REDHILL TRIAL: MORE POSITIVE NEWS.
Dr. David Graham, Baylor College of Medicine, presented results of the Phase III randomized, double blinded, placebo controlled, multicenter, parallel group study to assess the efficacy of anti-MAP therapy (RHB-104) in the treatment of Crohn's disease at the United European Gastroenterology (UEG) Week that took place in Vienna, October 20 - 24, 2018.
A previous press release announced significant remission levels for RHB-104-treated patients compared to controls at the 26 week time point. RedHill now announces that the remission was durable, i.e. significantly better than placebo controls at 52 weeks. This is one of the data slides shown.
This link provides the 22 slides shown by Dr. Graham at the UEG meeting (with permission). These slides provide details on the study design, data analysis methods, and results at primary and secondary endpoints as well as results on study subgroups, e.g. comparison on patients treated with anti-TNF drugs or corticosteroids versus controls.
Johnes.org is grateful to Dr. Graham and RedHill BioPharma for granting permission to provide this information to its readers.
WHY I DO THIS.
Once upon a time, about 15 years ago, there was a young Wisconsin girl named Lizi who was in 4H , a U.S. organization that provides experiences where young people learn by doing. Lizi decided to do a project to learn more about Johne's disease, something she had seen on her family's farm. She searched the web and found Johnes.org. Lizi used the information and images she found there to create a poster which she exhibited at the Lodi Agricultural Fair and Dane County Fair in Wisconsin, winning a blue ribbon for her efforts. Here is a picture of Lizi's poster.
This story came to light when Lizi was in my Veterinary Bacteriology & Mycology class, Fall semester in 2017, learning (again) about Johne's disease. Lizi shared this picture of her poster and granted me permission to tell her story here. The adjacent photo shows Lizi with a newborn calf on her family's farm. She will graduate with her DVM degree May, 2020.
You never know what kind of impact knowledge sharing will have.
This is why I do this.
Michael.T. Collins, DVM, PhD, DACVM.
JOHNES.ORG VERSION 4.0
We are pleased to announce this new version (4.0) of Johnes.org. The content has been updated and expanded, and the site has been enhanced with more images. The image gallery has been particularly popular with past users, so we expanded this feature and encourage readers to use these images in the furtherance of our Johne's education effort. We also invite your feedback, especially if you find errors that require correcting.
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OVINE PARATUBERCULOSIS IN URUGUAY
Eleven cases of Johne’s disease are described in this case report. All originate from a 735 head flock of sheep in Colonia, Uruguay. Six animals had the multibacillary form of the disease (abundant acid-fast bacteria), and 5 had the paucibacillary form with minimal lesions. All animals were infected with the S-strain of MAP. This is only the second time the S-strain of MAP has been reported in South America, the other being from a sheep in Argentina.
Comment: This report has a lovely scanning electron micrograph of MAP inside macrophages, an excellent picture of the thickened intestine, and good histopathology images, both H&E stained and ZN-stained. The article notes that Johne’s disease is widespread in Uruguayan cattle but has not been documented as a problem in sheep until this case report. This report is newsworthy for documenting S-strain MAP infections in sheep in Uruguay and for the relatively young journal in which the report appears.
This is an open-access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
COMPARISON OF TWO PCRS FOR DIAGNOSIS OF PARATUBERCULOSIS IN SHEEP
Julie Arsenault and colleagues just reported a comparison of PCR assays to detect MAP in fecal samples from ewes culled from 7 flocks in Quebec, Canada (see JVDI OnlineFirst, 02-NOV-2018, link below). This is a novel contribution to Johne’s disease research since there are not many reports of diagnostic test accuracy on sheep are available from animals in North America.
The case definition for being MAP-infected was based on isolation of MAP in culture from tissues and was met by 44 ewes in the study. Another 30 culled ewes from these same flocks were deemed not MAP-infected based on culture for MAP from tissues and histopathology. The in-house real-time IS900 PCR sensitivity (Se) & specificity (Sp) were 84% and 93%. By comparison, a commercial PCR kit (Tetracore) had values of 52% (Se) and 93% (Sp), assuming “suspect” classified samples were considered negative. The Tetracore Se & Sp values were 63% and 87% if suspects were classified as positive because Se goes up, but Sp goes down as you move the cut-off for defining a “positive”.
Other interesting observations: A commercial, ELISA had and Se/Sp of 14% and 100% on these same ewes further verifying that ELISA is not particularly useful when used on sheep. And among the ELISA-positive ewes 3 had multibacillary lesions (lots of MAP observed) and 1 had paucibacillary lesions (few or no MAP observed). Fecal culture Se was 21% (3 multibacillary and 2 paucibacillary).
Comment: Evaluation of diagnostic assays is tricky business. The case definition is crucial! This study used a standard, well-accepted case definition for MAP-infected sheep, i.e. the sheep considered as “cases” were culture-positive from mesenteric lymph nodes, ileum or feces. The trickier part is the case definition for not MAP-infected. While it is relevant to test animals residing in the same flocks as the MAP-infected animals, it is also important to test animals in flocks that are 100% certain to be MAP-free. This higher standard for not MAP-infected, testing MAP-free flocks, was not achieved in the study making specificity estimates questionable (acknowledged by the authors). Because PCR assays may be more sensitive than the “gold standard” used to define not infected ewes there may be instances where the PCR was correct and the case definition for being not MAP-infected was wrong. And, the study was relatively small making the 95% confidence limits on Se and Sp estimates fairly large.
There is much to be learned from the study details, including the supplementary information. Check out Fig.1 to see from where MAP was most often isolated. Read this well-written article, in the Journal of Veterinary Diagnostic Investigation it is worth your time.
MAP AND TYPE I DIABETES MELLITUS (T1DM)
In 2006 Dr. Tom Dow hypothesized that MAP in cow’s milk could act as a trigger for Type 1 Diabetes Mellitus (T1DM) – see the journal Medical Hypotheses 67:782-785, 2006. He now draws together the body of scientific work published since that time, much of it from the laboratory of Dr. Leonardo Sechi, that backs up this highly probable causal association in a short You Tube video related to milk. Watch both and judge for yourself.
FIRST REPORT OF CHRONIC ENTERITIS IN HUMANS, LATER KNOWN AS CROHN’S DISEASE (1913).
October 25, 2018
105 years ago today, Thomas Kennedy Dalziel (1861-1924) published the first report of the chronic inflammatory intestinal condition that is now called Crohn’s disease; named for the first of three authors of the 1932 report describing the pathology and clinical presentation of this regional ileitis. Dalziel’s paper describes several cases, three of which have pathology reports. Noteworthy is that Dalziel mentions the gross and microscopic similarities of the intestines he removed from patients with those from cases of Johne’s disease in cattle. He mentions the 1895 work of Johne (misspelled as Henny) and Frothingham and cites the early work on the Johne’s disease pathology by McFadyen. The puzzling aspect is that while the pathology of the human and animal diseases is strikingly similar, acid-fast bacteria (MAP) can be seen in the animal tissues but not in the human tissues: a puzzle that remains today and is the essential feature leading some experts to view the human and animal forms of this chronic enteritis as having different causes.
Comment: This historically important publication (British Medical Journal vol. 2, no. 2756, pp 1068-1070, October 25, 1913) is made available by JSTOR at the link provided below. Without agencies such as JSTOR it is hard to obtain older literature such as this.
Thomas K. Dalziel was known for his charm, kindliness, extraordinary teaching skills, and marvelous manipulative dexterity. He was considered the best technical surgeon in the West of Scotland. His contributions to the medical literature were considerable, dealing mainly with abdominal surgery. His writings, including this “classic” paper, demonstrate a concise grasp of a new disease entity, chronic interstitial enteritis, later to become known as Crohn's disease. It is generally believed that Dalziel was the first to draw attention to this condition (Diseases of the Colon and Rectum 32:12, pp 1076-1078, 1989).
NEW PHAGE-BASED DIAGNOSTIC TEST COMING TO MARKET.
At the 2018 meeting of the European Association of Veterinary Laboratory Diagnosticians (14-17 October, 2018) Pelletier et al. reported on the use of a new phage-based assay called Actiphage™ Rapid kit from PBD Biotech to detect MAP in blood samples from bovine calves. Details are provided in the two page abstract (link below).
Comment: This report is interesting from two perspectives. The first is the biology of MAP infections in dairy calves. This the first report of MAP detection in blood samples of 3 different calves soon after birth; 1, 15, and 84 days of age for the three different calves. The calves reverted to test-negative after the single MAP detection. The second perspective is the promise of improved diagnostics for paratuberculosis using phages to enhance DNA extraction of MAP DNA from clinical samples to enhance the diagnostic sensitivity of real-time PCR assays for MAP.
SURVEY OF MAP INFECTION IN CANADIAN DAIRY HERDS
Canadian colleagues at three veterinary schools in Canada teamed up to do the first all-Canada survey to estimate the prevalence of MAP infected dairy herds. The study collected samples from 362 dairy herds in 10 Canadian provinces using environmental fecal cultures as the diagnostic test.
True prevalence estimates were 66% for farms in Western Canada, 54% in Ontario, 24% in Québec, and 47% in Atlantic Canada. Herds housed in tie-stalls had a lower prevalence than freestall-housed herds, and herds with 101–150 and >151 cows had higher prevalence than herds with ≤100 cows. This was the first time MAP prevalence was determined using 1 detection method, performed in 1 laboratory, and within a single year across Canada, enabling direct comparisons of prevalence among regions, housing types, and herd sizes.
This was the first time MAP prevalence was determined using 1 detection method, performed in 1 laboratory, and within a single year across Canada, enabling direct comparisons of prevalence among regions, housing types, and herd sizes. The authors did an elegant job of judging the sensitivity and specificity of their sampling method. Their survey findings are similar those done in Europe and a bit lower than estimates for U.S. dairy herds.
LANDMARK PAPER DEFINING CROHN’S DISEASE (1932)
Eighty-six years ago today, Burrill B. Crohn, Leon Ginzburg, and Gordon D. Oppenheimer published a paper titled Regional Ileitis – A Pathologic and Clinical Entity in the Journal of the American Medical Association (vol. 99, no. 16, pp 1323-1329, October 15, 1932). Honoring the importance of this report, the article was later reprinted as a Landmark Article in The Mount Sinai Journal of Medicine (vol 67, no. 3, pp 263-268, May 2006). We provide the original JAMA article here for users interested in reading this influential publication in its original form. Note: the reprinted version in the Mount Sinai Journal of Medicine has better print quality. The picture of B.B. Crohn is credited to Wikipedia.
Comment: I appreciate history as I grow older. Also, it is important to read original published reports to avoid misquoting or perpetuating misunderstandings. Interesting note: As described in Wikipedia, Crohn always preferred the medically descriptive terms "regional ileitis" and "regional enteritis" to "Crohn's disease", but he was not able to prevent the appropriation of his name for the disease.
Without providing much detail, B.B. Crohn’s article mentions efforts to determine if Mycobacterium tuberculosis was involved in the regional ileitis cases he described including culture for M. tuberculosis, inoculation of lymph node homogenates from five patients into guinea pigs, rabbits, and chickens, and acid-fast staining of tissue sections. He concludes that M. tuberculosis was not a cause of these cases of regional ileitis. However, he never mentions the 1913 report by Dalziel or makes any mention of Mycobacterium paratuberculosis or the similarities of regional ileitis in humans to that of cattle, as described by H.A. Johne in 1895. How might history be different had Dr. Crohn mentioned the possibility of M. a. paratuberculosis (MAP)?
MAP & CROHN'S & REDHILL BIOPHARMA - MORE DETAILS.
Primary endpoint successfully achieved - superior remission rate at week 26 in patients treated with RHB-104 (p= 0.013).
Key secondary endpoints also met, demonstrating consistent benefit to Crohn’s disease patients treated with RHB-104.
Comment: The real proof is in the final peer reviewed publication: Repeating comments from the prior new item, if the final published results of this trial are consistent with the claims in this press release, it represents a final piece of evidence indicating that MAP is a cause of Crohn’s disease. This would heighten the need for veterinary medicine, animal agriculture, and relevant governmental agencies concerned with food safety to limit contamination of food and water by MAP.
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