THYMECTOMY FOR MYASTHENIA GRAVIS

Thymectomy plus prednisone improves outcomes in patients with non-thymomatous myasthenia gravis (MG), compared with prednisone alone, according to results from the two-year extension of the MGTX randomized trial.

"Most of us had a hunch that thymectomy was helping this group of MG patients, despite them not having a thymoma to remove," Dr. Gil I. Wolfe from University at Buffalo Jacobs School of Medicine and Biomedical Sciences, Buffalo, New York told Reuters Health. "What was most surprising was the degree that thymectomy reduced hospitalization requirements and how after five years it contributed to such a high proportion of subjects reaching minimal manifestation status for the disease."

The 36-month MGTX randomized controlled study showed that thymectomy in combination with a standardized prednisone protocol was superior to prednisone alone in improving myasthenic weakness and lowering corticosteroid requirements in patients with non-thymomatous myasthenia gravis who were positive for acetylcholine receptor antibodies.

Dr. Wolfe and colleagues now report results of the two-year extension study to assess the durability of the treatment response. Overall, 68 patients entered the extension study, 50 of whom completed the 60-month visit.

As in the main trial, patients in the thymectomy plus prednisone group had significantly greater improvement in Quantitative Myasthenia Gravis scores and significantly lower mean prednisone doses from month 0 to month 60, compared with the prednisone alone group, according to the January 25th Lancet Neurology online report.

The proportion of patients achieving minimal manifestation status at month 60 was significantly higher in the thymectomy plus prednisone group (23/26, 88%) than in the prednisone alone group (14/24, 58%).

From month 0 to month 60, the proportion of patients requiring azathioprine or intravenous immunoglobulin was significantly lower in the thymectomy plus prednisone group than in the prednisone alone group.

Between months 36 and 60, only two patients in each group showed signs of clinical worsening.

"The extension study reinforces the benefit of thymectomy noted in the randomized controlled MGTX, shows continued benefits at five years, and dispels doubts about the procedure's benefits or the longevity of its effects," the researchers conclude.

"I certainly think that thymectomy should be part of the early discussion between the health care provider and the patient," Dr. Wolfe said. "Now I won't argue strongly that if a patient is really doing well on an initial stab at immunotherapy and tolerating it well and really having minimal or perhaps no issues related to myasthenia, that one should do a hard sell to push the patient toward thymectomy. It could be considered, but there are patients who can be managed without it."

"But for those patients who are just not doing as well as one would hope after the initial immunotherapy attempt, I do think it needs to be part of the conversation," he said. "I think the initial trial and the extension study provide a foundation of evidence to support the need for that conversation."

"Based on the cost of some of our immunotherapies for MG and the reduced need for hospitalizations, the one-time ticket price of a thymectomy, even in the U.S. where everything seems to cost more when it comes to health care, can be quite cost-effective," Dr. Wolfe said.

Dr. Sonia Berrih-Aknin from Sorbonne Universite and UPMC Universite Paris 6, who co-authored an editorial related to this report, told Reuters Health by email, "I was surprised by the fact that after five years of thymectomy, the therapeutic effects were even better than after three years, indicating that: 1) the surgery has long-term effect; and 2) an absence of short-term therapeutic effect is not synonymous of no-effect."

"One could think that removing the culprit organ should have short-term and direct effects, but this work clearly shows that the mechanisms are probably complex," she said. "It is possible that autoreactive T cells (and possibly B cells) from the thymus migrate to the periphery and pursue their pathogenicity. Their persistence in the periphery could explain why the effects are long-term."

"The molecular mechanisms that could explain the beneficial effects of thymectomy remain to be known," Dr. Berrih-Aknin said. "That could eventually help to define more precisely the patients who are not susceptible to benefit from surgery."

HPV VACCINATION IS APROGRESS

The HPV vaccine is a "critical" health tool and access to it should be scaled up as swiftly as possible, especially in poorer countries, cancer experts said on Monday.

Figures from the World Health Organization's International Agency for Research on Cancer (IARC) showed an estimated 570,000 new cases of cervical cancer were diagnosed worldwide in 2018, making it the fourth most common cancer in women globally.

Each year, more than 310,000 women die from cervical cancer, and the vast majority of deaths are in poorer countries where immunization rates against the human papillomavirus (HPV) that causes it are low.

In wealthy countries, some anti-vaccine campaigners are also persuading parents to refuse the shot for their children, leaving them at risk, IARC said.

"Unfounded rumours about HPV vaccines continue to unnecessarily delay or impede the scaling up of vaccination," IARC's director Elisabete Weiderpass said in a statement.

She said IARC was committed to fighting cervical cancer and "unequivocally confirms the efficacy and safety" of HPV shots.

Britain's GSK makes an HPV vaccine called Cervarix, which targets two strains of the virus, while Merck makes a rival shot, Gardasil, which targets nine strains.

In a separate statement addressed to the WHO last week, the GAVI vaccines alliance also urged greater support for HPV shots, saying it aimed to immunize 40 million girls in poorer countries against HPV by 2020.

This would avert an estimated 900,000 deaths, GAVI said.

IARC said reducing the cost of vaccines in poorer countries would play a vital role in increasing access to them. It said it was working with the generic drugmaker Serum Institute of India to develop an HPV shot that "could provide a high-quality alternative at a lower cost."

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CHRONIC PPI USE INCREASE GASTRIC CANCER RISK

Use of a proton-pump inhibitor (PPI) after Helicobacter pylori eradication more than doubles the risk for gastric cancer, according to a population-based study from Hong Kong.

The "clear dose-response and time-response" trend in PPI use and gastric cancer risk observed suggests the need for "caution when prescribing long-term PPIs to these patients even after successful eradication of H. pylori," write Wai Keung Leung, MBChB, MD, from Queen Mary Hospital, Hong Kong, and colleagues.

The study was published online October 31 in Gut.

The researchers point out, however, that this was an observational study, which can't prove cause and effect.

The new results also conflict with a recently published, US Food and Drug Administration–mandated follow-up study conducted with pantoprazole, said David A. Johnson, MD, chief of gastroenterology at Eastern Virginia Medical School in Norfolk (Aliment Pharmacol Ther. 2016;43:73-82).

"No increased risk [for gastric cancer] was observed with prolonged PPI exposure," he said.

Dr Johnson, who was asked for comment, also stated that the study has a "geographic bias" because it is from Hong Kong and "specific risks for gastric cancer are well recognized in Asian patients."

In the new study, Dr Leung and colleagues partly focused on H pylori infection and its relationship with gastric cancer.

H pylori eradication has been shown to reduce the risk for gastric cancer by 33% to 47%, but many patients develop gastric cancer even after eradication of H pylori. PPI therapy, "although generally considered safe," is associated with worsening gastric atrophy, particularly in H pylori–infected patients, the researchers point out. A recent meta-analysis found a 43% increased risk for gastric cancer among long-term PPI users, but it is was unable to adjust for H pylori, the major confounding factor.

Using a territory-wide health database in Hong Kong, Dr Leung and colleagues compared the risk for gastric cancer in PPI users and histamine-2 receptor antagonist (H2RA) users among 63,397 adults successfully treated with a 7-day course of triple therapy to eradicate H pylori between 2003 and 2012. 

"PPIs are much more potent than H2RA in terms of gastric acid suppression, and previous studies did not reveal any association between gastric cancer development and H2RA. Hence, H2RA was selected as a negative control exposure in our study," the researchers explain.

During a median follow-up of 7.6 years, 153 (0.24%) people developed gastric cancer after H pylori eradication therapy, mostly in noncardia regions (62%). None of the patients with gastric cancer tested positive for H pylori at diagnosis, but all had long-standing gastritis. The median age at cancer diagnosis was 71.4 years, and the median time from H pylori eradication to gastric cancer was 4.9 years.

After propensity score adjustment, people taking PPIs at least weekly had a greater than twofold increased risk for gastric cancer development (hazard ratio [HR], 2.44; 95% confidence interval [CI], 1.42 - 4.20). The propensity score–adjusted absolute risk difference between PPI use and non-PPI use was 4.29 excess gastric cancer cases per 10,000 person-years.

H2RA users had no increased risk (HR, 0.72; 95% CI, 0.48 - 1.07), which "further supports the specific role of PPIs on gastric cancer development," the researchers say.

After stratification by tumor site, PPI use was only significantly associated with an increased risk for noncardia gastric cancer (HR, 2.59; 95% CI, 1.42 - 4.72) but not cardia cancer (HR, 1.97; 95% CI, 0.57 - 6.82); "although this result should be interpreted with caution as this subgroup analysis has a relatively small number of cardia cancers," the researchers say.

Gastric cancer risk increased with longer duration of PPI use. The HR was 5.04 (95% CI, 1.23 - 20.61) for 1 year of use or longer, 6.65 (95% CI, 1.62 - 27.26) for 2 years of use or longer, and 8.34 (95% CI, 2.02 - 34.41) for 3 years use or longer.

More frequent use was also associated with greater risk. When compared with the reference group (less than weekly use), gastric cancer risk progressively increased with more frequent PPI use. The HR was 2.43 (95% CI, 1.37 - 4.31) for weekly to less than daily use, increasing to 4.55 (95% CI, 1.12 - 18.52) for daily PPI use.

The results remained significant by various sensitivity analyses.

A strength of the study is its use of data from a large population-based database with complete information on subsequent diagnoses and drug prescriptions, which minimizes selection, information, and recall biases, the researchers say. Use of strict exclusion criteria as well as propensity score adjustment to control for potential confounders and restricting the sample to patients with successful H pylorieradication are other strengths.

In terms of study weaknesses, the researchers  lacked information on some risk factors, such as diet, family history, and socioeconomic status.  And despite the large sample of more than 63,000 H pylori–infected patients, the small number of gastric cancer cases did not allow for any "meaningful evaluation of the dosage effect and role of different PPIs," the researchers say. 

The team also notes that PPIs users may have a higher chance of undergoing endoscopy than non-PPI users, leading to discovery of more gastric cancers due to surveillance bias.

Dr Johnson said there was another study weakness: "Important" demographic variables that are risk factors for gastric cancer — such as  smoking, alcohol use, obesity, diet, and family history — are not accounted for.  

He also made a general observation about PPI-related research: "Most studies showed that any potential effects of PPIs tend to disappear with time and that the most likely explanation for the effects is confounding by indication rather than causality."

Despite these limitations, Dr Leung and colleagues write that, to their knowledge, "this is the first study to demonstrate that long-term PPIs use, even after H. pylori eradication therapy, is still associated with an increased risk of gastric cancer. This is likely related to the profound acid suppression of PPIs that worsens atrophic gastritis, particularly in those patients with established gastric atrophy as a result of chronic H. pylori-induced inflammation."

EDITOR'S NOTE: The story has been updated to included comments from an expert not involved with the study.

The study had no specific funding. Dr Leung has received honorarium for attending advisory board meetings of Takeda and Abbott Laboratories. Dr Johnson has or has had financial ties to Pfizer Inc, which makes a PPI; Epigenomics; WebMD; CRH Medical; and Medtronic.

STATIN USE INCREASE DIABETES RISK

Long-term statin use is associated with an increased risk of type 2 diabetes of approximately 30% in individuals at high risk of the disease, even after taking into account known risk factors and potential confounders, say US researchers.

They looked at the development of diabetes among statin users in the Diabetes Prevention Program (DPP), which included more than 3200 participants.

Over 10 years, statin use was linked to a 36% increased risk of being diagnosed with type 2 diabetes, falling to 27% after taking into account baseline risk factors and clinical criteria used to determine the need for statins.

The findings are consistent with previous studies suggesting that statin use substantially increases the risk of type 2 diabetes.

The new study was published online October 23 in BMJ Open Diabetes Research & Care by lead author Jill P Crandall, MD, department of medicine and diabetes research center, Albert Einstein College of Medicine, New York, New York, and colleagues.

As previously reported by Medscape Medical News, a study of more than 8700 Finnish men aged 45 to 73 years showed that over 6 years of statins therapy were linked to a 46% increased risk of type 2 diabetes — more than double prior estimates.

This was followed by recent data from the Australian Longitudinal Study on Women's Health, which indicated that, among almost 8400 women aged 76 to 82 years, the risk of new-onset diabetes ranged from 17% with the lowest statin doses to 51% with the highest doses.

Despite accumulating evidence, the current researchers still maintain that the overall healthcare advice remains unchanged — the benefits of statins outweigh the risks.

"For individual patients, a potential modest increase in diabetes risk clearly needs to be balanced against the consistent and highly significant reductions in myocardial infarction, stroke, and cardiovascular death associated with statin treatment," they state.

They add: "Nonetheless, glucose status should be monitored and healthy lifestyle behaviors reinforced in high-risk patients who are prescribed statins for cardiovascular disease prophylaxis."

First Look at Diabetes Risk From Statins in High-Risk Patients

The researchers point out that the diabetogenic effect of statins has previously been studied in individuals typically at relatively low risk of diabetes and that the incidence of disease was based on self-report, rather than being the primary outcome.

They therefore set out to examine the issue in DPP participants, which included 3234 US adults randomized to intensive lifestyle intervention, metformin, or placebo.

After a mean follow-up of 3.2 years, participants were invited to take part in the DPP outcomes study, which included quarterly lifestyle sessions alongside open-label metformin for those originally randomized to the drug and two additional lifestyle programs per year for those originally randomized to the lifestyle intervention.

Approximately 50% of DPP participants were from ethnic groups and 20% were aged ≥ 60 years. To be included, they had to be aged ≥ 25 years and have a body mass index ≥ 24 kg/m². They also had to have a fasting plasma glucose (FPG) of 95–125 mg/dL and impaired glucose tolerance, placing them at high risk of type 2 diabetes.

The primary end point was diabetes diagnosis using an annual 75-g oral glucose tolerance test or semiannual FPG level with repeat confirmation testing. Lipids and blood pressure were assessed annually and statin use was based on self-report.

From a baseline of approximately 4%, statin use progressively increased at the 10-year follow-up to reach 35% in the placebo group, 37% in the metformin group, and 33% in the lifestyle intervention group (P = .36 between groups).

Simvastatin was the most commonly used statin, taken by 40% of participants, followed by atorvastatin by 37% and, much less frequently, lovastatin and pravastatin, by 9% and 8%, respectively.

Statins users were typically older and more likely to be men than nonusers but did not differ by ethnicity. Compared with nonusers, they also had modestly higher baseline FPG and HbA_1c, higher baseline low-density lipoprotein (LDL) cholesterol and triglycerides, and were more likely to have a history of cardiovascular disease and hypertension.

Taking into account age, sex, and ethnicity, researchers found that statin use was associated with a significantly increased risk of developing diabetes, at a hazard ratio (HR) of 1.36 for all three groups combined.

Further adjustment for baseline diabetes risk factors, including family history of diabetes and FPG, reduced the HR to 1.35, and additional adjustment for statin treatment confounders, such as blood pressure, cholesterol levels, baseline cardiovascular risk factors, and socioeconomic status, lowered the HR to 1.27.

Diabetes risk did not differ depending on statin potency or magnitude of LDL-cholesterol reduction, although longer statin use was significantly associated with greater diabetes risk (HR per visit with statin use, 1.06; P=.007).

Mechanisms Underlying Effect "Poorly Understood"

Discussing the findings, the researchers say that "it has been suggested that statins may 'uncover' diabetes in individuals at high risk, which on a population basis, could result in modest increase in diabetes risk."

They point out, however, that "variation in baseline diabetes risk factors failed to explain the further risk associated with statin therapy in our cohort, and the HR estimate was greatest among our lifestyle participants, who experienced the largest study-related reductions in diabetes risk."

The mechanisms underlying any diabetogenic effect of statins are "poorly understood," they add.

Although several studies have looked at changes in insulin sensitivity during statin use, "we saw no evidence of an effect of statins to modify insulin resistance, assessed as fasting insulin concentrations," they write.

And although statins have been reported to reduce pancreatic beta-cell insulin secretion in vitro, "the relevance to insulin secretion in vivo is not known," they state.

Taken together, evidence from studies published so far points to "an acceleration of typical glycemic deterioration, rather than a unique or statin-specific mechanism," they conclude.