Human prion disease and relative risk associated with chronic wasting disease in Colorado deer and elk.
Here is a summary of an article involving prion diseases written by a collaborative group of Colorado researchers. As one of the authors, I have borrowed liberally from the original article (MaWhinney et al., Emerg Infect Dis. 2006, 12 (10). 1527-35). The article (which contains complete references and a discussion of limitations) can be accessed at http://www.cdc.gov/ncidod/EID/vol12no10/06-0019.htm . For background on prion diseases (which elicit no immune response) see the CDC and Wikipedia sites: http://www.cdc.gov/ncidod/dvrd/prions/ and http://en.wikipedia.org/wiki/Prion .
An emerging wildlife epizootic of chronic wasting disease (CWD), a contagious prion disease among deer and elk, has potential public health implications. CWD is related to other mammalian transmissible spongiform encephalopathies (TSEs) or prion diseases such as Creutzfeldt-Jakob disease (CJD) in humans, bovine spongiform encephalopathy (BSE or mad cow disease) in cattle, and scrapie in sheep. In prion diseases a normally produced brain protein accumulates in an abnormal misfolded and aggregated form, resulting in neuron destruction and a universally fatal outcome after a prolonged and variable incubation period.
The highest reported CWD prevalence is in a contiguous region spanning parts of Colorado, Wyoming and Nebraska with estimated prevalence of 5% in mule deer, 2% in white-tailed deer, and 0.5% in elk. In Colorado, CWD was first noted in the 1960s in captive deer and in a wild elk in 1981. There are not clear epidemiological connections between original and more recent cases, suggesting unidentified risk factors contribute to the relatively wide and unpredictable geographic CWD distribution.
Humans and animals can acquire TSEs by consuming prion contaminated food. Cannibalistic outbreaks of prion disease include an epidemic of kuru among the New Guinea Fore tribe and epizootic BSE in the United Kingdom (UK) caused by feeding protein supplements derived from prion infected cattle offal to cattle. Food-based prion transmission between species also occurs, although a phenomenon known as the “species barrier” decreases transmission efficiency. In vitro studies suggest this natural barrier reduces human susceptibility to animal prion diseases. Human prion disease has not yet been linked with CWD.
The otherwise reassuring molecular evidence of species barriers is clouded by disparate experiences with scrapie and BSE as food-borne human pathogens. Scrapie exposure has not been demonstrated to increase CJD risk despite extensive human exposure. Conversely, in Britain, consumption of BSE infected cattle led to an epidemic of variant CJD (vCJD) starting in the mid-1990s. As of 10/2/07, only 166 cases (161 deaths) of vCJD have been identified in the UK despite the dietary exposure of millions. Recent studies suggest little chance of large numbers of future vCJD cases.
Data that define human CWD exposure from consumption of infected game do not exist. However in seven Colorado counties considered endemic areas for CWD, 75% of hunting licenses are issued locally; suggesting county residents consume the majority of regionally harvested game. We used Colorado death certificate data to evaluate CJD death rates. Risk of CJD has not increased for residents of counties where CWD is endemic (adjusted relative risk (RR) = 0.81, 95% CI, 0.40-1.63). [RR >1.0 would indicate an increased CJD risk given CWD County residence.] Nor has the rate of CJD increased over time (five year RR = 0.92, 95% CI, 0.73-1.16).
In Colorado, human prion disease resulting from CWD exposure is either rare or non-existent. However, given uncertainties in the incubation period, exposure, and clinical presentation, the possibility that the CWD agent might cause human disease cannot be eliminated.
26 October 2007
Microglia and their Role
Microglia are the residing phagocytic immune cell within the central nervous system (CNS), that are important in innate and adaptive immunity [1, 2]. They have many similar characteristics to macrophages and dendritic cells. However, microglia are also suggested that they help support the brain much like astroglia and oligodendroglia [2]. Microglia are derived from the hematopoeitic lineage and enter the brain as an immature cell. The major function of microglia is to clear debris from apoptotic cells but they also detect and destroy possible pathogens. There are several ways to activate microglia. Direct activation is where microglia are stimulated directly, such as when lipipolysaccride (LPS) from bacteria cell wall binds to Toll-like receptors (TLR) on the microglia. Indirect activation is when a neuron is damaged via a neurotoxin and the protein from the destroyed cell activates microglia. There is also a mixed pathway approach to activating microglia, example HIV gp 120 and prions, they act as a direct neurotoxin and directly stimulant microglia. Once activated, microglia change morphology (they become amoeboid cell) and there is an up regulation of cellular receptors, like MHC class I and MCH class II, TLR, mannose receptors, and complement receptors [1, 2]. Activated microglia secrete several proinflammatory cytokines (TNFα and IL-1β), neurotoxins, reactive oxygen species (ROS) and reactive nitrogen species (RNS) which destroy the infection along with surrounding neurons.
Many studies has investigated the role of microglia in neurodegenerative diseases, such as Parkinson’s disease (PD), Alzheimer’s disease (AD), multiple sclerosis (MS), HIV syndrome dementia, and prion relative disease. In AD brains, reactive microglia where found in plagues in the cortical region. A look closer at post-mortem PD brains revealed an increased levels of proinflammatory cytokines and oxidative stress indicating activation of microglia within the substantia nigra (SN).
It is suggested that some of the secreted factors from microglia contributing to neurodegeneration. One study found that the combined affect of TNFα and IL-1β induced neurodegeneration. Within a rat model, 1-2 weeks after LPS introduction microglia were at maximum activation and degeneration of neurons occurred at 3-4 weeks. In a different study it was found that a single injected of a “cytokine cocktail” (TNFα, IL-1β and IFNγ) into the SN was sufficient to cause neural degeneration. It was also demonstrated, in vivo, that the free radicals that where produced by activated microglia where the major contributor to neurodegeneration. These studies concluded that activation of microglia induced by LPS can cause inflammation mediated neurodegeneration [1]. There is on going research on the role of activated microglia and neurodegenerative disease.
1. Bin Liu and Jau-Shyong Hong. Role of Microglia in Inflammation-mediated Neurodegenerative Disease: Mechanisms and Strategies for Therpeutic Intervention. J. of Pharmacology and Experimental Therapeutics. 304(1) 1-7. 2003.
2. Rock, R. Bryan et al. Role of Microglia in Central Nervous System Infections. Clinical Microbiology Reviews. 17(4) 942-964. 2004.
Many studies has investigated the role of microglia in neurodegenerative diseases, such as Parkinson’s disease (PD), Alzheimer’s disease (AD), multiple sclerosis (MS), HIV syndrome dementia, and prion relative disease. In AD brains, reactive microglia where found in plagues in the cortical region. A look closer at post-mortem PD brains revealed an increased levels of proinflammatory cytokines and oxidative stress indicating activation of microglia within the substantia nigra (SN).
It is suggested that some of the secreted factors from microglia contributing to neurodegeneration. One study found that the combined affect of TNFα and IL-1β induced neurodegeneration. Within a rat model, 1-2 weeks after LPS introduction microglia were at maximum activation and degeneration of neurons occurred at 3-4 weeks. In a different study it was found that a single injected of a “cytokine cocktail” (TNFα, IL-1β and IFNγ) into the SN was sufficient to cause neural degeneration. It was also demonstrated, in vivo, that the free radicals that where produced by activated microglia where the major contributor to neurodegeneration. These studies concluded that activation of microglia induced by LPS can cause inflammation mediated neurodegeneration [1]. There is on going research on the role of activated microglia and neurodegenerative disease.
1. Bin Liu and Jau-Shyong Hong. Role of Microglia in Inflammation-mediated Neurodegenerative Disease: Mechanisms and Strategies for Therpeutic Intervention. J. of Pharmacology and Experimental Therapeutics. 304(1) 1-7. 2003.
2. Rock, R. Bryan et al. Role of Microglia in Central Nervous System Infections. Clinical Microbiology Reviews. 17(4) 942-964. 2004.
25 October 2007
Organ Transplantation Across Different Blood Groups
There are 4 blood types (A, B, AB, and O), each referred to by the letter of the inherited antigenpresent on the red blood cell surface. People with blood type A will have antibodies to the B antigen, whereas people with blood type B will have antibodies to the A antigen. People with blood type AB will have no preformed antibodies, and people with blood type O have no antigens on their red blood cell surface and thus have antibodies to both A and B antigens. Due to these preformed antibodies, organ transplantation from an ABO-incompatible donor does not work because of a complement mediated hyperacute rejection against the blood group antigen(s) present on the vascular endothelial cells of the donor organ.
Due to limited organ availability leading to a high mortality for young children, physicians have used their knowledge of immunology to work around this ABO issue. Newborns and infants have a relative immature immune system, with very low A or B antibody titers till 1 year of age. Furthermore, the complement system is not fully proficient in young infants. Due to these two key facts, successful heart and liver transplantations from ABO-incompatible donors have been performed in infants. These children did not experience hyperacute rejection and had the same outcome as related to survival and quality of graft when compared to ABO compatible recipients.
As the transplanted children became older (and developed a more mature immune system), they did NOT develop antibodies to the blood type antigen(s) expressed by the donor organ. The development of this “B-cell tolerance” is similar to mechanisms used in T-cell tolerance of clonal deletion and anergy. For children > 1 year and adults, more aggressive therapies to circumvent the B cell response have been tried which include: plasmapheresis, which removes all preformed antibody; splenectomy, which decreases new antibody formation, however, severely affects how people can fight off certain bacterial infection; and lastly, pharmacological B cell modulators, such as rituxamib (anti-CD20 monoclonal antibody) and mycophenolate mofetil (inhibits B cell proliferation). Though all of the above are marvelous techniques to stretch a scarce resource, the best solution would be more available organs. Please sign you organ donation cards!
West, Transplantation 2006;81:301-307.
Yamada, Journal of Pediatric Surgery 2006;21:1976-1979.
West, New England Journal of Medicine 2001;344:793-800.
Due to limited organ availability leading to a high mortality for young children, physicians have used their knowledge of immunology to work around this ABO issue. Newborns and infants have a relative immature immune system, with very low A or B antibody titers till 1 year of age. Furthermore, the complement system is not fully proficient in young infants. Due to these two key facts, successful heart and liver transplantations from ABO-incompatible donors have been performed in infants. These children did not experience hyperacute rejection and had the same outcome as related to survival and quality of graft when compared to ABO compatible recipients.
As the transplanted children became older (and developed a more mature immune system), they did NOT develop antibodies to the blood type antigen(s) expressed by the donor organ. The development of this “B-cell tolerance” is similar to mechanisms used in T-cell tolerance of clonal deletion and anergy. For children > 1 year and adults, more aggressive therapies to circumvent the B cell response have been tried which include: plasmapheresis, which removes all preformed antibody; splenectomy, which decreases new antibody formation, however, severely affects how people can fight off certain bacterial infection; and lastly, pharmacological B cell modulators, such as rituxamib (anti-CD20 monoclonal antibody) and mycophenolate mofetil (inhibits B cell proliferation). Though all of the above are marvelous techniques to stretch a scarce resource, the best solution would be more available organs. Please sign you organ donation cards!
West, Transplantation 2006;81:301-307.
Yamada, Journal of Pediatric Surgery 2006;21:1976-1979.
West, New England Journal of Medicine 2001;344:793-800.
24 October 2007
Diacerein
Diacerein is a drug used in the treatment of osteoarthritis. It works by inhibiting interleukin-1. At therapeutically useful concentrations, it counteracts the effects of cytockines on newly secreted proteins, metalloproteinase activity and nitric oxide production. However, nitric oxide blockers alone are inneffective, implicating that a specific gene program is turned on in cytokine-stimulated chondrocytes, and diacerein may prevent metabolic alterations caused by cytokine exposure in chondrocytes.
http://www.cochrane.org/reviews/en/ab005117.html
This study took 2000 people with hip or knee osteoarthritis, and compared their improvements with patients taking placebo's or NSAIDS. Results showed small, consistent benefit in improvement in pain, and benefitted more than placebo or NSAIDS patients.
http://ebm.bmj.com/cgi/content/full/12/3/74 Had a similar study, but their conclusions were that diacerein is comprobably to NSAIDS during treatment of osteoarthritis. However, post-treatment showed diacerein reduced pain more than placebo or NSAIDs and improved function more than NSAIDs
http://www.cochrane.org/reviews/en/ab005117.html
This study took 2000 people with hip or knee osteoarthritis, and compared their improvements with patients taking placebo's or NSAIDS. Results showed small, consistent benefit in improvement in pain, and benefitted more than placebo or NSAIDS patients.
http://ebm.bmj.com/cgi/content/full/12/3/74 Had a similar study, but their conclusions were that diacerein is comprobably to NSAIDS during treatment of osteoarthritis. However, post-treatment showed diacerein reduced pain more than placebo or NSAIDs and improved function more than NSAIDs
22 October 2007
Immunology and Neurology: the two systems are painfully linked
Pain has long been considered a neurological function which serves as a survival purpose under normal circumstances by protecting the individual from further danger. But when pain goes wrong and becomes chronic it no longer serves a relevant function. About ~one-sixth of the world population is afflicted with a form of chronic pain (1). Neuropathic pain, a form of chronic pain, can arise from trauma, inflammation, or infection but just how it occurs remains a dilemma. And how to treat such pain remains a huge problem; drugs such as anticonvulsants, opioids, gabapentin, and others that are thought to affect primarily neuronal activity fail in the great majority of patients (2).
As more studies were performed, it was realized that not only the nervous system was involved. Here is some of what is known about immune factors in this situation: active macrophages are recruited to the site of injury. Delaying macrophage recruitment to the site of injury also delays the development of neuropathic pain in animal models. Conversely, active attraction of macrophages enhances pain (3). The proinflammatory cytokines TNF, IL-1, and IL-6 seem to be key players.
Neuronally derived signals upon injury trigger the activation of glial cells (astrocytes and microglia). Once this happens, glia amplify pain by producing and releasing the above mentioned cytokines. These immune-derived factors increase at the site of trauma matching with the progression of pain. The effect of these immune-derived molecules ‘upset’ neurons making them more excitable. The more upset the neurons become, the more signaling molecules they release, and the more pro-inflammatory cytokines are released by glia—a vicious cycle. Treatment such as thalidomide, which decreases TNF, prevents neuropathic pain. This pain is also prevented in IL-6 knockout mice (4). But these treatments would be challenging in a clinical setting.
Why then do drugs such as opioids, that suppress neuronal activity, remain ineffective in long-term treatment of neuropathic pain? The answer involves the glial cells, especially microglia, which are releasing the inflammatory products. The evidence: first, treatment of neuropathic pain in animal models with an opioid and a reagent known to attenuate microglia activity (i.e., Minocycline or AV411: both in clinical trials) results in longer lasting pain relief with lower cytokine levels (5). This provided evidence that opioids were also acting on microglia; it was further shown that when opiates bind to microglial opiate receptors, more pro-inflammatory products are released.
Second, it is now known that neuronal opiate receptors are stereoselective and the microglia opioid receptors are not (6). This would suggest that it’s possible to separate the neuronal mediated pain suppressive opiate effects from the pain enhancing effects via microglia. Perhaps by a structural modification of opiates that prevents binding to the microglial receptor.
The take home message—prevention of opioid activation of microglia appears to be clinically relevant and has implications for understanding how pain states occur as well as how they may best be treated. While it is much more complicated than just this cell type and these immune mediators, it is certainly a new avenue to explore.
If you’re really interested in the topic, one of the forerunners in this field—Linda Watkins of CU Boulder—will be giving a seminar Wednesday, 10/24 at noon entitled “Curing chronic pain: New hope on the horizon”. It will be in the auditorium where IMMUNO 7630 is held.
1. Campbell et al. 2006. Neuron 52:77-92.
2. Finnerup et al. 2005. Pain 118:289-305.
3. Liu et al. 2000. Pain 86:25-32.
4. Cui et al. 2000. Pain 88:239-248.
5. Ledeboer et al. Pain 115:71-83.
6. Watkins et al. Brain Res Reviews in press
As more studies were performed, it was realized that not only the nervous system was involved. Here is some of what is known about immune factors in this situation: active macrophages are recruited to the site of injury. Delaying macrophage recruitment to the site of injury also delays the development of neuropathic pain in animal models. Conversely, active attraction of macrophages enhances pain (3). The proinflammatory cytokines TNF, IL-1, and IL-6 seem to be key players.
Neuronally derived signals upon injury trigger the activation of glial cells (astrocytes and microglia). Once this happens, glia amplify pain by producing and releasing the above mentioned cytokines. These immune-derived factors increase at the site of trauma matching with the progression of pain. The effect of these immune-derived molecules ‘upset’ neurons making them more excitable. The more upset the neurons become, the more signaling molecules they release, and the more pro-inflammatory cytokines are released by glia—a vicious cycle. Treatment such as thalidomide, which decreases TNF, prevents neuropathic pain. This pain is also prevented in IL-6 knockout mice (4). But these treatments would be challenging in a clinical setting.
Why then do drugs such as opioids, that suppress neuronal activity, remain ineffective in long-term treatment of neuropathic pain? The answer involves the glial cells, especially microglia, which are releasing the inflammatory products. The evidence: first, treatment of neuropathic pain in animal models with an opioid and a reagent known to attenuate microglia activity (i.e., Minocycline or AV411: both in clinical trials) results in longer lasting pain relief with lower cytokine levels (5). This provided evidence that opioids were also acting on microglia; it was further shown that when opiates bind to microglial opiate receptors, more pro-inflammatory products are released.
Second, it is now known that neuronal opiate receptors are stereoselective and the microglia opioid receptors are not (6). This would suggest that it’s possible to separate the neuronal mediated pain suppressive opiate effects from the pain enhancing effects via microglia. Perhaps by a structural modification of opiates that prevents binding to the microglial receptor.
The take home message—prevention of opioid activation of microglia appears to be clinically relevant and has implications for understanding how pain states occur as well as how they may best be treated. While it is much more complicated than just this cell type and these immune mediators, it is certainly a new avenue to explore.
If you’re really interested in the topic, one of the forerunners in this field—Linda Watkins of CU Boulder—will be giving a seminar Wednesday, 10/24 at noon entitled “Curing chronic pain: New hope on the horizon”. It will be in the auditorium where IMMUNO 7630 is held.
1. Campbell et al. 2006. Neuron 52:77-92.
2. Finnerup et al. 2005. Pain 118:289-305.
3. Liu et al. 2000. Pain 86:25-32.
4. Cui et al. 2000. Pain 88:239-248.
5. Ledeboer et al. Pain 115:71-83.
6. Watkins et al. Brain Res Reviews in press
21 October 2007
Ankylosing spondylitis and TNF-α antagonist therapies
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.
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.
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