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Posts Tagged ‘rheumatoid arthritis’


Cancer Drugs Shed Light on Rheumatism

Reporter: Irina Robu, PhD

The human body is often described as being ‘at war’. By this, it is meant that the body is constantly under attack from things that are trying to do it harm. These include toxins, bacteria, fungi, parasites and viruses. The human immune system is one of the most effective defense mechanisms known to nature and can sometimes can be overwhelmed by disease. Yet, on occasions our immune systems turn on our own tissue and attack it which can trigger conditions such as type I diabetes, rheumatoid arthritis and lupus.
In the case of rheumatoid arthritis, immune cells start to attack tissues in the joins which causes them to become painful, stiff and swollen. It is known that one third of those who develop rheumatoid arthritis, feel the horrible effects of the disease within two years of its onset.
Immunologist Adrian Hayday, which is a researcher at Francis Crick Institute of London says that the current treatment for rheumatoid arthritis require patients to take the drugs for the rest of their lives. But, researchers such as Hayday found an unexpected ally in the battle against autoimmune disease, cancer.
However, there is a positive consequence to the discovery that cancer immunotherapies have the effect of triggering autoimmune diseases and for the first-time rheumatoid arthritis can be detected at the earliest stages. At present, people are not diagnosed with the condition until symptoms have already made their lives so unpleasant, they have gone to see their doctors. As a result, research backed by Cancer Research UK and Arthritis Research UK, has been launched with the aim of uncovering the roots of autoimmune disease from research on cancer patients.
The scientists mentioned stress that their work is only now start and warn that it will still take several years of research to get substantial results. Nevertheless, uncovering the first stages of an autoimmune disease emerging in a person’s body should give researchers a vital lead in ultimately developing treatments that will prevent or halt a range of conditions that currently cause a great deal of misery and require constant medication.
Our immune defenses consist of a range of cells and proteins that notice invading micro-organisms and attack them. The first line of defense, yet, consists of simple physical barriers similar to skin, which blocks invaders from entering your body. When this defense is penetrated, they are attacked by a number of agents. The key cells, leukocytes seek out and destroy disease-causing organisms. Neutrophils rush to the site of an infection and attack invading bacteria. Helper T-cells give instructions to other cells while killer T-cells punch holes in infected cells so that their contents ooze out. After these macrophages clean up the mess left behind.
Another significant agent is the B-cell, which produces antibodies that lock on to sites on the surface of bacteria or viruses and immobilize them until macrophages consume them. These cells can live a long time and can answer quickly following a second exposure to the same infections. In conclusion, suppressor T-cells act when an infection has been distributed with and the immune system needs to be reassured, the killer cells may keep on attacking, as they do in autoimmune diseases. By slowing down the immune system, regulatory T-cells prevent damage to “good” cells.

Source

https://www.theguardian.com/science/2018/mar/03/immunotherapy-cancer-patients-rheumatoid-arthritis-robin-mckie

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Carotid Ultrasound more sensitive for Detecting Subclinical Atherosclerosis in patients with rheumatoid arthritis (RA) than CT with calculation of Coronary Artery Calcification Scores

Reporter: Aviva Lev-Ari, PhD, RN

Ultrasound Predicts CVD Risk in Arthritis

Published: Oct 8, 2013 | Updated: Oct 8, 2013

By Nancy Walsh, Staff Writer, MedPage Today
Reviewed by Zalman S. Agus, MD; Emeritus Professor, Perelman School of Medicine at the University of Pennsylvania and Dorothy Caputo, MA, BSN, RN, Nurse Planner

 

Carotid ultrasound was more sensitive for detecting subclinical atherosclerosis in patients with rheumatoid arthritis (RA) than CT with calculation of coronary artery calcification scores, Spanish researchers found.

Among a group of 60 patients classified as being at moderate cardiovascular risk on a conventional scoring system, the presence of severe abnormalities on ultrasound reclassified 51 as being at high or very high risk, according to Miguel A. Gonzalez-Gay, MD, of Universitario Marques de Valdecilla in Santander, and colleagues.

And of those 51 reclassified patients, only 12 would have been reclassified as being at high or very high cardiovascular risk using a coronary artery calcification score,the researchers reported in the NovemberAnnals of the Rheumatic Diseases.

Patients with RA are at markedly increased risk for cardiovascular disease (CVD), both from conventional risk factors and the ongoing systemic inflammation associated with RA.

Comprehensive management of these patients therefore should include risk assessment and appropriate interventions, but “adequate stratification of the CV risk in patients with RA is still far from being completely established,” Gonzalez-Gay and colleagues noted.

The insensitivity of conventional risk assessments such as the Systematic Coronary Risk Evaluation (SCORE), even when modified by the European League Against Rheumatism(mSCORE) to account for the increased background risk in RA, has been confirmed byreports of ischemic heart disease among patients not considered to be at elevated risk on these measures.

These researchers previously suggested that carotid ultrasonography be added to the overall risk assessment of RA patients, particularly those with moderate SCORE risk, but whether other noninvasive approaches such as coronary artery calcification also could be useful has been uncertain.

Therefore, they enrolled 95 rheumatoid arthritis patients with no history of cardiovascular events and no diabetes or chronic renal disease.

Most were women, mean age was 59, and mean disease duration was 11 years.

Rheumatoid factor and/or anticyclic citrullinated peptide was present in 72%, and extra-articular manifestations in 16%.

All patients had carotid ultrasonography to assess for plaque and multi-detector CT scanning to detect coronary artery calcification.

Carotid intima-media thickness of 0.90 or the presence of plaque was considered predictive of CVD on ultrasound.

A coronary artery calcification score of zero was considered normal, and a score over 100 indicated a high likelihood of coronary artery disease.

Patients also were given conventional SCORE ratings, based on factors such as age, sex, smoking, blood pressure, and atherogenic index, as well as mSCORE ratings, to estimate the 10-year risk for a fatal cardiovascular event.

The mean SCORE was 2.30, and the mean mSCORE was 2.78.

Cardiovascular risk according to mSCORE was low in 21, moderate in 60, and high or very high in 14.

Most patients with low mSCOREs also had scores of zero for coronary artery calcification, and none of the low mSCORE patients had calcification scores above 100.

But 57% of patients with calcification scores of zero had carotid plaques identified on ultrasound, as did 76.3% of patients with calcification scores between 1 and 100.

While calcification scores above 100 weren’t much more sensitive than mSCOREs for detection of high risk (23.6% versus 19.4%), almost all (70 of 72) patients with high or very high risk were identified with carotid ultrasound, for a sensitivity of 97.2% (95% CI 90.3-99.7).

And when the ultrasound model of intima-media thickness above 0.9 mm and/or carotid plaque also included mSCOREs above 5%, all 72 were correctly identified, for a sensitivity of 100% (95% CI 95-100).

This lack of sensitivity for calcification scores likely reflects the finding that arterial calcification is a later vascular development, and its absence doesn’t rule out the presence of the more vulnerable noncalcified plaques, the researchers explained.

“These results support the use of carotid ultrasonography as the imaging technique of choice for detection of high/very high CV risk in RA patients with moderate mSCORE,” they said.

In an editorial accompanying the study, Patrick H. Dessein, MD, of the University of Witwatersrand in Johannesburg, South Africa, and Anne G. Semb, MD, of Diakonhjemmet Hospital in Oslo, Norway, noted that the use of ultrasound more than tripled the number of patients considered to be at high risk.

If only mSCORE was used for risk stratification, they pointed out, many patients “in routine clinical settings” would be unlikely to receive preventive treatments, “with the serious consequences this has.”

Dessein and Semb also noted that there were certain limitations to this study, including its cross-sectional design and inclusion of patients with long disease duration.

“It remains to be clarified whether carotid ultrasound is as helpful among patients with early disease versus those with longstanding disease in enhancing CVD risk stratification,” the editorialists wrote.

The authors reported no conflicting interests.

From the American Heart Association:

http://www.medpagetoday.com/Rheumatology/Arthritis/42138?xid=nl_mpt_DHE_2013-10-09&utm_content=&utm_medium=email&utm_campaign=DailyHeadlines&utm_source=WC&eun=g99985d0r&userid=99985&email=avivalev-ari@alum.berkeley.edu&mu_id=5099207

 

 

 

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Rheumatoid Arthritis Risk

Reporter: Larry H Bernstein, MD, FCAP

Liu Y, Aryee MJ, Padyukov L, et al.
Nat Biotechnol. 2013 Jan 20;31(2):142-7.   http://dx.doi.org/10.1038/nbt.2487. Epub 2013 Jan 20.
The concordance rate for identical twins is only 12%-15%, which tells us that
  • other influences are even more important.
  • the “dark matter” of disease risk might be found in epigenetics,
  • defined as heritable changes in the genome without changes in DNA sequences.

Epigenome-wide association data implicate DNA methylation.
http://www.medscape.com//view-article/778573

Genetics of Rheumatic Disease – Medscape: Medical News, Full …Common variants at CD40 and other loci confer risk of rheumatoid arthritis. …
EF, Lee AT, Padyukov L, Alfredsson L, Coblyn J, et al.: … MM, Klei L, Daly MJ …www.medscape.com/viewarticle/717475  
High impact publications – Ongoing research – Karolinska …
Epigenome-wide association data implicate DNA methylation as an intermediary of genetic risk in rheumatoid arthritis
Liu Y, Aryee MJ, Padyukov L, Fallin MD …
http://www.ki.se/ki/jsp/polopoly.jsp?d=7324&a=61979&l=en
Arthritis Research & Therapy
… Seldin MF, Remmers EF, Lee AT, Padyukov L, Alfredsson L, Coblyn J, et al.: … other loci confer risk of rheumatoid arthritis. Nat …
Liu Y, Helms C , Liao W, Zaba LC …   http://www.arthritis-research.com/content/12/3/r116
CHEST Journal
TRAF1-C5 as a risk locus for rheumatoid arthritis—a genomewide ... Liu G; et al . Whole-genome …
Padyukov L; et al. MHC2TA is associated with http://www. journal.publications.chestnet.org/article.aspx?articleid=1086542
Arthritis Research & Therapy 2010, 12:R116 Published: 16 June 2010    http://dx.doi.org/10.1186/ar3053
The electronic version of this article is the complete one and can be found online at: http://arthritis-research.com/content/12/3/R116
JE Hollis-Moffatt, M Chen-Xu, R Topless, N Dalbeth, … and TR Merriman

Only one independent genetic association with rheumatoid arthritis within the KIAA1109-TENR-IL2-IL21 locus in Caucasian sample sets:

Genetic associations implicate aberrant activation and regulation of autoreactive T-cells as central to RA. In addition to the established human leukocyte antigen locus DRB1, other genes more recently confirmed (either through wide replication or combined analysis at a genome-wide level of significance, P ≤ 10-8) as playing a role in the development of RA are the protein

Aside from HLA-DRB1 and PTPN22, the effects are weak (odds ratio (OR) < 1.3). Most of these loci are also implicated as risk factors in other autoimmune phenotypes [12].
There is extensive linkage disequilibrium across the region,

  • hampering fine-mapping efforts [13],
  • there are two independent autoimmune associated regions within the KIAA1109-TENR-IL2-IL21 gene cluster.
We aimed to consolidate all available data on two SNPs independently associated with autoimmunity within the KIAA1109-TENR-IL2-IL21 gene cluster:
  • rs6822844 (minor allele protective) and rs17388568 (minor allele susceptible),
each into a single meta-analysis of association with RA that included previously published data, new genotype data from Australasia, and
publicly-available data from the Wellcome Trust Case Control Consortium (WTCCC).
 The single nucleotide polymorphism (SNP) rs6822844 within the KIAA1109-TENR-IL2-IL21 gene cluster
  • has been associated with rheumatoid arthritis (RA).

Other variants within this cluster, including

  • rs17388568 that is not in linkage disequilibrium (LD) with rs6822844, and
  • rs907715 that is in moderate LD with rs6822844 and rs17388568, have been associated with a number of autoimmune phenotypes,
    • including type 1 diabetes (T1D).

Here we aimed to:

  1. confirm at a genome-wide level of significance association of rs6822844 with RA
  2. evaluate whether or not there were effects independent of rs6822844 on RA at the KIAA1109-TENR-IL2-IL21 locus.

confirmation of association of rs6822844 with rheumatoid arthritis at a genome-wide level of significance

A total of 842 Australasian RA patients and 1,115 controls of European Caucasian ancestry were

  • genotyped for rs6822844, rs17388568 and rs907715.

Meta-analysis of these data with published and publicly-available data was conducted using STATA.
Imputed RA and control genotypes were obtained for

  • rs6822844, rs17388568 and rs907715 from 100% of the WTCCC dataset (1,856 cases, 2,933 controls) using the publicly available WTCCC data
    • using the program IMPUTE [25] and HapMap (NCBI Build 36 (db126b)) CEU data as reference haplotype set.

Of the Australasian case sample set, 99.1% of subjects for rs6822844, 99.1% of subjects for rs17388568 and 98.9% of subjects for rs9077015 were successfully genotyped and, for the 505 member control sample set, 97.4% of subjects for rs6822844, 99.4% of subjects for rs17388568 and 99.4% of subjects for rs9077015 were successfully genotyped. The remaining New Zealand control genotypes (n = 610) were obtained from the genome-wide data, with 100% successfully genotyped for rs17388568 and 99.6% imputed for rs6822844 and rs907715.
Testing for departures from Hardy-Weinberg equilibrium, for the significance of any difference in minor allele frequencies between patients and controls, calculating odds ratios and conditional association testing was done using the PLINK software package. Logistic regression analysis was applied to the Australasian case-control sample set to stratify data according to gender, RF, CCP and SE status using the STATA 8.0 data analysis and statistics software package (StataCorp, College Station, Texas, USA). Meta-analysis was done using the STATA 8.0 metan software package and cumulative P- values reported. The Mantel-Haenszel test was used to estimate the average conditional common odds ratio between these two independent cohorts and to test for heterogeneity between the groups. P- values from the North American Rheumatoid Arthritis Consortium (NARAC) study, which could not be combined using meta-analysis owing to unavailability of allele counts, were combined using Fisher’s method.

No statistically significant evidence for association was observed in the Australasian sample set for rs6822844 (odds ratio (OR) = 0.95 (0.80 to 1.12), P = 0.54), or rs17388568 (OR = 1.03 (0.90 to 1.19), P = 0.65) or rs907715 (OR = 0.98 (0.86 to 1.12), P = 0.69). When combined in a meta-analysis using data from a total of 9,772 cases and 10,909 controls

  • there was a genome-wide level of significance supporting association of rs6822844 with RA (OR = 0.86 (0.82 to 0.91), P = 8.8 × 10-8, P = 2.1 × 10-8 including NARAC data).

Meta-analysis of rs17388568, using a total of 6,585 cases and 7,528 controls, revealed

  • no significant association with RA (OR = 1.03, (0.98 to 1.09); P = 0.22) and
  • meta-analysis of rs907715 using a total of 2,689 cases and 4,045 controls revealed a
  • trend towards association (OR = 0.93 (0.87 to 1.00), P = 0.07).
    • this trend wasnot independent of the association at   rs6822844.

Zhernakova et al. [21] and Coenen et al. [28] both reported association of the KIAA1109-TENR-IL2-IL21 region with RA in overlapping Dutch case-control cohorts. We used data from the former study, as it was the only one to type rs6822844. The meta-analysis provided very strong (genome-wide) support

  • for rs6822844 playing a role in the development of RA (OR = 0.86 (0.82 to 0.91), P = 8.8 × 10-8).

The NARAC GWAS data (OR rs6822844 = 0.84 (0.74-0.96), P = 0.011) [7] were combined with the meta-analysis result, yielding P = 2.1 × 10-8.

The KIAA1109-TENR-IL2-IL21 gene cluster, that encodes aninterleukin (IL-21)that plays an important role in Th17 cell biology, is the

  • 20th locus for which there is a genome-wide (P ≤ 5 ×10-8) level of support for association with RA.

As for most other autoimmune diseases, with the notable exception of T1D, rs6822844 is the dominant association in the locus. The KIAA1109-TENR-IL2-IL21 locus also

    • confers susceptibility to other autoimmune phenotypes with a heterogeneous pattern of association.

 

Genetic “Tags” Linked with RA Risk
Chemical “tags” that attach to DNA and regulate the activity of genes

  • appear to play a role in the development of rheumatoid arthritis.
    1. These results were published in Nature Biotechnology.
Genes play an important role in rheumatoid arthritis (RA) and many other common chronic diseases, but often do not tell the entire story. Factors that regulate the activity of genes are also thought to be important.

    • These factors include chemical tags that bind to DNA.
If the tagging of certain genes is found to contribute to a disease, it could point to news ways to treat the disease. One of the challenges in studying these tags, however, is

  • determining the sequence of events;
  • some tags may occur prior to disease and influence disease development,
  • while other tags may occur as a result of the disease.
To explore genes and their chemical tags in relation to RA,

  • researchers conducted a study among a group of people with RA and a comparison group of people without RA.
  • The researchers were able to identify DNA sites that were tagged differently in people with RA and that appeared to affect the risk of RA.
  • Most of these sites were in an area of the genome that has been linked with autoimmune disease.
In a prepared statement, the senior author of the study summarized the importance of these findings for patients: “Since RA is a disease in which the body’s immune system turns on itself,

    • current treatments often involve suppressing the entire immune system, which can have serious side effects.

The results of this study may allow clinicians to instead directly target the culpable genes and/or their tags.”

Reference: Liu Y, Aryee MJ, Padyukov L et al. Epigenome-wide association data implicate DNA methylation as an intermediary of genetic risk in rheumatoid arthritis. Nature Biotechnology. Early online publication January 20, 2013;
New Risk Gene for Rheumatoid Arthritis and Lupus Opens Door to More Effective Treatments
gene variant on STAT4 on chromosome 2
http://phys.org/news108298062/
Study identifies genetic risk factor for rheumatoid arthritis, lupus Sept 6, 2007
A genetic variation has been identified that increases the risk of two chronic, autoimmune inflammatory diseases: rheumatoid arthritis (RA) and systemic lupus erythematosus (lupus).
These research findings result from a long-time collaboration between the Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases and other organizations.
These results appear in the Sept. 6 issue of the New England Journal of Medicine.
“Although both diseases are believed to have a strong genetic component, identifying the relevant genes has been extremely difficult,” says study coauthor Elaine Remmers, Ph.D.  Dr. Remmers and her colleagues
  • tested variants within 13 candidate genes located in a region of chromosome 2,
  • which they had previously linked with RA,
  • for association with disease in large collections of RA and lupus patients and controls.

Among the variants were several disease-associated single nucleotide polymorphisms (SNPs) —

  • small differences in DNA sequence that represent the most common genetic variations between individuals —
  • in a large segment of the STAT4 gene.

The STAT4 gene encodes a protein that plays an important role in the regulation and activation of certain cells of the immune system.

“It may be too early to predict the impact of identifying the STAT4 gene as a susceptibility locus for rheumatoid arthritis — whether the presence of the variant and others will serve as

  • a predictor of disease,
  • disease outcome or
  • response to therapy,”
says coauthor and NARAC principal investigator Peter K. Gregersen, M.D., of The Feinstein Institute for Medical Research,  in Manhasset, N.Y.

  • “It also remains to be found whether the STAT4 pathway plays such a crucial role in RA and lupus that
  • new therapies targeting this pathway would be effective in these and perhaps other autoimmune diseases.”

One variant form of the gene was present at a significantly higher frequency in RA patient samples from the North American Rheumatoid Arthritis Consortium (NARAC) as compared with controls.
The scientists replicated that result in two independent collections of RA cases and controls. The researchers also found that the same variant of the STAT4 gene was

  • even more strongly linked with lupus in three independent collections of patients and controls.

Frequency data on the genetic profiles of the patients and controls suggest that individuals who carry two copies of the disease-risk variant form of the STAT4 gene have a 60 percent increased risk for RA and more than double the risk for lupus compared with people who carry no copies of the variant form. The research also suggests

  • a shared disease pathway for RA and lupus.

“For this complex disease, rheumatoid arthritis, this is the first instance of a genetic linkage study

  1. leading to a chromosomal location, which then,
  2. in a genetic association study, identified a disease susceptibility gene,” says Dr. Gregersen.

The study’s success, according to NIAMS Director Stephen I. Katz, M.D., Ph.D., can be attributed in part to the uncommon and longstanding collaboration between NIAMS intramural researchers and other scientists the Institute supports around the country. “This work required the collection and genotyping of thousands of RA and lupus cases and controls, a task that would have been difficult to accomplish without the strong partnerships we forged,” he says. NARAC was established 10 years ago by Dr. Gregersen, NIAMS Clinical Director and Genetics and Genomics Branch Chief Daniel Kastner, M.D., Ph.D., and investigators at several academic health centers to facilitate the collection and analysis of RA genetic samples. Adds Dr. Remmers,

“Although we do not yet know precisely how the disease-associated variant of the STAT4 gene increases the risk for developing RA or lupus,
  • it is very exciting to know that this gene plays a fundamental role in these important autoimmune diseases.
” Source: National Institute of Arthritis and Musculoskeletal and Skin Diseases
English: A hand affected by rheumatoid arthritis

English: A hand affected by rheumatoid arthritis (Photo credit: Wikipedia)

Rheumatoid arthritis (1)

Rheumatoid arthritis (1) (Photo credit: Wikipedia)

Typisches Röntgenbild einer Rheumatoiden Arthr...

Typisches Röntgenbild einer Rheumatoiden Arthritis. (Photo credit: Wikipedia)

Related articles

1. Monoclonal IgG antibodies generated from joint-derived B cells of RA patients have a strong bias toward citrullinated autoantigen recognition.
Amara K, Steen J, Murray F, Morbach H, Fernandez-Rodriguez BM, Joshua V, Engström M, Snir O, Israelsson L, Catrina AI, Wardemann H, Corti D, Meffre E, Klareskog L, Malmström V.
J Exp Med. 2013 Feb 25. [Epub ahead of print]  PMID: 23440041 [PubMed – as supplied by publisher]

2. Ambient air pollution exposures and risk of rheumatoid arthritis in the Nurses’ Health Study.
Hart JE, Källberg H, Laden F, Costenbader KH, Yanosky JD, Klareskog L, Alfredsson L, Karlson EW.
Arthritis Care Res (Hoboken). 2013 Feb 11.   http://dx. doi.org/10.1002/acr.21975. [Epub ahead of print]     PMID: 23401426 [PubMed – as supplied by publisher]

3. Epigenome-wide association data implicate DNA methylation as an intermediary of genetic risk in rheumatoid arthritis.
Liu Y, Aryee MJ, Padyukov L, Fallin MD, Hesselberg E, Runarsson A, Reinius L, Acevedo N, Taub M, Ronninger M, Shchetynsky K, Scheynius A, Kere J, Alfredsson L, Klareskog L, Ekström TJ, Feinberg AP.
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4. Multiplex analyses of antibodies against citrullinated peptides in individuals prior to development of rheumatoid arthritis.
Brink M, Hansson M, Mathsson L, Jakobsson PJ, Holmdahl R, Hallmans G, Stenlund H, Rönnelid J, Klareskog L, Dahlqvist SR.
Arthritis Rheum. 2013 Jan 10.    http://dx. do.org/10.1002/art.37835. [Epub ahead of print]    PMID: 23310951 [PubMed – as supplied by publisher]

5. Rare, low-frequency, and common variants in the protein-coding sequence of biological candidate genes from GWASs contribute to risk of rheumatoid arthritis.
Diogo D, Kurreeman F, Stahl EA, Liao KP, Gupta N, Greenberg JD, Rivas MA, …Alfredsson L; CRRNA; RACI, Sunyaev S, Martin J,…, Klareskog L, Padyukov L, Raychaudhuri S, Plenge RM.
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6. Genetic variation in the serotonin receptor gene affects immune responses in rheumatoid arthritis.
Snir O, Hesselberg E, Amoudruz P, Klareskog L, … Padyukov L, Malmström V, Seddighzadeh M.
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7. Polymorphisms in peptidylarginine deiminase associate with rheumatoid arthritis in diverse Asian populations: evidence from MyEIRA study and meta-analysis.
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8. High-density genetic mapping identifies new susceptibility loci for rheumatoid arthritis.
Eyre S, Bowes J, Diogo D, Lee A, Barton A, Martin P,…; BRAGGSS; Wellcome Trust Case Control Consortium, … Klareskog L, Gregersen PK, Worthington J.
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9. The Swedish twin registry: establishment of a biobank and other recent developments.
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10. Validation of a multiplex chip-based assay for the detection of autoantibodies against citrullinated peptides.
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Curator/Reporter: Aviral Vatsa PhD MBBS

This post is in the second part of the reviews that focuses on the current status of drug delivery to bone and the issues facing this field. The first part can be accessed here

Annual treatment costs for musculoskeletal diseases in the US are roughly 7.7% (~ $849 billion) of total gross domestic product. Such disorders are the main cause of physical disability in US. Almost half of all chronic conditions in people can be attributed to bone and joint disorders. In addition there is increasing ageing population and associated increases in osteoporosis and other diseases, rising incidences of degenerative intervertebral disk diseases and numbers of revision orthopedic arthroplasty surgeries, and increases in spinal fusions. All these factors contribute towards the increasing requirement of bone regeneration and reconstruction methods and products. Delivery of therapeutic grade products to bone has various challenges. Parenteral administration limits the efficient delivery of drugs to the required site of injury and local delivery methods are often expensive and invasive. The theme issue of Advance Drug Delivery reviews focuses on the current status of drug delivery to bone and the issues facing this field. Here is the second part of these reviews and research articles.

1. Targeting polymer therapeutics to bone [1]

Abstract

An aging population in the developing world has led to an increase in musculoskeletal diseases such as osteoporosis and bone metastases. Left untreated many bone diseases cause debilitating pain and in the case of cancer, death. Many potential drugs are effective in treating diseases but result in side effects preventing their efficacy in the clinic. Bone, however, provides a unique environment of inorganic solids, which can be exploited in order to effectively target drugs to diseased tissue. By integration of bone targeting moieties to drug-carrying water-soluble polymers, the payload to diseased area can be increased while side effects decreased. The realization of clinically relevant bone targeted polymer therapeutics depends on (1) understanding bone targeting moiety interactions, (2) development of controlled drug delivery systems, as well as (3) understanding drug interactions. The latter makes it possible to develop bone targeted synergistic drug delivery systems.


2. Development of macromolecular prodrug for rheumatoid arthritis [2]

Abstract

Rheumatoid arthritis (RA) is a chronic autoimmune disease that is considered to be one of the major public health problems worldwide. The development of therapies that target tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and co-stimulatory pathways that regulate the immune system have revolutionized the care of patients with RA. Despite these advances, many patients continue to experience symptomatic and functional impairment. To address this issue, more recent therapies that have been developed are designed to target intracellular signaling pathways involved in immunoregulation. Though this approach has been encouraging, there have been major challenges with respect to off-target organ side effects and systemic toxicities related to the widespread distribution of these signaling pathways in multiple cell types and tissues. These limitations have led to an increasing interest in the development of strategies for the macromolecularization of anti-rheumatic drugs, which could target them to the inflamed joints. This approach enhances the efficacy of the therapeutic agent with respect to synovial inflammation, while markedly reducing non-target organ adverse side effects. In this manuscript, we provide a comprehensive overview of the rational design and optimization of macromolecular prodrugs for treatment of RA. The superior and the sustained efficacy of the prodrug may be partially attributed to their Extravasation through Leaky Vasculature and subsequent Inflammatory cell-mediated Sequestration (ELVIS) in the arthritic joints. This biologic process provides a plausible mechanism, by which macromolecular prodrugs preferentially target arthritic joints and illustrates the potential benefits of applying this therapeutic strategy to the treatment of other inflammatory diseases.

 

3. Peptide-based delivery to bone [3]

Abstract

Peptides are attractive as novel therapeutic reagents, since they are flexible in adopting and mimicking the local structural features of proteins. Versatile capabilities to perform organic synthetic manipulations are another unique feature of peptides compared to protein-based medicines, such as antibodies. On the other hand, a disadvantage of using a peptide for a therapeutic purpose is its low stability and/or high level of aggregation. During the past two decades, numerous peptides were developed for the treatment of bone diseases, and some peptides have already been used for local applications to repair bone defects in the clinic. However, very few peptides have the ability to form bone themselves. We herein summarize the effects of the therapeutic peptides on bone loss and/or local bone defects, including the results from basic studies. We also herein describe some possible methods for overcoming the obstacles associated with using therapeutic peptide candidates.


4. Growth factor delivery: How surface interactions modulate release in vitro and in vivo [4]

Abstract

Biomaterial scaffolds have been extensively used to deliver growth factors to induce new bone formation. The pharmacokinetics of growth factor delivery has been a critical regulator of their clinical success. This review will focus on the surface interactions that control the non-covalent incorporation of growth factors into scaffolds and the mechanisms that control growth factor release from clinically relevant biomaterials. We will focus on the delivery of recombinant human bone morphogenetic protein-2 from materials currently used in the clinical practice, but also suggest how general mechanisms that control growth factor incorporation and release delineated with this growth factor could extend to other systems. A better understanding of the changing mechanisms that control growth factor release during the different stages of preclinical development could instruct the development of future scaffolds for currently untreatable injuries and diseases.


5. Biomaterial delivery of morphogens to mimic the natural healing cascade in bone[5]

Abstract

Complications in treatment of large bone defects using bone grafting still remain. Our understanding of the endogenous bone regeneration cascade has inspired the exploration of a wide variety of growth factors (GFs) in an effort to mimic the natural signaling that controls bone healing. Biomaterial-based delivery of single exogenous GFs has shown therapeutic efficacy, and this likely relates to its ability to recruit and promote replication of cells involved in tissue development and the healing process. However, as the natural bone healing cascade involves the action of multiple factors, each acting in a specific spatiotemporal pattern, strategies aiming to mimic the critical aspects of this process will likely benefit from the usage of multiple therapeutic agents. This article reviews the current status of approaches to deliver single GFs, as well as ongoing efforts to develop sophisticated delivery platforms to deliver multiple lineage-directing morphogens (multiple GFs) during bone healing.

6. Studies of bone morphogenetic protein-based surgical repair[6]

Abstract

Over the past several decades, recombinant human bone morphogenetic proteins (rhBMPs) have been the most extensively studied and widely used osteoinductive agents for clinical bone repair. Since rhBMP-2 and rhBMP-7 were cleared by the U.S. Food and Drug Administration for certain clinical uses, millions of patients worldwide have been treated with rhBMPs for various musculoskeletal disorders. Current clinical applications include treatment of long bone fracture non-unions, spinal surgeries, and oral maxillofacial surgeries. Considering the growing number of recent publications related to clincal research of rhBMPs, there exists enormous promise for these proteins to be used in bone regenerative medicine. The authors take this opportunity to review the rhBMP literature paying specific attention to the current applications of rhBMPs in bone repair and spine surgery. The prospective future of rhBMPs delivered in combination with tissue engineered scaffolds is also reviewed.


7. Strategies for controlled delivery of growth factors and cells for bone regeneration[7]

Abstract

The controlled delivery of growth factors and cells within biomaterial carriers can enhance and accelerate functional bone formation. The carrier system can be designed with pre-programmed release kinetics to deliver bioactive molecules in a localized, spatiotemporal manner most similar to the natural wound healing process. The carrier can also act as an extracellular matrix-mimicking substrate for promoting osteoprogenitor cellular infiltration and proliferation for integrative tissue repair. This review discusses the role of various regenerative factors involved in bone healing and their appropriate combinations with different delivery systems for augmenting bone regeneration. The general requirements of protein, cell and gene therapy are described, with elaboration on how the selection of materials, configurations and processing affects growth factor and cell delivery and regenerative efficacy in both in vitro and in vivo applications for bone tissue engineering.

8. Bone repair cells for craniofacial regeneration[8]

Abstract

Reconstruction of complex craniofacial deformities is a clinical challenge in situations of injury, congenital defects or disease. The use of cell-based therapies represents one of the most advanced methods for enhancing the regenerative response for craniofacial wound healing. Both somatic and stem cells have been adopted in the treatment of complex osseous defects and advances have been made in finding the most adequate scaffold for the delivery of cell therapies in human regenerative medicine. As an example of such approaches for clinical application for craniofacial regeneration, Ixmyelocel-T or bone repair cells are a source of bone marrow derived stem and progenitor cells. They are produced through the use of single pass perfusion bioreactors for CD90+ mesenchymal stem cells and CD14+ monocyte/macrophage progenitor cells. The application of ixmyelocel-T has shown potential in the regeneration of muscular, vascular, nervous and osseous tissue. The purpose of this manuscript is to highlight cell therapies used to repair bony and soft tissue defects in the oral and craniofacial complex. The field at this point remains at an early stage, however this review will provide insights into the progress being made using cell therapies for eventual development into clinical practice.


9. Gene therapy approaches to regenerating bone[9]

Abstract

Bone formation and regeneration therapies continue to require optimization and improvement because many skeletal disorders remain undertreated. Clinical solutions to nonunion fractures and osteoporotic vertebral compression fractures, for example, remain suboptimal and better therapeutic approaches must be created. The widespread use of recombinant human bone morphogenetic proteins (rhBMPs) for spine fusion was recently questioned by a series of reports in a special issue of The Spine Journal, which elucidated the side effects and complications of direct rhBMP treatments. Gene therapy – both direct (in vivo) and cell-mediated (ex vivo) – has long been studied extensively to provide much needed improvements in bone regeneration. In this article, we review recent advances in gene therapy research whose aims are in vivo or ex vivo bone regeneration or formation. We examine appropriate vectors, safety issues, and rates of bone formation. The use of animal models and their relevance for translation of research results to the clinical setting are also discussed in order to provide the reader with a critical view. Finally, we elucidate the main challenges and hurdles faced by gene therapy aimed at bone regeneration as well as expected future trends in this field.

10. Gene delivery to bone[10]

Abstract

Gene delivery to bone is useful both as an experimental tool and as a potential therapeutic strategy. Among its advantages over protein delivery are the potential for directed, sustained and regulated expression of authentically processed, nascent proteins. Although no clinical trials have been initiated, there is a substantial pre-clinical literature documenting the successful transfer of genes to bone, and their intraosseous expression. Recombinant vectors derived from adenovirus, retrovirus and lentivirus, as well as non-viral vectors, have been used for this purpose. Both ex vivo and in vivo strategies, including gene-activated matrices, have been explored. Ex vivo delivery has often employed mesenchymal stem cells (MSCs), partly because of their ability to differentiate into osteoblasts. MSCs also have the potential to home to bone after systemic administration, which could serve as a useful way to deliver transgenes in a disseminated fashion for the treatment of diseases affecting the whole skeleton, such as osteoporosis orosteogenesis imperfecta. Local delivery of osteogenic transgenes, particularly those encoding bone morphogenetic proteins, has shown great promise in a number of applications where it is necessary to regenerate bone. These include healing large segmental defects in long bones and the cranium, as well as spinal fusion and treating avascular necrosis.

11. RNA therapeutics targeting osteoclast-mediated excessive bone resorption[11]

Abstract

RNA interference (RNAi) is a sequence-specific post-transcriptional gene silencing technique developed with dramatically increasing utility for both scientific and therapeutic purposes. Short interfering RNA (siRNA) is currently exploited to regulate protein expression relevant to many therapeutic applications, and commonly used as a tool for elucidating disease-associated genes. Osteoporosis and their associated osteoporotic fragility fractures in both men and women are rapidly becoming a global healthcare crisis as average life expectancy increases worldwide. New therapeutics are needed for this increasing patient population. This review describes the diversity of molecular targets suitable for RNAi-based gene knock down in osteoclasts to control osteoclast-mediated excessive bone resorption. We identify strategies for developing targeted siRNA delivery and efficient gene silencing, and describe opportunities and challenges of introducing siRNA as a therapeutic approach to hard and connective tissue disorders.

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[7] T. N. Vo, F. K. Kasper, and A. G. Mikos, “Strategies for controlled delivery of growth factors and cells for bone regeneration,” Advanced Drug Delivery Reviews, vol. 64, no. 12, pp. 1292–1309, Sep. 2012.

[8] G. Pagni, D. Kaigler, G. Rasperini, G. Avila-Ortiz, R. Bartel, and W. V. Giannobile, “Bone repair cells for craniofacial regeneration,” Advanced Drug Delivery Reviews, vol. 64, no. 12, pp. 1310–1319, Sep. 2012.

[9] N. Kimelman Bleich, I. Kallai, J. R. Lieberman, E. M. Schwarz, G. Pelled, and D. Gazit, “Gene therapy approaches to regenerating bone,” Advanced Drug Delivery Reviews, vol. 64, no. 12, pp. 1320–1330, Sep. 2012.

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[11] Y. Wang and D. W. Grainger, “RNA therapeutics targeting osteoclast-mediated excessive bone resorption,” Advanced Drug Delivery Reviews, vol. 64, no. 12, pp. 1341–1357, Sep. 2012.

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