Saturday, October 23, 2010

Targeting the inflammasome - new ventures for a hospitalist

When the undefined, unclear, obscure clinical presentation makes its appearance on the hospital stage, taking the patient as a hostage, the internist will always carry the flag of the best patient's advocate and passionately fight against the darkness of uncertainty.

In the classic case of the patients with fever of unknown origin we'll attempt to elaborate a list of the most common diagnosis, and once everything else has been ruled out, we'll leave to the end the strange and uncommon diseases, which in the case one of those is attributed and descifered as as the culprit of the patient's maladie, then not only a therapeutic opportunity can be offered to the patient, but of course, the internist's personal experience will broaden and solidify, as well as his/her ego boost up.

What is a similar challenge is when patients with an established rare diagnosis appear, with exacerbations of the disease that are uncontrolled with the usual medications. Then, the main issue will be whom to ask for help especially if the potential likelihood of not having an alternative therapy arises.

Well, we had in the teaching service a patient with Familial Mediterranean Fever (FMF). Yes. This is one of those diseases that everybody can just pop out in trivia and board questions without having ever seen one in their lives. This young patient had a very prominent abdominal pain as well as severe diarrhea - this last one, worsened with colchicine, which is by the way, the standard of care in this disease. Our question was whether this patient may be refractory to colchicine, and if this would be the case, what other alternative we would be able to offer her.

As a background, the FMF is a clinical entity manifested as recurrent attacks of serositis. Attacks can last sometime up to 5 days and the recurrence is variable - some patients have recurrence every few weeks to months to every few years. Stress (physical and emotional) has been linked as a trigger. Most commonly affects the peritoneum (90% of cases), the pleura (45% of cases), scrotum (5% of cases) and pericardium (1%). Patients can as well have acute monoarticular arthritis. Some patients can develop at long term complications such as amyloidosis.

The management is generally succesful with the use of colchicine. However, 5 to 10% of patients can have persistence of FMF's symptoms despite colchicine. Available choices are Interferon alpha and methylprednisolone. It has been described as well, that dietary changes with elimination of lactose as well as gluten in some patients, may help to avoid the colchicine intolerance.

Going back to our case, she has had intolerance to both IFN-alpha as well as methylprednisolone in the past, therefore creating a therapeutic challenge; as well, her diarrhea worsened with colchicine and did not improve despite the use of anti-diarrheal medications.

After expert discussion with the Rheumatologists, which by the way included the Pediatric Rheumatologist, we decided to use one of two drugs that blocks the Interelukin 1 action - either an IL-1 trap called Rilonacept or a soluble IL-1 receptor blocker called Anakinra.

Of note, as a hospitalist, my experience with either drug was only limited to some patients with Rheumatoid Arthritis treated with Anakinra. I looked in the literature which dates back to 2007 when this drug was suggested as a therapeutic alternative to colchicine in patients with FMF; I found as well some reported cases of its use as a salvage therapy in patients refractory to conventional treatment, such as this case and this other one.

More information about the pathogenesis of chronic inflammatory diseases which for ages its pathophysiology has been an enigma to clinicians is appearing. This article explains the role of IL-1 in this chronic inflammatory diseases as well as the role of the inflammasome which is a cytosolic multi-protein complex, which regulates the caspase-1 dependent processing of inflammatory cytokines IL-1β and IL-18.

The patient received anakinra with an impressive improvement in her clinical symptoms within 24 hours. Her pain subsided as well as her fever. The caveat is that the administration of this drug requires daily injections, which the patient is willing to take in order to avoid the devastating attacks. Further discussion with the insurance company will be needed to assess whether coverage for weekly rilonacept injections can be obtained.

This case brought to me several lessons. First, this was an opportunity to review the new pathophysiologic mechanisms of recurrent febrile and inflammatory diseases as well as understand based on this, the new pharmacologic approaches to these diseases. The use of IL-1 pathway antagonists has a very broad application; for me as a hospitalist, knowing about anakinra, canakinumab or rilonacept, permits me to manage a different language and be able to sustain a different level of conversation with our Rheumatology subspecialists, as well as share my fascination with my residents and medical students.

I am very interested in following the long term outcome of this patients and hopefully the increased understanding of the mechanisms of disease may yield a really curative approach in the next 10-20 years.

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