Anticytokine therapy effective in treating CAPS

Naples, Fla. - The recent identification of a gene responsible for a cluster of debilitating diseases collectively known as cryopyrin-associated periodic syndrome (CAPS) has led to extremely effective anticytokine therapy.

Cryopyrin-associated periodic syndrome is a new terminology for a disease cluster that includes Muckle-Wells syndrome (MWS), familial cold urticaria and neonatal-onset multisystem inflammatory disease (NOMID), all of which are rare yet devastating for the affected individual. Fortunately, the gene responsible for MWS and mutations of the same gene responsible for familial cold urticaria were recently identified, leading to effective therapies for the disease.

Muckle-Wells syndrome is characterized by urticaria, systemic amyloidosis and deafness. One in four affected patients will get amyloidosis and the deposition of amyloid in the kidney may lead to end stage renal failure.

The clinical features of urticaria and flu-like symptoms (fever, arthralgia, conjuntivitis) seen in MWS appear to overlap with familial cold urticaria, though the latter is less severe as there is no amyloidosis or deafness. The unusual urticarial rash in these patients occurs in a daily circadian rhythm and can appear anywhere on the body particularly on the trunk and limbs, but rarely on the face. It usually gets worse as the day progresses, as well as with changes in temperature and stress.

Interestingly, the rash is rarely itchy, which is unusual for urticaria, because urticaria is almost by definition associated with pruritus. Until recently, these conditions were considered untreatable, as standard antihistamine regimens commonly used in urticaria do not help and anti-inflammatory agents such as NSAIDS and corticosteroids used for the fever and joint pains simply are ineffective in these patients. The wheals are mediated by interleukin-1 and not by the release of histamine and degranulating mast cells, according to Kieron S. Leslie, M.D., department of dermatology, University of California, San Francisco.

“Essentially it is like having the flu everyday of your life. Patients suffer greatly with rash, fevers, joint pains and incredible tiredness, amounting to a severely debilitating condition. Continued research on these diseases has allowed a further understanding of a very important inflammatory pathway and the elucidation of the shared pathogenesis of this cluster of diseases and has led to a near miraculous therapy for these patients in the form of anticytokine therapy,” Dr. Leslie says.

The gene product in this disease cluster is called cryopyrin, which activates interleukin-1 - a cytokine-causing inflammation. According to Dr. Leslie, emerging anticytokine therapies used for these diseases appear to be very promising. The first is anakinra (Kineret, Amgen), which is an interleukin-1 receptor antagonist. Though the drug is licensed to treat rheumatoid arthritis and is considered a third- or fourth-line biological therapy for this indication, anakinra is extremely effective for the treatment of CAPS.

Anakinra injection

Within two hours of receiving a single subcutaneous injection of anakinra, patients experience a complete remission, erasing the flu-like symptoms and urticaria. The limiting factors of this therapy are that the injections are painful and that the effect lasts only a day, requiring daily therapeutic injections.

However, Dr. Leslie says, affected patients are only more than willing to comply with the therapeutic regimen, as “being sick” is no longer an option. Also, systemic amyloidosis is considered to be an end-stage disease process, however, the administration of anakinra has also resulted in resolution of the amyloidosis within a few months of treatment, significantly improving renal function.

“The amazing and near immediate effect of anakinra is truly exciting, as these patients experience for the first time what normalcy is, and realize how sick they really were. No biological therapy has ever shown this level of efficacy,” Dr. Leslie tells Dermatology Times.

Another emerging therapeutic drug currently undergoing clinical trials for the treatment of CAPS is ACZ885 or canakinumab (Ilaris, Novartis), a monoclonal antibody designed to target interleukin-1 beta. An early study with this therapy saw complete clinical remissions in patients for a median 186 days after a single IV infusion. No serious adverse events were recorded to date.

“Studies addressing a subcutaneous dosing for the drug are currently underway and so far it has been extremely efficacious for the treatment of CAPS,” Dr. Leslie says.

Recently, the Food and Drug Administration approved a third drug for the treatment of CAPS called Arcalyst (rilonacept, Regeneron), the first licensed drug indicated for this indication. The drug has the benefit of once weekly doses, which again, in terms of treatment frequency, seems to be better than anakinra. All three drugs block interleukin-1 in a slightly different way, and, according to Dr. Leslie, all three drugs seem to be very effective and work extremely well.

Many inflammatory processes have an elevated level of interleukin-1 and it is considered to be key player in inflammatory processes. It appears that in CAPS, the disease is purely mediated by interleukin-1, because when it is blocked, there is a total response, making it a clean model to study in interleukin-1 biology.

According to Dr. Leslie, interleukin-1 plays a central role in the pathogenesis of several disease processes including staphylococcus and listeria infections, gout, pseudogout as well as inflammatory diseases such as psoriasis and pyoderma gangrenosum. Therefore, there is potential for the application of these up and coming anti-cytokine drugs that successfully block interleukin-1, not only for rare diseases but also much more common diseases.

“Cryopyrin-associated periodic syndrome can teach us a lot because its pathway seems to be so critical in so many different disease processes,” Dr. Leslie says. “Therefore, these fledgling anticytokine therapies could really be a great potential for better treating and managing common diseases with a related pathogenesis.”

Disclosures: Dr. Leslie is a principal investigator for Novartis.