 g) and Processed M & S (−5.7%, or −0.3 g/100 g), trends also observed in the analysis of nutrient content in per capita terms.


No category presented statistically significant changes in the arithmetic mean of saturated fat content between 2015 and 2018.


Results were also heterogeneous at the country level (Table A4, Appendix A).


Particu- larly for Breakfast Cereals, there were more countries reporting an increase in the weighted mean of saturated fat rather than a decrease.


A notable example was Denmark (increments of 0.3 g/100 g or 42%).


Results are relatively better for S, D & C and Processed M & S, for which more than 70% of the countries presented some reduction in the market-weighted saturated fat content.


For these categories, the average change was −5% across the assessed countries.


A similar trend was also observed for Sweet Biscuits and Savoury Snacks, for which declines in the weighted saturated fat content were estimated for 70% of the coun- tries.


Considering Sweet Biscuits, notable reductions of the weighted mean of saturated fat content were observed in the UK (−2.7 g/100 g or −30%), Netherlands (−1.9 g/100 g or −20%), Ireland (−1.8 g/100 g or −20%) and Sweden (−1.6 g/100 g or −19%).


Likewise, the weighted saturated fat content in Processed M & S products sold in the Netherlands, Poland and Slovakia decreased by more than 15% (or more than 0.7 g/100 g) over the last years.


Similar trends were also identified for Savoury Snacks in Germany (−0.8 g/100 g or −15%).


Table 4 presents the overall statistics for the distributions of salt content in eight food categories (Ready Meals, S, D & C, Baked Goods, Processed M & S, Processed F & V, R, P & N, Savoury Snacks, Soup) across European countries in 2015 and 2018.

For Baked Goods, Processed M & S, Savoury Snacks and Processed F & V products, the market-weighted mean is higher than the arithmetic mean, which denotes that products with salt content higher than the arithmetic mean are proportionally and persistently sold in larger quantities than those with less.

Furthermore, maximum values for S, D & C indicate that some of these products (a particular type of dry sauce) have several times more salt per 100 g than the daily salt intake recommended by the EU national health-related organisations.

The tests for differences between means presented a statistically significant decline in the market-weighted mean only for Processed M & S. However, none of the arithmetic means unveiled statistical evidence of reduced salt content for the selected category.

This indicates that in this category, products with salt content less than the arithmetic mean gained market share over those with salt content above the arithmetic mean.

Baked Goods was the only category to report a higher market-weighted mean in 2018 compared to 2015, in statistically significant terms (p < 0.0001).

Its arithmetic mean also showed an increase in the respective saturated fat content, albeit not statistically significant.

The upward/downward trend in sales of salt content of Baked Goods and Processed M & S can be also visualised in the estimated per capita daily changes.


There were substantial variations between 2015 and 2018 in salt levels of manufactured foods throughout Europe (Table A5Results for the overall changes in fibre content are present in Table 5.

Since the market- weighted mean is higher than the arithmetic mean only for Baked Goods, R, P & N and Processed F & V, it is possible to note that products with relatively higher fibre content were proportionally and persistently sold in larger quantities than those with less fibre content.

A significant decrease from 2015 to 2018 in the weighted mean estimates points out that there were proportionally less sales coming from products with higher than arithmetic mean fibre contents for Ready Meals.

It is worth mentioning that the levels of fibre sold through products belonging to this category were already lower when compared to other analysed categories.

When assessing the evolution of the weighted mean fibre content at the national level, the results of Table A6 (Appendix A) also show remarkable heterogeneity among European countries.

While approximately 60% of the countries had increased weighted mean fibre content in Sweet Spreads and Soups, the magnitude of this increment is, on average, not more than 2%.

For other categories-such as Breakfast Cereals, R, P & N, Processed F & V and Savoury Snacks, only 30% of the countries presented an increase in their weighted mean fibre content over the past years.

However, increases in the weighted mean fibre content were found for 6 or more categories in Switzerland, Bulgaria, Slovakia and Spain.

Specifically, for Ready Meals, there were reductions observed in 9 out of the 24 analysed countries, reaching −0.6 g/100 g (−7%) in the case of Denmark and −0.3 g/100 g (−5%) in the Czech Republic.


We assessed the changes in the market-weighted nutrient mean only for products/brands that were available on the market both in 2015 and 2018.

This enabled us to better analyse the overall market dynamics as well as the reformulation trends in Europe.

Figures 11-14 present the estimated changes in the market-weighted mean of sugars, saturated fat, salt and fibre content for products of the same brand and name observed in both years ("paired" products), which are plotted against the "unpaired" market-weighted nutrient means (reported in the Sections 3.2.1-3.2.4), calculated based on all products available in Euromonitor's database in any specific year.

Significance levels are also shown for the weighted means that are statistically different from zero.

In contrast, the weighted mean of sugars content in Breakfast Cereals and Soft Drinks dropped slightly more in paired products.

This could indicate that products with higher market share had their sugars content reduced, and/or that products with a relatively low amount of total sugars per 100 g had their sales increased.

It might also represent some reformulation effort from the leading brands towards reducing the sugars content in prod- ucts of these categories.

The weighted mean of salt content in paired products of Baked Goods also followed similar trends, as they had a smaller statistically significant increase when compared to unpaired products.


For fibre, Figure 14 shows identical trends in the market-weighted mean fibre content for paired and unpaired products in Ready Meals.

This indicates that products with high fibre content may have been removed from the market, or products that have been intro- duced contained relatively low amounts of fibre.

At the same time, it is also possible that some reformulation towards increasing the fibre content in some of those products per- sisting in the market was carried out.


This paper analysed the trends of the nutritional quality of packaged food and soft drinks with respect to nutrients of public health priority, i.e., sugars, salt, saturated fat and fibre.

We paired commercially available food composition data with market share and sales data and assessed 14 packaged foods and drinks categories sold in 22 European countries between 2015 and 2018.

We provided novel insights on (i) how much of these nutrients were sold through these product groups in 2018 vs. 2015, (ii) how much the content of these nutrients changed in the food and drink offers and (iii) by analysing market-weighted mean nutrient contents, how the combination of nutrient content, sales and consumer preferences have evolved against public health nutrition objectives towards reducing intakes of sugars, saturated fat, salt and increasing those of fibre.


First, our daily per capita estimates for Europe indicate that the largest volumes of nutrient sales come from few product categories: Soft Drinks, Confectionary, Dairy and Baked Goods represent almost 80% of daily per capita sugars sales.

For saturated fat, Dairy, Processed M & S, Baked Goods and Sweet Biscuits also accounted for a similar share of the estimated daily per capita sales.

Salt sold through Processed M & S, Baked Goods and S, D & C accounted for 75% of the total per capita sales.

At the same time, only two categories (Baked Goods and Processed F & V) were responsible for almost 60% of per capita sales of fibre.


In addition, the results of the absolute changes in daily per capita sales in Europe suggest that few categories presented improvements in their nutritional content: sugars in Breakfast Cereals and Soft Drinks, saturated fat in Processed M & S, Sweet Biscuits and Baked Goods, salt in Processed M & S and Processed F & V and fibre in Savoury Snacks, Breakfast Cereals and Sweet Biscuits.

Despite the progress observed in these categories, the magnitudes of the estimated changes lag behind when compared to the targets/benchmarks established by several initiatives, such as the 10% reduction for added sugars over a 5-year period [8], and the decreases of 16% and 5% for salt [5] and saturated fat [7] respectively, in 4-year periods.


While the European aggregate estimates are useful to track changes in nutrient sales over time, they also hide severe heterogeneities among countries.

For example, approximately 75% of the analysed countries presented some decrease in per capita levels of sugars sales attributable to Soft Drinks.

On the other hand, the overall reduction in per capita sales of salt attributable to Processed M & S could be mainly attributed to only 4 countries.

Likewise, few countries were the main contributors to the recent changes observed in daily per capita volumes of total sugars and fibres sold as Breakfast Cereals.


Yet, despite some improvements observed in a few categories and nutrients, the progress against public health objectives on the amounts of sugars, saturated fat, salt and fibre being sold to European citizens through packaged food and soft drinks is modest.

The amounts sold remain close to the 2015 levels (70 g/pc/day for sugars, 8 g/pc/day for saturated fat, 3 g/pc/day for salt and 7 g/pc/day for fibre on a basis of approximately 600 kcal/pc/day), and when compared to reference intake values from the Food Information to Consumers (FIC) regulation (90 g/pc/day for sugars, 20 g/pc/day for saturated fat, 6 g/pc/day for salt) and adequate intake of 25 g/pc/day for fibre [29], all on a reference basis of 2000 kcal/pc/day, it is possible to note that the levels of sugars and salt are of the most concern.


Second, beyond identifying great variability of the nutritional composition within and among packaged food and soft drinks categories, our estimates of the market-share weighted mean nutrient values suggest that the aggregated amount of sugars sold to European citizens was reduced only in 2 out of the 9 analysed categories (Breakfast Cereals and Soft Drinks), and even increased in the case of Sweet Biscuits.

For saturated fat, reductions were observed in 2 out of the 9 assessed categories (Sweet Biscuits and Processed M & S), and for salt, reductions were observed only for products belonging to Processed M & S, and a significant increase was even estimated for Baked Goods.

In general, the magnitudes of the improvements were rather small since the overall amounts of sugars, saturated fat and salt sold through these categories decreased by 3.3%, 4.4% and 2.1%, respectively.

Moreover, statistically significant decreases in the market-share weighted fibre content were estimated for 1 out of the 9 assessed categories (Ready Meals) and overall, amounts of fibre sold across all product groups decreased by 2.1% between 2015 and 2018.

In addition, our comparative analysis between the market-share weighted nutrient mean of paired and unpaired products point to large differences in sales and reformulation dynamics.

For some categories and nutrients (such as saturated fat in Processed M & S, saturated fat and sugars in Sweet Biscuits), the changes might be explained by the net effect of the introduction/discontinuation of products with lower/high nutrient content between 2015 and 2018.

For others (e.g., sugars in Breakfast Cereals and Soft Drinks and salt in Baked Goods), overall changes could be attributable to reductions/increases in market share of products with relatively high/low nutrient content, but also to some reformulation of those products which have been persistently sold in the European market.


Nevertheless, for the nutrients and categories in which a statistically significant change in the market-weighted nutrient content was identified, similar trends were also observed for their daily per capita nutrient sales.

These findings consistently reflect different aspects of the overall quality of the food: the nutrient composition of the food supply and the average availability, market success of food and drinks with better or not so good nutrient profiles and the preferences of European citizens towards these products.

In addition, the fact that most of the categories did not present a statistically significant change in their market-weighted nutrient content may indicate that just reformulating products or launching new ones with better nutrient profiles does not suffice to markedly impact sales and population diets if consumer preference for such products does not increase contemporaneously.

Arguably, policies need to also address in parallel the food environment, supporting actions on educating, informing and incentivising consumers towards healthier choices.


Third, our results also suggest modest progress in the nutritional content of the food supply across the European countries.

For some categories, such as Dairy, Sweet Biscuits and Confectionary, decreases of more than 5% in the respective market-share weighted total sugars content (in g/100 g) were observed only for 5 out of the 22 countries analysed; for others (e.g., S, D & C), there were only 2 countries achieving this level of reduction.

Considering the EU Added Sugar Annex [8] and its 10% added sugar reduction target by 2020 against the 2015 baseline level, our findings suggest that countries risk falling short on their commitments to reduce the content of sugars in packaged foods and soft drinks.

Similarly, the number of countries that had their market-share weighted mean of saturated fat reduced by more than 5% varies from 4 (e.g., for Dairy and Breakfast Cereals) to 9 countries (e.g., for Processed M & S).

Decreases of more than 5% in the market-share weighted mean of salt were more frequent for Ready Meals and Processed F & V (9 countries) and Processed M & S and Savoury Snacks (7 countries).

In the case of fibre, increases of more than 5% in the market-share weighted mean for Sweet Spreads and Soup were found for 7 countries, while for Sweet Biscuits and Ready Meals, this threshold was achieved in 6 and 5 countries, respectively.

Results are even more worrying for other categories (such as Breakfast Cereals, Processed F & V and Savoury Snacks), as they point to decreases in the market-share weighted mean of fibre for more than 70% of the analysed countries.