The Possible Role of MAP in Sarcoidosis

 

Mycobacterium avium spp paratuberculosis (MAP) has been found in a number of different human diseases. The role that MAP plays in any of these conditions is still the subject of debate, and further research is necessary. Human Para will add research studies as they are released.

Mycobacteria, whether tuberculosis (TB) or non-tuberculosis (NTM), seem to play an important role in the development of sarcoidosis in a group of patients. Since MAP is considered a NTM, the following studies may be of interest to patients and health care providers who would like to explore the possible role of MAP in sarcoidosis. We look forward to further research studies defining this relationship in the future.

Identification of Mycobacterium avium Complex in Sarcoidosis. (June 1996)
All 7 sarcoidosis patient’s blood samples showed a strong reaction to MAP antibodies, which is comparable to patients with known mycobacterial diseases. Also, MAP (or an M. avium species) was identified in the majority of the skin and cerebral spinal fluid samples of sarcoidosis patients. The researchers concluded that this data supported the theory that a mycobacterial species was involved in the cause of sarcoidosis.

Quantitative Analysis of Mycobacterial and Propionibacterial DNA in Lymph Nodes of Japanese and European Patients with Sarcoidosis. (January 2002)
Lymph node biopsy samples from 108 sarcoidosis patients were tested for a number of different bacterial DNA. DNA from the genus Propionibacterium was present in all but 2 sarcoidosis samples, but MAP DNA (IS900 series) was absent. The researchers concluded that Propionibacterium species are more likely than Mycobacteria species to be involved in the etiology of sarcoidosis, not only in Japanese but also in European patients with sarcoidosis. However, because Propionibacterium are the most common commensal bacteria in Japanese patients, their high number may not reflect causality of sarcoidosis.

Molecular evidence for the role of mycobacteria in sarcoidosis: a meta-analysis. (September 2007)
This meta-analysis reviewed 31 studies through 2006 which looked at the detection of mycobacteria in sarcoidosis. All reviewed studies used PCR for mycobacterial DNA detection. Overall, 231 out of 874 (26.4%) sarcoidosis patients were positive for the presence of mycobacteria. of the 231 positive results, 187 were positive for tuberculosis and 43 samples were positive for non-tuberculosis mycobacteria. Interestingly, patients who were positive for mycobacteria showed a tendency of chronic disease which did not respond to immunosuppressants. “The results of the present study suggest an association between mycobacteria (both Mycobacteria tuberculosis complex and non-tuberculous) and sarcoidosis.”

Evidence for Mycobacteria in Sarcoidosis. (November 2011)
An infectious agent has long been suspected as the cause of sarcoidosis, and mycobacteria were considered a likely culprit. Recent advances in technology indicate that mycobacteria likely play a role in at least some sarcoidosis cases. The authors review the published research and conclude that there is a tuberculosis variant or a related non-tuberculosis mycobacteria species that is associated with sarcoidosis. They base their conclusion on evidence which finds mycobacterial DNA and antigens (p36,  hsp65, hsp70 and mKatG) prevalent in sarcoidosis patient samples. Additionally, “it may be that in the susceptible host, sensitization to the right microbial antigens (mycobacterial, propionibacterial, or other) may be sufficient to trigger sarcoidosis.” It is possibly that mycobacteria are necessary only to trigger the disease and break immune tolerance, and not to maintain the disease.

Oral antimycobacterial therapy in chronic cutaneous sarcoidosis: a randomized, single-masked, placebo-controlled study. (September 2013)
In this placebo controlled trial of 30 patients with chronic skin tuberculosis lesions, a regimen of levofloxacin, ethambutol, azithromycin, and rifampin (CLEAR) was given for 8 weeks and the patients were followed for 180 days after beginning treatment. (Some patients were using immunosuppressant therapy as well, but these patients were randomized between the treated and placebo groups.) The patients receiving the CLEAR medication had a significant reduction in lesion diameter and granulomatous inflammation, which was associated with a decrease in symptoms. 5 patients had complete healing of their lesions and there was no recurrence at the 180 day benchmark. Similar improvement was not seen in the placebo group. Additionally, a significance change in gene expression related to immune response was observed in the CLEAR group after treatment.

Effects of broad-spectrum antimycobacterial therapy on chronic pulmonary sarcoidosis. (November 2013)
Similar to the above study, 15 pulmonary sarcoidosis patients with reduced forced vital capacities (FVC – a measure of the air can be exhaled during a forced breath) were given an antibiotic regime of levofloxacin, ethambutol, azithromycin, and rifampin (CLEAR) for 8 weeks. The CLEAR regimen was shown to improve FVC, functional capacity and quality of life. Some adverse effects were noted.

Sarcoidosis: Role of non-tuberculosis mycobacteria and Mycobacterium tuberculosis. (December 2014)
This study reviews the research on the relation of tuberculosis (TB) and non-tuberculosis mycobacteria (NTM) to sarcoidosis. The authors observe that the increase in the rate of NTM diseases in the Western world  is associated with a decline of TB. They hypothesize that “TB and sarcoidosis may have a similar causal agent, namely NTM, and these may even be different clinical manifestations of the same disease in the patient.” A prime candidate for the causal agent of sarcoidosis would be a “slow-growing mycobacteria species with low pathogenic potential, but with the capability of eliciting a type IV immune response.” Researchers have also found the cell-wall deficient form of TB in sarcoidosis patient samples.

Immunological Evidence for the Role of Mycobacteria in Sarcoidosis: A Meta-Analysis. (August 2016)
13 research studies with a total of 733 (353 sarcoidosis and 380 control) patients were reviewed in this meta-analysis. About half of the samples from sarcoidosis patients exhibited an immune response to M. tuberculosis (TB) antibodies, which was significant when compared to health controls. “It is important to note that mycobacterial (TB or NTM) antigens and not the active mycobacteria may play roles in the pathogenesis of sarcoidosis. One hypothesis is that an impediment in the removal of poorly degraded antigenic material may contribute to the pathogenesis of sarcoidosis.” Though not found in all patients, this study showed there is an association of mycobacteria, especially TB, with sarcoidosis.

Is there any association between Sarcoidosis and infectious agents?: a systematic review and meta-analysis. (November 2016)
58 studies with a total of 2467 sarcoidosis patients and 3656 healthy controls were reviewed in this met-analysis. The authors concluded that infectious agents such as Propionibacterium acnes and  mycobacteria were associated with sarcoidosis, while Borrelia, Rickettsia helveticaChlamydia pneumoniae, Epstein-barr virus and Retrovirus were not. It may be that the patient’s location may determine which infectious agents are involved. In looking specifically at mycobacteria, the researchers concluded that there was a strong association with sarcoidosis and TB and non-tuberculosis mycobacteria.

 

Phase II Trial of Antimycobacterial Therapy in Sarcoidosis

Under the direction of Dr. Wonder Drake of Vanderbuilt University, a Phase II trial of antimycobacterial therapy is recruiting participants with pulmonary sarcoidosis at 4 locations in Tennessee and Ohio. The CLEAR regime consists of Levofloxacin 500mg, Ethambutol 1200mg, Azithromycin 250, Rifampin 600mg, or Rifabutin 300mg per day. The study completion date is estimated to be May 2017. The Phase 1 trials (described above) showed significant improvement of sarcoidosis benchmarks for patients taking the CLEAR regimen.

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