Non tuberculosis mycrobacteria- risk using anti tnf

[my little penguin]

Tumor necrosis factor alpha (TNF-alpha) is a pro-inflammatory cytokine that is integral to host defense against granulomatous mycobacterial and fungal infections.36-38 Medications that target the TNF pathway are the cornerstone of treatment for autoimmune inflammatory conditions including rheumatoid arthritis, psoriasis, and Crohn's Disease. Five TNF-alpha inhibitors are currently approved: infliximab, adalimumab, golimumab, and certolizumab are anti-TNF alpha monoclonal antibodies, and etanercept is a soluble receptor fusion protein.39 In a U.S. study in new users of inflixamab, etanercept, or adalimumab anti-TNF therapy, the overall rates of NTM disease were five to tenfold higher than disease rates seen in the unexposed background RA and general populations and more common than TB.15 The drug-specific incidence rates per 100,000 patient-years and 95% confidence intervals were 35 (1-69) for etanercept, 116 (30-203) for infliximab, and 122 (3-241) for adalimumab. In South Korea a higher incidence of NTM disease of 230 per 100,000 patients was reported in two separate hospital-based reviews of 509 and 1165 patients treated with TNF antagonists.40,41 In a review of U.S. Food and Drug Administration MedWatch reports, just over half (55%) of NTM cases were pulmonary.25 In the U.S. and South Korea, 70% to 100% of NTM infections were in patients with rheumatoid arthritis who frequently have associated underlying lung disease including bronchiectasis and interstitial lung disease.15,25,41,42

Other biologic agents used in this setting include rituximab (anti-CD20 monoclonal antibody), abatacept (T-cell costimulator modulator), tocilizumab (anti-IL-6 monoclonal antibody), and ustekinumab (anti-IL-12 monoclonal antibody). There is a theoretical increased risk of NTM infection with these agents, but very little safety data exists and further study is required.39 At the present time, the evidence of NTM risk is limited to small case series of NTM disease in patients treated with rituximab (2 cases) and tocilizumab (4 cases, 3 were also taking prednisolone +/− tacrolimus and 2 had prior NTM infection).43,44 It should be noted that rituximab has been used as an adjunct to successfully treat otherwise recalcitrant chronic NTM infections in patients with auto-antibody states involving IFN-


Diagnosis, Prevention, and Treatment
Prospective screening is not recommended for any of immunosuppressed groups, unlike tuberculosis where there are clear benefits to screening for latent infection prior to the initiation of biologics and immunosuppressive therapy.23 However, some groups should be considered for further clinical work-up prior to initiation of biologic therapy. Patients with chronic cough that cannot be explained by usual causes should be considered for further workup for pulmonary NTM, including CT imaging and respiratory sampling.

Treatment is described in Table 3, and is species specific requiring antimicrobial susceptibility for all except MAC, unless macrolide-resistant MAC is suspected.23 When possible, decreasing or dropping immunosuppressive medications likely improves the likelihood of successful treatment.38 Non-biologics such as methotrexate should be considered, or second-line therapies such as abatacept or tocilizumab which are currently considered lower risk.15 Outcomes of treatment for pulmonary disease are variable. Case fatality rates range from <10% to 15% in U.S. studies with short term follow up. Winthrop et al. reported a higher case fatality rate of 39% with a median of 569 days (range 21-2127) between diagnosis and death. Evidence from a small Japanese case series suggests that pulmonary NTM disease in rheumatoid arthritis patients who stop biologics have generally positive outcomes with NTM treatment, or stable NTM disease with no treatment, and deaths were related to underlying lung disease including pulmonary aspergillosis and intersitial lung disease.43,47

Nontuberculous Mycobacteria Infections in Immunosuppressed Hosts
Emily Henkle, PhD, MPH and Kevin Winthrop, MD, MPH



From
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4710582/#!po=13.9706

 

[Tesscorm]

Thanks MLP.

Can you explain exactly what this means? I've never quite understood what they mean by patient years, confidence interval, etc.

The drug-specific incidence rates per 100,000 patient-years and 95% confidence intervals were 35 (1-69) for etanercept, 116 (30-203) for infliximab, and 122 (3-241) for adalimumab.

Thanks

 

[my little penguin]

The calculation of events per patient-year(s) is the number of incident cases divided by the amount of person-time at risk. The calculation can be accomplished by adding the number of patients in the group and multiplying that number times the years that patients are in a study in order to calculate the patient-years (denominator). Then divide the number of events (numerator) by the denominator.

Example: 100 patients are followed for 2 years. In this case, there are 200 patient-years of follow-up.
If there were 8 myocardial infarctions in the group, the rate would be 8 MIs per 200 patient years or 4 MIs per 100 patient-years.
The rate can be expressed in various ways, e.g., per 100, 1,000, 100,000, or 1 million patient-years. In some cases, authors report the average follow-up period as the mean and others use the median, which may result in some variation in results between studies.

Another example: Assume we have a study reporting one event at 1 year and one event at 4 years, but no events at year 2 and 3. This same information can be expressed as 2 events/10 (1+2+3+4=10) years or an event rate of 0.2 per person-year.

From
http://delfini.org/blog/?p=612

 

[my little penguin]

http://vanneman.umd.edu/socy601/601class05.ppt

 

[Tesscorm]

Thanks MLP. The powerpoint presentation was just a wee bit over my head!! :awe: but the patient years explanation was simple! Thanks! I've always gotten the gist of study conclusions just never exactly understood it.

 

[Tesscorm]

But, since we're on this... am I in the ballpark by believing the confidence interval of 95% means that if you were to rerun the same study on a new group of people, using same parameters (ie same number of people, same meds, same number of illnesses, etc.) that there is a 95% probability that you'd end up with the same result?

 

[my little penguin]

95% confidence level is good
Basically yes same results expected
From what I have read
Risk of NTM (non-tuberculosis mycrobacteria) is a much higher risk (5-10 fold higher ) than TB for folks on anti tnf
And is on the rise

So something to be aware of
Especially since non GI or folks used to dealing with biologics wouldn't know to look for it

 

[Tesscorm]

Thanks MLP.

When I read what you'd posted, on NTM, it caught my eye because even when S is not sick with a cold, flu, etc., S often has a bit of a chronic cough, especially in winter. But, really, this started when he was a little boy, years before crohns or remicade. We had it checked and nothing ever came of it. (FWIW, I don't know the connection but have read of others here who have crohns and have chronic coughs??? So, maybe there's some connection between crohns and a susceptibility to having a cough??? IDK...)

I read up on NTM and I'm not thinking this is what he has but, as you said, just something to be aware of...

 

[my little penguin]

Tesscom
NTM is extremely difficult to dx
Requires cultures to be grown over weeks to months
It can affect the lungs , skin lymph nodes etc...
Chest X-ray and tb skin test can help to get a dx
Biopsied are typically needed
Not something that would show up in regular bloodwork

 

[Tesscorm]

Yes, I understand. But, given that his cough has been an on- off-again thing for years before crohns/remi, at this point, I'm more inclined to think it's more of a mild allergic reaction (dust, etc.) that worsens in winter and/or a susceptibility to respiratory infections?? Along with the cough, he also clears his throat (cause of the cough?) and I've noticed that my mom also does that... so, perhaps, a bit of a genetic make-up?? (And, he really has had this on- off- cough and throat clearing since he was 5 or 6 years old.)

We never had biopsies done but it was never severe enough to reach that point.

He's had x-rays done, quite a few the last couple of years actually because of that chest pain he was having and then because of his chest infections last year and this year.

Not sure if I posted it here but, last year he went to the ER near his school because of chest infection/bronchitis and x-rays indicated there 'might' be a questionable mark on his lung. It was coincidental that we had a GI apptmt within a couple of days and, his GI immediately requested we get a copy of the original film, had S have more x-rays at his own hospital and have radiologist compare the two - all was determined to be clear (seems first x-ray was not a clear picture). Also, while trying to determine that chest pain he was having a couple of years ago, those chest x-rays found the issue of the enlarged ventricle! :yfaint: This has also been followed up for about 1.5-2 years with a cardio and has been determined to not be a problem...

So, I think, by this point, if it was undiagnosed NTM, wouldn't we be seeing more symptoms? ie the weight loss, fatigue, etc.?? Or some sign given the number of chest x-rays and heart related ultrasounds and MRI? And, would it come and go?

Having said all this, given his cough and that I'm now aware of NTM and its relationship to remicade, it is something I'll keep in mind (and, if coughing continues to be an issue, something I'll ask GI about at next apptmt).


But, if it were undiagnosed NTM, what signs/symptoms do you think would (or should) prompt further investigation?

 

[my little penguin]

Has he seen a pulmo with a lung function test ?
Including albuterol to see if lung function improves
Cough variant asthma would be higher on the list of concerns
You don't need to wheeze to have asthma
Since asthma like Crohns can cause scar tissue with uncontrolled inflammation
This can have an allergy component.
Ds asthma is managed by an allergist due to allergy triggers

 

[Tesscorm]

No, he didn't see a pulmo. And, I'm assuming 'no' to the tests - I imagine those tests would be run by pulmo only?? It was looked into when he was very young but probably only tests run by ped at the time. (Sounds almost neglectful now but, I wasn't so on top of doctors/tests/results years ago and, with two kids, I sometimes forget who had what tests for what reasons! :ybatty

S wants to switch to a new GP once he finishes school (summer/fall). At that time, I'll have S mention the regular cough/throat clearing to the new GP. Hopefully, I'll find him a GP that takes more than a cursory interest in symptoms given crohns and remi. But, and this is frustrating, if the GP is a bit of a 'oh, that's probably nothing, don't worry' type, at S's age, I'm limited to how much I can push/advocate with a GP.

If his cough doesn't clear up in the spring/summer, it'll be easier for me to push S to push the GP...

Different challenges when they're at this age; easier when everything is still in our control...

Thanks, MLP, for this info... definitely something I'll be keeping in mind and following up somehow...