My patient with rheumatoid arthritis might have been exposed to tuberculosis. Does immunosuppressive therapy affect the results of interferon gamma release assay (IGRA) testing for latent tuberculosis?

The weight of the evidence to date suggests that immunosuppressive therapy, including steroids, other oral immunosuppressants and anti-tumor-necrosis factor (TNF) agents, may negatively impact IGRA results.1

In some ways the finding of false-negative IGRA in the setting of immunosuppression is intuitive since many immunosuppressive agents are potent inhibitors of T cells and interferon-gamma response. 1,2 Despite this, the initial reports have been somewhat conflicting which makes a 2016 meta-analysis of the effect of immunosuppressive therapy on IGRA results in patient with autoimmune diseases (eg, rheumatoid arthritis, lupus, inflammatory bowel disease) particularly timely. 1

This meta-analysis found a significantly lower positive IGRA results among patients on immunosuppressive therapy ( O.R. 0.66, 95% C.I. 0.53-0.83). Breakdown by IGRA test showed a significant association between QuantiFERON-TB Gold In-Tube and lower positive results and a trend toward the same with T-SPOT though the latter did not reach statistical significance with fewer evaluable studies (O.R. 0.81, 95% C.I 0.6-1.1).   Breakdown by type of immunosuppressant showed significantly negative impact of corticossteroids, other oral immunosuppressants, and anti-TNF agents for all. Some studies have reported daily steroid doses as low as 7.5 mg-10 mg may adversely impact T-cell responsiveness in IGRA. 3,4

So, whenever possible, testing for latent TB should be performed before immunosuppressants are initiated.

Bonus Pearl: Did you know that an estimated one-third of the world’s population may have latent TB?

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References

  1. Wong SH, Gao Q, Tsoi KKF, et al. Effect of immunosuppressive therapy on interferon gamma release assay for latent tuberculosis screening in patients with autoimmune diseases: a systematic review and meta-analysis. Thorax 2016;71:64-72. https://thorax.bmj.com/content/thoraxjnl/71/1/64.full.pdf
  2. Sester U, Wilkens H, van Bentum K, et al. Impaired detection of Mycobacterium tuberculosis immunity in patents using high levels of immunosuppressive drugs. Eur Respir J 2009;34:702-10. https://erj.ersjournals.com/content/34/3/702
  3. Kleinert S, Kurzai O, Elias J, et al. Comparison of two interferon-gamma release assays and tuberculin skin test for detecting latent tuberculosis in patients with immune-mediated inflammatory diseases. Ann Rheum Dis 2010;69:782-4. https://ard.bmj.com/content/69/4/782
  4. Ponce de Leon D, Acevedo-Vasquez E, Alvizuri S, et al. Comparison of an interferon-gamma assay with tuberculin skin testing for detection of tuberculosis (TB) infection in patients with rheumatoid arthritis in a TB-endemic population. J Rheumatol 2008;35:776-81. https://www.ncbi.nlm.nih.gov/pubmed/18398944
My patient with rheumatoid arthritis might have been exposed to tuberculosis. Does immunosuppressive therapy affect the results of interferon gamma release assay (IGRA) testing for latent tuberculosis?

My patient with primary Sjogren’s syndrome has now been diagnosed with COPD despite lack of a significant smoking history. Is there a connection between Sjogren’s syndrome and COPD?

Increasing body of evidence suggests that COPD in patients with primary Sjögren’s syndrome (PSS) is not uncommon even among those who never smoked (1).

 
A 2015 study of patients with PSS reported that overall 41% of patients with PSS, including 30% of those who never smoked, fulfilled the Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria for COPD. More specifically, pulmonary function tests (PFTs) showed decreased vital capacity (VC), forced expiratory volume in 1 second (FEV-1)  and DLCO in patients with PSS. Importantly, lab inflammatory and serological features were poorly associated with PFT results, while radiographic signs of interstitial lung disease (ILG) were absent in one-half of patients with PSS and COPD (1).

 
A longitudinal study with a mean follow-up of 11 years found a 37% rate of development of COPD among patients with PSS (2). Another related study reported a poor correlation between respiratory symptoms and COPD disease as assessed by PFTs in PSS, with the authors recommending that PFTs be performed “liberally” in all patients with PSS regardless of symptoms (3).

 
Lastly, a population-based cohort study of female adults found significantly higher rate of COPD among patients with PSS compared to controls (4).

 
Although the exact pathogenic mechanism behind PSS-associated COPD is unclear, xerotrachea and impaired mucocilliary clearance, as well as inflammatory infiltrates in the exocrine glands of the airways, all leading to physical obstruction and bronchial hyperreactivity have been suggested (1).

 

Bonus Pearl: Did you know that COPD is associated with many other autoimmune diseases (eg, rheumatoid arthritis and systemic lupus erythematosus), and a genetic link has been implicated between COPD and autoimmunity? (5,6).

 

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References
1. Nilsson AM, Diaz S, Theander E, et al. Chronic obstructive pulmonary disease is common in never-smoking patients with primary Sjögren’s syndrome. J Rheumatol 2015;42:464-71. https://www.researchgate.net/publication/270907531_Chronic_Obstructive_Pulmonary_Disease_Is_Common_in_Never-smoking_Patients_with_Primary_Sjogren_Syndrome
2. Mandl T, Diaz S, Ekberg O, et al. Frequent development of chronic obstructive pulmonary disease in primary SS-result of a longitudinal follow-up. Rheumatology 2012;51:941-46. https://www.researchgate.net/publication/221760110_Frequent_development_of_chronic_obstructive_pulmonary_disease_in_primary_SS-results_of_a_longitudinal_follow-up
3. Bolmgren VS, Olssson P, Wollmer P, et al. Respiratory symptoms are poor predictors of concomitant chronic obstructive pulmonary disease in patients with primary Sjögren’s syndrome. Rheumatol Int 2017;37:813-18. https://link.springer.com/content/pdf/10.1007/s00296-017-3678-5.pdf
4. Shen TC, Wu BR, Chen HJ, et al. Risk of chronic obstructive pulmonary disease in female adults with primary Sjögren’s syndrome. A nationwide population-based cohort study. Medicine 2016; 95:1-6. http://europepmc.org/abstract/MED/26962839
5. Hemminki K, Liu X, Ji J et al. Subsequent COPD and lung cancer in patients with autoimmune disease. Eur Respir J 2011;37:463-74. https://www.ncbi.nlm.nih.gov/pubmed/21282811
6. Ji X, Niu X, Qian J, et al. A phenome-wide association study uncovers a role for autoimmunity in the development of chronic obstructive pulmonary disease. Resp Cell Mol Biol 2018;58:777-79. https://www.atsjournals.org/doi/10.1165/rcmb.2017-0409LE

My patient with primary Sjogren’s syndrome has now been diagnosed with COPD despite lack of a significant smoking history. Is there a connection between Sjogren’s syndrome and COPD?

Does methotrexate reduce the risk of cardiovascular events in patients with rheumatoid arthritis?

The weight of the evidence suggests that methotrexate reduces the overall risk of cardiovascular events (CVEs)—including myocardial infarction, congestive heart failure, stroke, and or major adverse cardiac events—in RA patients (RR 0.72, 95% CI 0.57-0.91)1.

Aside from its effect on controlling systemic inflammation, methotrexate has also been shown to increase HDL and reduce total cholesterol/HDL ratio in patients with RA compared with treated non-RA controls2. In vitro, methotrexate appears to activate mechanisms involved in reverse transport of cholesterol out of the cell to the circulation for eventual excretion3. Not surprisingly then, methotrexate has also been reported to decrease atherosclerotic plaque burden measured by carotid artery intima-media thickness2.

We tend to think of RA as a disease that primarily causes arthritis but its effects may extend far beyond the joints. Patients with RA have an increased risk of cardiovascular deaths compared to the general population4, likely due to a variety of factors, including accelerated atherosclerosis secondary to chronic inflammation. At baseline, RA patients also have an unfavorable lipid profile with decreased HDL and higher total cholesterol/HDL ratio.

Fun Final Fact: Did you know that methotrexate is on the WHO Model List of Essential Medicines (April 2015) not only as a cancer drug but for treatment of RA as well5?

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References:

  1. Roubille C, Richer V, Starnino T, McCourt C, McFarlane A, Fleming P, Siu S, Kraft J, Lynde C, Pope J, Gulliver W, Keeling S, Dutz J, Bessette L, Bissonnette R, Haraoui B. The effects of tumour necrosis factor inhibitors, methotrexate, non-steroidal anti-inflammatory drugs and corticosteroids on cardiovascular events in rheumatoid arthritis, psoriasis and psoriatic arthritis: a systematic review and meta-analysis. Ann Rheum Dis. 2015;74:480-9. https://www.ncbi.nlm.nih.gov/pubmed/25561362
  2. Georgiadis AN, Voulgari PV, Argyropoulou MI, Alamanos Y, Elisaf M, Tselepis AD, Drosos AA. Early treatment reduces the cardiovascular risk factors in newly diagnosed rheumatoid arthritis patients. Semin Arthritis Rheum 2008;38:13-9. https://www.ncbi.nlm.nih.gov/pubmed/18191989
  3. Reiss AB, Carsons SE, Anwar K, Rao S, Edelman SD, Zhang H, Fernandez P, Cronstein BN, Chan ES. Atheroprotective effects of methotrexate on reverse cholesterol transport proteins and foam cell transformation in human THP-1 monocyte/macrophages. Arthritis Rheum 2008;58:3675-83. https://www.ncbi.nlm.nih.gov/pubmed/19035488
  4. Aviña-Zubieta JA, Choi HK, Sadatsafavi M, Etminan M, Esdaile JM, Lacaille D. Risk of cardiovascular mortality in patients with rheumatoid arthritis: a meta-analysis of observational studies. Arthritis Rheum 2008; 59:1690-7. https://www.ncbi.nlm.nih.gov/pubmed/19035419
  5. WHO Model List of Essential Medicines (April 2015). http://www.who.int/medicines/publications/essentialmedicines/en/

 

Contributed by Brian Li, Medical Student, Harvard Medical School

Does methotrexate reduce the risk of cardiovascular events in patients with rheumatoid arthritis?