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Genetic breakthrough for ankylosing spondylitis

In-depth scan of the human genome has resulted in the identification of two genes linked with a common rheumatological disease

Ankylosing spondylitis (AS) is a chronicform of arthritis that attacks the spine,causing the vertebrae to fuse, resulting inloss of normal curvature, as well asaffecting other joints and organs. Newfindings concerning the genetic basis ofthe disease could lead to novel therapiesfor the condition, which is thought toaffect around one in 200 men and one in500 women, usually developing duringadolescence and young adulthood.

The discovery of the genes, ARTS1and IL23R, represent aconsiderable advance inour knowledge of thegenetic basis of AS;until now only one gene(HLA-B27) has beenknown to be influentialin the condition. Pro-fessor John Reveille,Director of Rheumatol-ogy and Clinical Immu-nogenetics at theUniversity of TexasMedical School (TX,USA) and one of thelead researchers on theproject, explains. “Nowwe have found two newgenes. Together withHLA-B27, these genesaccount for roughly70% of the overall cause. This meanswe’ve almost nailed this disease.”

The discovery of both genes is theresult of a comprehensive scan of thehuman genome, using a method knownas genome-wide association scanning, tocompare the DNA of thousands of suf-ferers with healthy controls to find whatgenetic differences there are between thetwo groups. Reveille is convinced thatfurther discoveries concerning thegenetics that underlie AS are soon to bemade; “Within the next year, I predict

we will have identified all the genes thatplay a role in this insidious disease.There is more exciting news to come.”

Scientists believe that AS is triggered insusceptible individuals by common gutbacteria, although the exact mechanismbehind this is unclear at present.

“This looks very promising as a potential treatment for ankylosing spondylitis.”

The researchers hope to next studythe genes’ functions in model organismsin order to elucidate the precise patho-genetic mechanisms that lead to AS,with a view to improving diagnosticsand drug discovery.

IL23R has previously been linked toCrohn’s disease (an inflammatory boweldisease) and psoriasis (a skin disease).The implication of the gene in AS goessome way to accounting for the frequent,and hitherto unexplained, co-occuranceof these conditions. Furthermore, this

suggests that drugs used to treat Crohn’sdisease and psoriasis may be useful intreating AS, and vice-versa.

Professor Matthew Brown of theWellcome Trust Centre for HumanGenetics at the University of Oxford,who worked on the project, reveals, “Atreatment for Crohn’s disease that inhib-its the activity of this gene is alreadyundergoing human trials. This looksvery promising as a potential treatmentfor ankylosing spondylitis.”

The discovery comesduring a remarkableperiod of productivityfor the Wellcome TrustCase Control Consor-tium. The group hasdiscovered more geneslinked to common dis-eases in the last yearthan have been made inthe entire history of thefield. This study in par-ticular also identifiedtwo genes linked toGrave’s disease, anautoimmune conditionthat affects the thyroidgland, as well as geneticcontributions to breastcancer and multiplesclerosis. However, the

most significant discoveries are thoselinked to AS.

The work, a result of collaborationbetween the Australo–Anglo–AmericanSpondylitis Consortium and theWellcome Trust Case Control Consor-tium, can be read in full in the online,October 21st issue, of Nature Genetics.

Source: Wellcome Trust Case Control Consortium.

Association scan of 14,500 nonsynonymous SNPs

in four diseases identifies autoimmunity variants.

Nature Genetics, (2007) (Epub ahead of print).

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542 Future Rheuma

Priority Paper AlertsThe cost–effectiveness of etanercept and infliximab for the treatment of patients with psoriatic arthritis. Vergel YB, Hawkins NS, Claxton K et al.: Rheumatology 46(11), 1729–1735 (2007). A probabilistic decision analytic model was constructed that analyzes the cost–effectiveness of two TNF antagonists (etanercept and infliximab) and palliative care. The success of each treatment was judged using quality-adjusted life years (QALYs) derived from the Health Assessment Questionnaire. The model was extrapolated beyond the trial period to a 10-year and lifetime horizon using the available evidence and expert-opinion-based assumptions. At a 10-year time horizon the incremental cost–effectiveness ratio was found to be between £26,361 and £30,628 per QALY for etanercept compared with palliative care, and between £165,363 and £205,345 for infliximab compared with etanercept. Only the results for etanercept fall within cost-effectiveness estimates for the UK National Health Service, as defined by the National Institute for Health and Clinical Excellence. This is due to the higher acquisition and administration costs of infliximab, despite little superior effectiveness compared with etanercept. Further research into short-term effectiveness, utility parameters and the assumptions of the model is called for.

EULAR evidence based recommendations for the management of fibromyalgia syndrome.Carville SF, Arendt-Nielsen S, Bliddal H et al.: Ann. Rheum. Dis. DOI: 10.1136/ard.2007.071522 (2007).Copyright © 2007 BMJ Publishing Group Ltd & European League Against Rheumatism A systematic review of clinical trials of treatments for fibromylagia syndrome (FMS) was conducted in order to determine a consensus set of evidence-based guidelines for treatment. A multidisciplinary group was formed to appraise the trials using predesignated criteria for search stategy, participants, outcome measures and methods of data collection and analysis. A literature review was conducted using the keywords ‘fibromyalgia’, ‘treatment or management’ and ‘trial’. Studies that did not use ACR classification, were not clinical trials, or included patients with chronic fatigue syndrome or myalgic encephalomyelitis were not included. Outcome was assessed by changes in pain assessed by visual analogue scale, and fibromyalgia impact questionnaire. Only high-quality studies were used, after being judged randomly, blinded and having allocation concealed. This gave 98 eligible studies, although in many the sample size was small and the quality of the study was insufficient for strong recommendations to be made. Treatment options were categorized as antidepressents, analgesics, ‘other pharmogalogical’, exercise, cognitive behavioral therapy, education, dietary interventions and ‘other nonpharmocalogical’ treatments. Finally a consensus of nine recommendations emerged for the management of FMS.

Reduced response to painkillers in

fibromyalgia sufferers explained

New findings by researchersfrom the University of Mich-igan Health System (MI,USA) helps to explain whysome fibromyalgia sufferersrespond poorly to pain reliefmedication.

Fibromyalgia is character-ized by specific or diffuse painin the muscles, joints andbones, fatigue and a widerange of other symptoms. Suf-ferers often claim that opioidpainkillers aimed at relievingpain, such as morphine andcodeine, have little effect.

Research published recentlyin The Journal of Neuroscienceappears to explain this anec-dotal observation. It has beenfound that the receptors in thebrain that bind opioid pain-killers have reduced bindingactivity in fibromyalgiapatients, resulting in reducedeffectiveness of pain reliefmedication.

“The finding is significant because it has been difficult to

determine the cause of pain in patients with fibromyalgia”

Positron emission tomogra-phy (PET) scans of the brainsof fibromyalgia sufferers revealthat the µ-opioid receptors(which are targeted by opioidpainkillers) of patients have areduced availability whencompared with those ofhealthy individuals. This

reduced binding activity wasfound to be localized mainlyin the nucleus accumbens, theanterior cingulate and theamygdala, all of which areinvolved in processing anddampening pain signals.Because the painkillers cannotbind the receptors they areunable to effectively alleviatethe patient’s pain.

The findings have impor-tant implications in the diag-nosis and treatment of thecondition, as explained by DrRichard Harris, researcher inthe Division of Rheumatol-ogy within the Department ofInternal Medicine, and leadauthor of the paper. “Thefinding is significant becauseit has been difficult to deter-mine the cause of pain inpatients with fibromyalgia, tothe point that acceptance ofthe condition by medicalpractitioners has been slow.”

The PET scans alsorevealed a link to depression.It was shown that fibromyal-gia patients with more depres-sive symptoms were especiallydeficient in µ-opioid recep-tors in the amygdala, a regionof the brain thought tomodulate mood and theemotional dimension of pain.

Source: Harris RE, Clauw DJ, Scott

DJ, McLean SA, Gracely RH, Zubi-

eta JK. Decreased central mu-opioid

receptor availability in fibromyalgia.

J. Neurosci. 27(37), 10,000–10,006

(2007).

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Potential new treatment for systemic lupus erythematosusResearchers in Indiana, USA, have of muscles, joints, kidneys and other The report, published in the Sep-

developed a new technique that mayoffer a way to treat the autoimmunedisease systemic lupus erythematosus(SLE). Current treatment relies on highdoses of steroids and other medicationthat often have serious side-effects,making the development of a safe alter-native an important breakthrough inthe field.

SLE is an autoimmune disease inwhich the body’s immune systemattacks healthy cells, leading to damage

organs. Using a treatment known asfolate-hapten-targeted immuno-therapy Dr Philip Low and colleaguesof Purdue Univeristy (IN, USA) wereable to target abnormal immune cellsfor destruction while leaving healthycells alone.

This approach resulted in a largereduction in damage to kidneys andother tissues, as well as a 10-monthextended lifespan in treated mice whencompared with untreated mice.

tember/October issue of ACS Mole-cular Pharmaceutics, concludes that:“this therapy warrants further evalua-tion as a possible approach fortreatment of SLE in humans.”

Source: Varghese B, Haase N, Low PS: Deple-

tion of folate-receptor-positive macrophages

leads to alleviation of symptoms and prolonged

survival in two murine models of systemic lupus

erythematosus. Mol. Pharm. 4(5), 679–685

(2007).

Gold-standard arthritis therapy

Scientists at the Duke UniversityMedical Center (NC, USA) haveuncovered the mechanism bywhich gold salts, traditionally usedto treat inflammation, reduceswelling, raising the possibility ofnew gold-based treatments. DavidPisetsky, chief of the division ofrheumatology and immunology atDuke and co-author of the paper,explains, “Scientists have neverreally understood why gold works.Now that we have a better handleon its action, we may be able touse that mechanism to create newand better gold-like drugs totreat arthritis.”

Gold has been used as a remedyfor joint pain since the early1900s; however, the treatment hasa number of side effects includingrashes, mouth sores, kidney dam-age and, occasionally, interruptionof the production of new bloodcells. As a result, gold salts havefallen out of favor as treatmentoptions, replaced instead by treat-ments such as methotrexate andbiologically engineered drugs. Butrecent research may lead to new,gold-based pharmaceuticals.

‘…the discovery concerning HMBG1 is of special importance in

arthritic disease…’

Pisetsky and colleagues from theUniversity of Pittsburgh (PA,USA) and the Karolinska Insti-tute, Sweden, have uncoveredthe molecular basis of gold’seffect. It appears that gold saltsblock the release of HMGB1from the nucleus. HMGB1plays an important role in tran-scription inside the cell. Whenreleased, however, it stimulatesthe immune system and causesinflammation. Pisetsky explainsthat the discovery concerningHMBG1 is of special impor-tance in arthritic disease as“there is an unusually highamount of it in the synovial tis-sue and fluid around the joints –where arthritis occurs.”

By interfering with interferon-band nitric oxide, molecules whichaid the release of HGMB1 fromthe cell, gold salts are able toreduce the amount of extracellularHGMB1.

It is hoped that this discoverywill lead to new arthritis therapies,although further studies arerequired to confirm that the samemechanism is active in vivo andnot just under laboratoryconditions.

Source: www.dukehealth.org/Health-

Library/News/10159?from=RSS

future science groupfuture science group www.futuremedici

Potential new mechanism for synovial inflammation in degenerative arthritis

Researchers from the University of Leeds and Cardiff Uni-

versity have uncovered what may be a novel source ofinflammation in sufferers of osteoarthritis (OA).

Synovitis has been shown to occur in early OA patients,when the articular cartilage appears to remain intact. Thisanomaly, along with recent findings that implicate theenthesis in spinal joint inflammation, prompted ProfessorsMichael Benjamin, of Cardiff University (UK), and Den-nis McGonagle, of the University of Leeds (UK), to turntheir attention to the enthesis, the site of attachment of theligament or tendon to the bone, as a possible source ofinflammation.

They specifically focused on what they call the ‘syno-vial–entheseal complex’ (SEC), a functional unit compris-ing the enthesis and adjacent synovium. The authorshypothesized that fibrocartilage may draw nourishmentfrom the synovium, meaning that if the enthesis is dam-aged then the fibrocartilage may break down, aggravatingthe associated synovium, thereby causing inflammation.

Testing this hypothesis, 49 entheses were taken fromcadavers and preserved for examination. Many SECs werelocated close to the articular cartilage, however were alsofound at 47% of locations examined away from the articu-lar cartilage. At many attachment sites, changes in theentheses mirrored those typically found in articular carti-lage. “Such changes at certain entheses could be directlyrelevant to older subjects with joint symptoms due todegenerative disease and some of the symptoms could beemanating from the SEC,” McGonagle concluded.

Source: Benjamin M, McGonagle D: Histopathologic changes at syn-

ovio-entheseal complexes suggesting a novel mechanism for synovitis

in osteoarthritis and spondylarthritis. Arthritis & Rheumatism

DOI: 10.1002/art.23078 (2007) (Epub ahead of print).

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