Question
A 24-year-old man comes to the physician for a follow-up evaluation for chronic lower back pain. He has back stiffness that lasts all morning and slowly improves throughout the day. He has tried multiple over-the-counter medications, including ibuprofen, without any improvement in his symptoms. Physical examination shows tenderness over the iliac crest bilaterally and limited range of motion of the lumbar spine with forward flexion. The results of HLA-B27 testing are positive. An x-ray of the lumbar spine shows fusion of the lumbar vertebrae and sacroiliac joints. The physician plans to prescribe a new medication but first orders a tuberculin skin test to assess for the risk of latent tuberculosis reactivation. Inhibition of which of the following is the most likely primary mechanism of action of this drug?
| A. |
Inosine monophosphate dehydrogenase
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| B. |
TNF-a
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| C. |
NF-?B
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| D. |
Calcineurin
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Show Answer
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Correct Answer � B
Explanation
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Ans-B-TNF-a
This young man presents with findings suggestive of ankylosing spondylitis (chronic lower back pain with morning stiffness, tenderness over sacroiliac joint indicating sacroiliitis, decreased spine mobility, and positive HLA-B27 test), which is confirmed by x-ray showing fusion of adjacent vertebrae (“bamboo spine”). The first choice medication (NSAID) did not prove effective here. Second-line drugs may cause reactivation of latent tuberculosis by disrupting granuloma stabilization.
Inosine monophosphate dehydrogenase
Inosine monophosphate dehydrogenase (IMPDH) controls the synthesis of purine nucleotides, which are needed for cellular proliferation. IMPDH inhibitors, such as mycophenolate mofetil and ribavirin, inhibit lymphocyte proliferation and are used as immunosuppressants (e.g., to prevent organ rejection after transplantation). They are not routinely used in the management of ankylosing spondylitis. An active systemic infection, including tuberculosis, is a contraindication to IMPDH inhibitor use. Tuberculin testing is used to detect latent tuberculosis and is not routinely indicated before initiating treatment with IMPDH inhibitors.
TNF-a
TNF-a is a cytokine that upregulates inflammation in numerous conditions, including ankylosing spondylitis (AS). TNF-a inhibitors can improve spine mobility and reduce pain in patients with AS. However, the pro-inflammatory action of TNF-a also plays a key role in granuloma formation and containment of tuberculosis. Inhibition of TNF-a could disrupt the granulomas, thereby releasing intracellular mycobacteria and reactivating latent tuberculosis. Thus, TNF-a inhibitors are contraindicated in individuals with latent tuberculosis, necessitating routine screening tests before initiation of treatment in all individuals.
NF-B
Nuclear factor B (NF-B), which promotes pro-inflammatory cytokine COX-2 production, is inhibited by glucocorticoids. While temporary intra-articular glucocorticoids may be used in severe cases of ankylosing spondylitis (AS), this does not reactivate latent tuberculosis. In contrast, chronic use of systemic glucocorticoids can reactivate latent tuberculosis and would justify tuberculin skin testing. However, long-term high-dose steroids are not recommended in AS cases.
Calcineurin
Calcineurin is a protein phosphatase enzyme involved in IL-2 dependent T-cell activation and proliferation. Calcineurin inhibitors, such as tacrolimus and cyclosporine, are potent immunosuppressants. While long-term use of calcineurin inhibitors may increase the risk of infection, they are not associated with reactivation of latent tuberculosis. In addition, these drugs are not used in the management of ankylosing spondylitis.
