Ankylosing Spondylitis (AS) is unique as both an inflammatory disease and type of arthritis due to the rapid bone formation that occurs during the progression of the disease. Bone formation occurs in response to muscle tears during physical activity or persistent inflammatory events in certain joints/regions of the body (i.e. sacroiliac joint, spine - usually lumbar, hips, knees, feet). This can be particularly dangerous to patients in regards to their spine and rib cage. As the vertebrae fuse, they form outgrowths (called syndesmophytes) and immobilize the spine. This immobilization of the spine may then inhibit normal breathing and lung capacity of the patient. (Mayo Clinic)
Bone deposition and the extreme inflammatory component of this disease are leading to the latest "rage" for AS therapeutics: TNF-α antagonist therapy. In regards to inflammation, TNF-α does not release from its binding site which causes much of the persisting inflammation. As a result, lymphocytes are recruited to the area leading to more inflammation and tissue damage which, in AS, leads to bone formation. As TNF-α plays a major role in the progression of AS, TNF-α antagonists such as Entanercept (Enbrel), Infliximab (Remicade), and Adalimumab (Humira) are being studied and prescribed. Each of these drugs has shown to be effective in treating axial and peripheral arthritis (Lasalle and Deodhar).
Entanercept is a fusion protein made from two soluble human TNF-α receptors which are linked to the Fc portion of human IgG1 and is administered via injection once or twice per week under the skin of the thigh, abdomen, or upper arm. Infliximab is a chimerica monoclonal antibody that is human/mouse and is administered as intravenously for 2-3 hours every few weeks or months. According to Braun, et al in "Current Opinion in Rheumatology", patients require a 5 mg/kg dosage of Infliximab every 6 to 12 weeks in order to maintain a tonic level of disease suppression. Adalimumab is a human IgG1 antibody and is administered via injection under the skin of the thigh or abdomen once a week or once every other week. Very few studies have been performed on this drug to date. In all these studies, patients indicated significant improvements in morning stiffness and tender and swollen joints. Radiographic results also showed a marked slowing in the progression of bone formation. The results of Enteracept and Infliximab were enhanced when administered in conjunction with a disease modifying antirheumatic drug known as Methotrextate.
One serious drawback to these drugs is their cost. Many patients spend thousands of dollars per dosage; none of which is covered by insurance. Another cause for concern is that no long term studies have been performed since these drugs are so new on the market. Another interesting fact is that no studies have been performed comparing the efficacy of these drugs to each other. One thing I questioned in my research of these drugs is that each researcher seems to downplay or completely write off the side effects and negative outcomes of their studies and pushes these drugs as miracle workers.
*To see a picture of syndesmophytes (bone outgrowths of the spine) and how it was surgically corrected. This is incredibly graphic so please be careful if you have problems looking at surgery pictures.
Interesting Reading:
-Braun, J. et al. "Biologic therapies in the spondyloarthritis". Current Opinion in Rheumatology. 2003 Jul: 15: 394-407.
-Dougados, M. et al. "Conventional treatments for ankylosing spondylitis". Annals of the Rheumatic Diseases. 2002 Dec: 61 Suppl. 3: iii40-50.
-Han, C. et al. "The impact of infliximab treatment on quality of life in patients with inflammatory rheumatic diseases". Arthritis Research Therapy. 2007 Oct: 9: R103.
-Kolarz, B. et al. "Autoimmune aspects of treatment with TNF-alpha inhibitors". (originally published in Polish)
1. Lasalle, SP and AA Deodhar. "Appropriate management of axial spondyloarthritis". Current Rheumatology Reports. 2007 Oct: 9: 375-382.
2. Mayo Clinic. "Ankylosing spondylitis". http://www.mayoclinic.com/health/ankylosing-spondylitis/DS00483
3. Mayo Clinic. "TNF-alpha inhibitors: Treatment for inflammatory diseases". http://www.mayoclinic.com/health/rheumatoid-arthritis/AR00039
4. Moreland, LW. "Drugs that block tumour necrosis factor: experience in patients with Rheumatoid Arthritis". Pharmacoeconomics. 2004: 22 Suppl.1: 39-53.
Subscribe to:
Post Comments (Atom)
3 comments:
Methotrexate (also Methotrextate, MTX) is an inhibitor of folate synthesis, and typically used as a cancer therapy: what is it's purpose in AS therapy? To kill activated T lymphocytes? If so, then wouldn't life-long MTX treatment also eventually cause massive GI and epidermal destruction? You note that the authors don't discuss the side-effects of this style of treatment: it sounds like the side-effects could be horrible! Maybe that's why they leave it out...
Here is a comment by Ed Chan in Arthritis Research, 2002: "Despite the recent introduction of biological response modifiers and potent new small-molecule antirheumatic drugs, the efficacy of methotrexate is nearly unsurpassed in the treatment of inflammatory arthritis. Although methotrexate was first introduced as an antiproliferative agent that inhibits the synthesis of purines and pyrimidines for the therapy of malignancies, it is now clear that many of the anti-inflammatory effects of methotrexate are mediated by adenosine. This nucleoside, acting at one or more of its receptors, is a potent endogenous anti-inflammatory mediator." In fact, in one form of severe combined immunodeficiency disease, adenosine accumulates due to an enzyme defect, and it almost completely inhibits the formation of both T and B cells, without affecting any other systems.
Hey Fritz! I did some research in response to your question on Methotrexate. From all of the literature that I have read so far, there is no known mechanism or understanding of the purpose of Methotrexate which makes it an efficacious treatment in AS. According to Creemers, et al, 11 patients enrolled in an open study showed an improvement in C-reactive protein, erythrocyte sedimentation rate, and a reduction in symptoms in pain. Conversely, Roychowdhury, et al, performed a random, double-blind, placebo-controlled study. They found that there was no improvement in disease progression or pain management in patients who were on Methotrexate.
Reported side effects of Methotrexate are nausea, vomiting, diarrhea, skin rash, reduction in circulating blood cells, liver damage, and lung fibrosis.
Reported side effects of TNF-α inhibitors are increased frequency of infections - particularly tuberculosis, and in some cases leukemia and lymphoma.
1. Ankylosing Spondylitis Research. "Medication use in ankylosing spondylitis: Methotrexate". http://www.asresearch.co.uk/text/methotrexate.htm
2. Creemers MC, Franssen MJ, van de Putte LB, Gribnau FW, van Riel PL. Methotrexate in severe ankylosing spondylitis: an open study. Journal of Rheumatology. 1995;22:1104–7.
3. Roychowdhury B, Bintley-Bagot S, Bulgen DY, Thompson RN, Tunn EJ, Moots RJ. Is methotrexate effective in ankylosing spondylitis?. Letter to the Editor. Rheumatology. 2002; 41: 1330-1332.
4. Spondylitis Association of America. "Medications". http://www.spondylitis.org/about/as_med.aspx
Post a Comment