Case 23

Published on 18/02/2015 by admin

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Last modified 18/02/2015

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CASE 23

Jurgat is a 45-year-old woman of Indian descent with severe erosive deforming rheumatoid arthritis (RA) that began at the age of 22. She has had ongoing joint problems and more recently has experienced early signs of renal failure and some chest discomfort. She has tried without benefit all conventional anti-inflammatory therapies, including NSAIDs and chronic prednisone therapy (which left her with severe osteoporosis), as well as methotrexate and even cyclosporine. She became a good candidate for more experimental approaches but she has already experienced failure in a trial using antibody to human intercellular adhesion molecule (ICAM). What was the rationale for use of this agent? What is the potential pathophysiology behind her disease manifestations?

QUESTIONS FOR GROUP DISCUSSION

1. RA is a chronic inflammatory condition. Use a schematic to illustrate a typical inflammatory response. Include the following in your schematic:

(a) tissue damage

(b) activation of the intrinsic coagulation pathway

(c) activation of prekallikrein, leading to the generation of C5a and bradykinin

(d) C5a-mediated degranulation of mast cells leading to histamine release

(e) histamine-mediated expression of P-selectin on the endothelium

(f) bradykinin- and histamine-mediated increase in vascular permeability

(g) activation of tissue macrophages leading to the release of interleukin (IL)-1, tumor necrosis factor (TNF), IL-6, and chemokines

(h) effect of IL-1 and TNF on vascular endothelium including increase in ICAM-1, vascular cell adhesion molecule-1 (VCAM-1) and E-selectin, as well as chemokine secretion

(i) effect of IL-1 and TNF on leukocytes (increase in integrin [e.g., LFA-1] expression

(j) firm adhesion

(k) secretion of matrix metalloproteinases by tissue macrophages, activated endothelium, and activated leukocytes

(l) diapedesis (including PECAM-1/PECAM-1 interaction)

(m) chemotaxis to site of inflammation

(n) role of IL-6 in release of C-reactive protein (heat shock protein) from hepatocytes

2. Explain why C-reactive protein is a measure of inflammation.

3. The above steps (listed in question 1) represent an acute inflammatory response. In chronic inflammation, B cells and T cells also play a role. Explain how B cells and T cells would exacerbate the inflammatory process.

4. This patient has failed to improve during a trial using anti-ICAM antibodies. What is the rationale for this therapeutic approach?

5. Explain the rationale for using anti-TNF neutralizing agents for therapy.

6. Discuss the advantages and disadvantages (if any) for each of the following anti-TNF neutralizing agents: (a) murine antibodies, (b) chimeric antibodies, (c) humanized antibodies, and (d) fusion proteins.

7. Review the role of TNF in bacterial infections (see Case 12).

8. Discuss the innate and adaptive host defense mechanisms against Mycobacterium tuberculosis.

9. Explain why the Mantoux test should be administered to Jurgat before initiating therapy with a TNF-neutralizing agent.

10. Discuss the evidence that supports the fact that RA has a genetic component.

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