For the launch of our Liver-9-Line immunoblot test (to our press release “Liver Disease Diagnostics by Immunoblot” of May 16, 2011), I dug through a pile of literature on the topic of autoantibody-based diagnosis of autoimmune diseases of the liver. In the last week I picked it all up again and worked through it systematically.

The interior surface of the liver. A reproduction of a lithograph plate from Gray’s Anatomy.

The reason for my renewed interest is that we brought four more ELISA tests for liver diagnostics to the market two weeks ago. They are the Anti-LKM-1, Anti-SLA, Anti-gp210, and Anti-Sp100 tests, all designed for fully automated autoimmune diagnosis with our Alegria system. All four test systems assist the formulation of a diagnosis when autoimmune hepatitis (AIH) and primary biliary cirrhosis (PBC) are suspected, or for differential diagnosis when another disorder of the liver is assumed.

Autoimmune diseases of the liver

The requirements for successful treatment of liver disease naturally include a precise diagnosis. As a result, unexplained elevated liver enzymes generally lead the treating physician on a complicated search for the source of the abnormally elevated liver values. In addition to anamnesis and clinical findings, laboratory tests and the correct interpretation of the laboratory results play a critical role in this process.

If the doctor is able to rule out alcohol abuse, drug-induced hepatitis, and viral hepatitis (for example hepatitis B, C, or D), and if nothing points to hemochromatosis, alpha-1-antitrypsin deficiency, or Wilson’s disease (also called: hepatolenticular degeneration), the most likely suspects remaining are autoimmune liver diseases.

In cases of autoimmune liver disease, the body loses its ability to tolerate its own hepatocellular or cholangiocellular tissues in the liver. The causes of these diseases remain a mystery.

When it comes to autoimmune diseases of the liver, there are essentially three conditions to differentiate:

1. autoimmune hepatitis (AIH), of which there are two variants, type 1 AIH and type 2 AIH.
2. primary biliary cirrhosis (PBC)
3. primary sclerosing cholangitis (PSC)

The individual clinical presentations of these diseases may overlap, which is what makes the appraisal and interpretation of laboratory values, as well as the formation of a diagnosis, so difficult for these autoimmune diseases. Overlap syndromes are particularly common between autoimmune hepatitis and PBC; overlap between the autoimmune liver diseases and viral hepatitis C is also not uncommon. (Here you will find a background article on autoimmune liver disease diagnostics.)

Autoimmune hepatitis (AIH)

Type 1 autoimmune hepatitis (type 1 AIH) is considered “classic” autoimmune hepatitis. This disorder mostly occurs in young women and is typically characterized by the presence of antinuclear antibodies (ANA) and/or anti-smooth muscle antibodies (ASMA, or: SMA), with F-actin generally acting as the target antigen. Autoantibodies against the soluble liver antigen/liver pancreas antigen (anti-SLA/LP antibodies) are often also detected. Depending on the study, this is the case in up to 25% of affected patients.

In the past, this form of “SLA-positive AIH” was considered to be its own variant of autoimmune hepatitis and was formerly known as “type 3 autoimmune hepatitis” (“type 3 AIH”). Because this anti-SLA positive form of the disease is clinically and therapeutically no different from type 1 autoimmune hepatitis, the differentiation between type 1 and type 3 AIH was abandoned. Clearly different from type 1 AIH, type 2 AIH is primarily characterized by the presence of anti-LKM-1 and anti-LC-1 antibodies.

Figure 1 – A simplified scheme: serological differentiation of type 1 autoimmune hepatitis and type 2 autoimmune hepatitis.

The autoantibodies typically detected in cases of autoimmune hepatitis are: antinuclear antibodies (ANA), anti-smooth muscle antibodies (ASMA), LKM-1 antibodies, LC-1 antibodies, and anti-SLA/LP antibodies.

Primary biliary cirrhosis (PBC)

Primary biliary cirrhosis (PBC) is a chronic, progressive disease involving destruction of the small and intermediate bile ducts. It runs in families and is more common in women over 40 years of age. The diagnostic marker for PBC is detection of AMA, in particular AMA-M2. This test is complemented by the detection of anti-Sp100 and anti-gp210 autoantibodies.

Figure 2 – Simplified scheme: serodiagnosing primary biliary cirrhosis (PBC).

The autoantibodies typical of primary biliary cirrhosis (PBC) are: antimitochondrial antibodies (in particular AMA of subtype M2) and the antinuclear antibodies directed against the antigens sp100 and gp210.

Sclerosing cholangitis

Sclerosing cholangitis presents in at least two variants: the first is classical primary sclerosing cholangitis (PSC), which mostly affects adult men and for which the only (and nonspecific) reactivity is an atypical perinuclear antineutrophil cytoplasmic antibody (“xANCA pattern”), the second is a childhood disease called autoimmune sclerosing cholangitis (ASC) with serological characteristics resembling those of a type 1 autoimmune hepatitis.

Antibody diagnostics for cases of …

… autoimmune hepatitis (AIH) …

After ASMA, antinuclear antibodies (ANA) are the most frequently detected autoantibodies in patients with type 1 AIH. Although ANA have no specificity for type 1 AIH, they are considered to be marker antibodies for this disease. In a large proportion (up to 60%) of patients with type 1 AIH, both ANA and ASMA can be detected. Up to 15% of patients with type 1 AIH have only ANA; about a third (30-35%) of patients have exclusively ASMA.

Depending on the test, antibodies against SLA/LP (SLA/LP = soluble liver antigen / liver pancreas) are found in up to 25% of serum samples from patients with type 1 AIH. These SLA-positive patients were previously considered to have a variant of the disease called “type 3 autoimmune hepatitis”; today they are included with the type 1 autoimmune hepatitis patients.

… and of primary biliary cirrhosis (PBC) …

Serologically, an elevated level of IgM is typical of the symptoms of primary biliary cirrhosis (PBC). In over 90% of affected individuals, antimitochondrial antibodies (AMA) are also detected, especially those of the AMA-M2 subtype. Especially for PBC patients whose serum test negative for AMA, complementary detection of autoantibodies against Sp100 and gp210, as well as the detection of anti-centromere antibodies, are of particular diagnostic importance.

… and of primary sclerosing cholangitis

In case of primary sclerosing cholangitis (PSC), no particular antibodies are known to offer useful information for the diagnosis of this autoimmune disease. However, in up to 90% of PSC patients, atypical pANCA (“xANCA”) are detected, a result that does provide the physician with an important indicator for making a diagnosis. Occasionally, antinuclear antibodies (ANA) and/or anti-smooth muscle antibodies (ASMA) may be detected in low titres. – Please note: antimitochondrial antibodies are always absent in cases of PSC!

The individual autoantibodies “in close-up”:

Antinuclear antibodies (ANA)

After ASMA, ANA are the most commonly detected autoantibodies in cases of type 1 AIH. Although ANA have no specificity for type 1 AIH, they are considered a marker antibody for this disease. For the majority of type 1 AIH patients (60%), ANA and ASMA are both detectable. Exclusively ANA (without ASMA) are found in 10-15% of patients with type 1 AIH; exclusively ASMA (without ANA) are found in 30-35% of patients with type 1 AIH. – Notice! In 20-40% of cases, ANA and ASMA are also quite frequently found in cases of type II chronic hepatitis C infection!

Figure 3 – Serodiagnosis and laboratory testing for autoimmune liver diseases. Please contact me for references.

Anti-smooth muscle antibodies (ASMA)

At high titres, anti-smooth muscle antibodies (abbreviated: ASMA) are considered to be marker antibodies and a recognized diagnostic criterion for type 1 autoimmune hepatitis. The relevant autoantigen is F-actin. Autoantibodies against F-actin can be separately detected with our Liver-9-Line immunoblot test.

The diagnostic sensitivity of ASMA detection is 80%, which means that a negative ASMA result does not completely exclude autoimmune hepatitis. ASMA are very often associated with antinuclear antibodies (ANA). The ASMA titre has limited correlation to the activity of the disease.

In addition, low ASMA titres may also be found in cases of various viral infections, such as infectious mononucleosis, Epstein-Barr virus (EBV), or chronic hepatitis C. ASMA are also occasionally detected in patients with rheumatic diseases, primary biliary cirrhosis (PBC), or neoplastic disease.

SLA/LP antibodies

Antibodies against the SLA/LP autoantigen (the abbreviation stands for soluble liver antigen / liver pancreas antigen) are often detected in conjunction with ASMA or ANA (about 30% of anti-SLA positive serum samples also contain ASMA and/or ANA).

In patients who are assumed to have type 1 AIH, but test negative for ASMA or ANA (!), the individual detection of SLA/LP antibodies is particularly important for the formation of a diagnosis. In addition, SLA antibodies are indicative of a more severe progression of autoimmune disease. In addition to this, antibodies against the SLA/LP antigen are not detected in cases of viral hepatitis!

LKM-1 antibodies

Antibodies to liver kidney microsomal type 1 (anti-LKM-1) are markers for type 2 autoimmune hepatitis. The detection of anti-LKM-1 antibodies also allows for the differentiation of type 2 AIH from type 1 AIH.

In young patients, LKM-1 antibodies have a very high diagnostic sensitivity (70-93%). However, LKM-1 antibodies are also quite often found in patients infected with the hepatitis C virus (6-10%).

LC-1-Antibodies

Anti-LC-1 antibodies (LC-1 stands for liver cytosol type 1) are detectable in nearly half of young patients with type 2 autoimmune hepatitis. Their appearance partially overlaps with the anti-LKM-1 autoantibody; about half of the patients who are anti-LKM-1 positive also have the LC-1 antibodies as a second marker of type 2 AIH. Each of these antibodies may also come up alone.

Antibodies against LC-1 are largely specific for type 2 AIH. They correlate better with disease activity than do anti-LKM-1 antibodies.

Antimitochondrial antibodies (AMA)

Antimitochondrial antibodies, AMA, act as marker antibodies for primary biliary cirrhosis (PBC). They are detected in 90-95% of cases and are primarily directed against the M2-antigen (AMA-M2). AMA have a predictive value for PBC.

However, AMA-M2 antibodies are also detected in one out of every five SLE patients (17-23%) and nearly one out of five patients with Sjögren’s syndrome (22%). They are also regularly found in patients with scleroderma (8-18%) and rheumatoid arthritis (10%). Presumably, these patients have a greater risk of developing primary biliary cirrhosis in addition to their existing autoimmune disease.

Caution! – AMA detected by immunofluorescence (IFT) are not all associated with PBC. It is thus recommended that a positive immunofluorescence test be followed up with a separate test for AMA-M2 antibodies!

AMA detection: an AMA pattern in an immunofluorescence test is not always associated with PBC! A positive IFA should always be followed up with a separate AMA-M2 test. – Picture: antibodies against mitochondria (AMA-M2?), rat liver-kidney-stomach triple tissue by ORGENTEC Diagnostika. – © Barbara Fabian MSc, www.der-gruene-club.at

Sp100 antibodies

Antibodies to Sp100, directed against the multiple nuclear dots, a soluble nuclear protein of 100 kDa, have 95% specificity for primary biliary cirrhosis. These antibodies are detectable in up to 25% of patients with PBC.

Relatively often, in 48% of cases, Sp100 antibodies are detected among the PBC patients who are AMA-negative. Anti-Sp100 antibodies are only very rarely detected in patients with autoimmune hepatitis (AIH) and primary sclerosing cholangitis (PBC). Occasionally, these autoantibodies turn up in patients with rheumatic diseases (systemic lupus erythematosus, SLE: up to 10%, progressive systemic scleroderma, PSS: 5%, rheumatoid arthritis, RA: 3%, Sjögren’s syndrome, SS: 2%).

gp210 antibodies

With a specificity of nearly 100% (!), anti-gp210 antibodies are highly specific to primary biliary cirrhosis (PBC). They are regularly found in samples from AMA-negative patients with clinically observed PBC (in 21-47% of cases, depending on test), which underlines the significance of anti-gp210 detection for the diagnosis of PBC.

They are very rarely found in patients with autoimmune hepatitis, rheumatoid arthritis, polymyositis/dermatomyositis, or Sjögren’s syndrome. Antibodies against the gp210 antigen are associated with extrahepatic manifestations, such as arthritis. They are a prognostic marker and are indicative of an unfavourable outcome of PBC.

Suspicion of PSC: ANCA detection can help

Whereas type 1 autoimmune hepatitis, type 2 autoimmune hepatitis, and primary biliary cirrhosis (PBC) are characterized by typical autoantibody test results, no disease-specific autoantibodies are known for primary sclerosing cholangitis (PSC). However, pANCA and the “atypical pANCA pattern”, xANCA, are detected in up to 90% of cases.

In fact, ANCA detection for the diagnosis of primary sclerosing cholangitis is not specific. However, in some cases, an ANCA test may be helpful in the formation of a diagnosis when PSC is suspected.

References:

1. Bogdanos DP, Invernizzi P, Mackay IR, Vergani D. Autoimmune liver serology: Current diagnostic and clinical challenges. World J Gastroenterol 2008 June 7; 14(21): 3374-3387 – DOI: 10.3748/wjg.14.3374. ==>  free full text article
2. Bogdanos DP, Liaskos C, Pares A, Norman G, Rigopoulou EI, Caballeria L, Dalekos GN, Rodes J, Vergani D. Anti-gp210 antibody mirrors disease severity in primary biliary cirrhosis. Hepatology 45 (6):1583-1584, 2007.==>  free full text article
3. Crosignani A, Battezzati PM, Invernizzi P, Selmi C, Prina E, Podda M. Clinical features and management of primary biliary cirrhosis. World J Gastroenterol 2008 June 7; 14(21): 3313-3327 – DOI:10.3748/wjg.14.3368. ==> free full text article
4. Granito A, Muratori L, Muratori P, Pappas G, Guidi M, Cassani F, Volta U, Ferri A, Lenzi M, Bianchi FB. Antibodies to filamentous actin (F-actin) in type 1 autoimmune hepatitis. J Clin.Pathol. 59 (3):280-284, 2006. ==>  free full text article
5. Muratori P, Granito A, Pappas G, Pendino GM, Quarneti C, Cicola R, Menichella R, Ferri S, Cassani F, Bianchi FB, Lenzi M, and Muratori L. The serological profile of the autoimmune hepatitis/primary biliary cirrhosis overlap syndrome Am J Gastroenterol. 104 (6):1420-1425, 2009. ==> free full text article
6. Rigopoulou EI, Mytilinaiou M, Romanidou O, Liaskos C, and Dalekos GN. Autoimmune hepatitis-specific antibodies against soluble liver antigen and liver cytosol type 1 in patients with chronic viral hepatitis. J Autoimmune.Dis 4:2, 2007. ==> free full text article
7. Rust C, Beuers U. Overlap syndromes among autoimmune liver diseases. World J Gastroenterol 2008 June 7; 14(21): 3368-3373 – DOI:10.3748/wjg.14.3368. ==> free full text article

You will find more references on the ORGENTEC website >> Literature Service

Pictures:
The interior surface of the liver: reproduction from Gray’s Anatomy taken from the Wikimedia Commons Project

AMA detection: IFA picture by Barbara Fabian, MSc, Der GRÜNE CLUB AUTOIMMUN, www.der-gruene-club.at

The schemes are own work.

As we here at ORGENTEC Diagnostika set about developing a smartphone application for our company in mid-September of this year, we had no idea what an exciting field we were entering.

We were also amazed when we began to intensively explore the iTunes App store and Android Market to see “what the others were up to”. We tried out many things, looked at a large variety of very different apps, and loaded our iPhones up with a broad range of apps.

The ORGENTEC Autoimmunity Guide: Three screenshots of our company's mobile medical app on autoimmunity, autoimmune disorders, and autoimmune diseases diagnostics. - © ORGENTEC Diagnostika, Mainz

We also researched a lot of technical details, reading this blog and that. We learned a great deal about the market shares of the individual mobile operating systems (“Who is winning the race for domination on the mobile operating system market in which corner of the world? Apple’s iOS or the Android OS? Blackberry’s RIM or Windows Phone 7?”). We thus also had to involve ourselves to some extent in some “religious wars” (“iPhone or Android device?” – … there’s no question, is there?).

We soon resolved the initial technical questions and quickly found an experienced app developer and a professional graphics agency (we went back to the tried and true – a big thank you for a long and successful collaboration!).

The Birth of ORGENTEC Autoimmunity Guide

We immediately developed a sound concept and – nearly simultaneously – compiled the content of our first ORGENTEC app. Time was short because we planned to present the “ORGENTEC Autoimmunity Guide” to our customers and partners around the world at Medica 2011.

Everything went off without a hitch: the Autoimmunity Guide has been available at the Apple App Store and Android Marke since November 11, 2011! (For the news release of 28/11/2011: A New App: ORGENTEC Autoimmunity Guide – iOS and Android app for smartphones and tablet computers.)

As we spent weeks deeply immersed in the world of healthcare apps, we were absolutely fascinated. The world of apps that have something to do with health, healthcare, medicine, or public health is highly complex.

These apps cover a wide range. It reaches from an app about homeopathy to the healing powers of gemstones, to mobile diet planners and health tips. Vaccination calendars, fitness programs, nutrition tips, or online pharmacies: The number of healthcare and medical mobile apps has become nearly incomprehensible. However, the soundness and quality of these apps sometimes falls short. For a public health-related app, I find this to be not only unfortunate, but also bordering on negligent.

For quick download: The QR code for the ORGENTEC Autoimmunity Guide.

However, there are also some pearls among the ordinary and beacons in the darkness: some of the smartphone and tablet apps are really well made. Some of these health and life science applications are highly innovative and have completely new approaches. They not only present a clever idea skilfully and professionally; these apps meet high standards and the strict scientific benchmarks that should be applied to all aspects of modern medicine.

Public health-related apps for efficient doctor-patient interactions

These days, as I have found, some medical apps even allow public health care professionals to tap a broad, reliable source that lets them research the information and up-to-date data they need for their daily work – nearly anywhere and any time.

I am also certain that in the future, mobile healthcare apps will also have a large influence on direct doctor-patient interactions. In apps for mobile devices, physicians now have a completely new, fascinating, and interactive medium for successfully making their patients more aware of health issues. They also have new possibilities for promoting patient compliance and monitoring their adherence to a treatment plan.

Even well-respected public health organisations like the CDC or the UN are increasingly launching their own mobile applications.

There are now apps for a number of different subjects in the area of public health and for a large number of target groups. Well-respected public health organizations like the Centers for Disease Control and Prevention, the CDC, are increasingly launching their own apps. Even authorities like the United Nations have recognised the value and significance of mobile applications for reaching their goals.

So what about the small apps for the iPhone, Blackberry, and its ilk? – Those apps that can be bought for relatively little money and loaded onto a smartphone or tablet (these apps are often even free) allow the user to access very specific information, and directly deliver personalised data tailored to the user’s individual needs without requiring extensive searching on the Internet.

Mobile apps for tailor-made health communication

Businesses or organizations can use these apps – and this is what’s new – to reach people wherever they may be, because smartphone users carry their mobile devices around all of the time. With a well-made app, users can be reached around the clock and seven days a week, whether at work, on the road, or at home on the couch.

Generally, teens and young people have a higher affinity for technology than adults. For the so called “digital natives” mobile technology is a part of their lives and their main source of information. – © APatterson

According to a study by the Pew Internet Project, 35% of adults in the United States now own a smartphone. And, of course, this number is rising. In addition one quarter of the smartphone owners (25%) admitted in the study that they primarily use their mobile device to go online. There is thus enormous potential for communication between businesses and their dialog partners.

The apps may thus be used as a direct window into the organizations, firms, and companies – or a window looking out from the businesses. They are, after all, designed for communication between businesses and markets, not as unidirectional monologues.

The apps can also provide targeted product information to the consumer. In a well-made app, the client can quickly find the information needed – without a lot of effort and with a minimum of clicks. This is what makes apps and mobile devices so interesting for marketing.

Public health organizations, businesses in the area of health care, and even health insurance companies learned a while ago just what this is all about. There are so many good reasons to program an app and market it!

Mobile apps are, after all, designed for communication between businesses and markets, not as unidirectional monologues.

In order to convey their educational messages, some organizations and their app developers have chosen to use games. The California Poison Control System (CPCS), which runs the California Poison Control Call Center launched an app called “Choose Your Poison” early this last summer.

Mobile games convey the educational message

The Choose Your Poison app is a game for smartphones and tablet computers, which challenges the player to choose between two images. One image shows a medication, the other its “double”, a harmless candy that looks similar enough to the pill to be confusing.  The game is fun, interactive, and underscores an important poisoning prevention message: that medications can easily be mistaken for candy.

Smartphones like the iPhone increasingly become mobile devices for medical education and for monitoring patients' health. - © Yutaka Tsutano

The Choose Your Poison game is also available online at www.pillsvscandy.com. From the technical point of view, the app is based on this “classic” online game from the California Poison Control System, which has been very popular with parents and teachers. They played it with children to alert them to the danger of the colourful pills.

Why did they adapt such a successful online game for mobile smartphones as well? – According to Iana Simeonov, Director of Consumer Communication at the California Poison Control System, who spearheads technology and mobile health projects for the CPCS, the answer is quite simple: “By 2012, more smartphones will be shipped than desktop computers, and by 2013, people using their mobile device to search the Internet will overtake desktop Internet users for the first time. We wanted to be on the forefront of mobile health in the area of poison control and since younger people 18 to 29 tend to search for health information on their phones – a group likely to be of child bearing age – we felt it was important to make poison prevention information available this way.” For people of this generation, who are “digital natives”, mobile technology is a part of their lives and their main source of information. They have never known anything else.

Businesses or organizations can use these apps to reach people wherever they may be, because smartphone users carry their mobile devices around all of the time. - © canberkol

Another example of a well-made smartphone and tablet application is the Outbreaks Near Me app, which was introduced two years ago by researchers at the Massachusetts Institute of Technology (MIT) as part of the Informatics Program of the Children’s Hospital of Boston, and has been continually updated since. (For the press release of 12/01/2009: ‘Outbreaks Near Me’ app now available for Android mobile phones.)

An app from the HealthMap project makes it possible to keep track of infectious diseases, such as H1N1 influenza – also known as swine flu – worldwide. The user can also report an outbreak of infectious disease to the HealthMap project and its website to directly contribute to the project.

The UN AIDSinfo app: mobile medical app for valid data on AIDS

One very specific app has been extensively used by the scientists and aides of the Joint United Nations Program on HIV/AIDS to stay up to date: the United Nations AIDSinfo app.

According to the UN officials on the UN AIDS website, the goal of the UN AIDSinfo app is to better understand why and how HIV infections spread, and where specific treatments, care, and support programs are needed. The mobile healthcare app, available for the iPad, delivers detailed, valid data with a few touches to the screen – and this with the latest numbers for every individual country.

While some health apps present data to make it available to healthcare professionals, other apps are used to gather and compile medical data. It is not yet clear what importance mobile apps will have in epidemiological studies or in carrying out clinical studies; a number of studies – including scientific ones – are underway. The initial results are highly promising.

For the “digital natives”, mobile technology is a part of their lives and their main source of information. They have never known anything else.

Scientists from the University Health Network in Toronto are thus currently experimenting with a diabetes monitoring app for the iPhone that determines the blood sugar levels of juvenile diabetics and sends the relevant data directly to the scientists. The teen patients can thus be remotely monitored by their doctors. Data transmission and data handling are also made significantly simpler by this type of glucometer app. Current and established technologies are not able to adequately and meaningfully process the immense quantities of data produced, according to the participating scientists.

Diabetes management via iPhone app is well received by teenage diabetics

This experiment in monitoring diabetes with a glucose meter app is targeted at youth for two very simple reasons: Firstly, the transition from childhood to adulthood presents a particular challenge for diabetics. According to the researchers, it is very difficult to maintain good glycaemic control during this phase. Secondly, monitoring by iPhone is generally well received by teens, as they generally have a higher affinity for technology than adults. This greatly increases compliance with therapy, say the scientists (for the press release, published on 10/02/2011 on Bloomberg.com: bant iPhone app to help teens manage Type 1 Diabetes).

For every technical advance, and for all of the possibilities that mobile medical apps offer for the health of individuals and public health, health experts advise great diligence in the conception, design, and development of healthcare apps. It seems that too many apps are poorly made and riddled with incorrect information.

In a study published last May in the American Journal of Preventive Medicine, scientists Lorien C. Abroms and her colleagues investigated 47 iPhone applications for smoking cessation. The scientists found that most of the apps they looked at did not correspond to the current U.S. Public Health Service’s 2008 Clinical Practice Guidelines for Treating Tobacco Use and Dependence. “iPhone apps for smoking cessation rarely adhere to established guidelines for smoking cessation. It is recommended that current apps be revised and future apps be developed around evidence-based practices for smoking cessation,” according to the paper’s abstract.

Apps should be driven by science

“Quality apps are hard to find because many companies are in such a hurry to sell their apps,” says Alexander V. Prokhorov, M.D., Ph.D., Director of MD Anderson’s e-Health Technology Program and Professor in the Department of Behavioral Science. “And they don’t take the time to conduct a study to see if users adopt real, lasting change.” Alexander V. Prokhorov stipulates that developers must base their healthcare apps primarily on scientific facts.

Think of apps as tools that complement what you are doing offline. A good public-health-related app is always driven by and infused with science.

The app must naturally be useful as well, so that it appeals to consumers and clients: “Think of health apps as tools that complement what you’re doing offline,” says Jermaine McMillan, Project Director of MD Anderson’s e-Health Technology Program. A good public-health-related app, according to McMillan, is always driven by and infused with science. If it is also fun, so much the better!

Below, I have listed several apps in the healthcare field. I have described some of these apps in the blog post above. Although I have briefly checked to see which operating systems and devices these apps are available on, I recommend further research if you are interested, as my information may not be complete.

One more note: I have naturally briefly looked at all of these apps, tried some of them out, and tested others extensively. I have of course not been able to confirm the content and accuracy of the information delivered by these various apps in every case.

The hyperlinks are links to the download possibilities for the apps; they are not recommendations! I take no responsibility for the quality and correctness of these apps; this list of healthcare apps is meant to be a little glimpse into the world of healthcare apps. I will gladly accept any suggestions and recommendations!

Here are also some Internet links I used to write this blog post (all accessed 07/12/2011):

• Mobile Medical Applications  – Website of The U.S. Food and Drug Administration (FDA)
• Get Better Health App: MD Anderson Experts Offer Tips for Selecting Health Apps -  MD Anderson News Release 07/12/11 by The University of Texas MD Anderson Cancer Center
• Mobile & Web Apps to Prevent Cancer – Focused on Health – July 2011 by The University of Texas MD Anderson Cancer Center
• Public Health-related Apps Growing in Number, Popularity. Article by Charlotte Tucker, posted 11/11/2011; The Nations Health. 2011;41(8) – via Medscaoe News Today
• The Pew Internet Project: Americans and thier Cell Phones – Report on the study by Aaron Smith, Aug 15, 2011
• iPhone Apps for Smoking Cessation: A Content Analysis. Lorien C. Abroms et al. American Journal of Preventive Medicine, Volume 40, Issue 3, Pages 279-285, March 2011.
• The website on the UN AIDSinfo app – mobile tool to facilitate the use of AIDS-related data in countries and globally

AIDSinfo by National Library of Medicine. – AIDSinfo app for the iPhone, iPod touch, iPad

BMI Calculator by National Heart, Lung and Blood Institute. – iPhone app for quick assessment of body mass index

The BMI calculator app website: many mobile healtcare applications can be downloaded free of charge, for example this iPhone app by the US government. - © NHLBI

Bant by University Health Network and The Hospital for Sick Children, Toronto. -  a diabetes management app for the iPhone and iPod touch

Calorie Tracker by Livestrong.com. – Calorie Tracker for iPhone app, iPad app, Calorie Tracker Windows Mobile App, and Calorie Tracker Blackberry App

CDC Vaccine Schedule by Austin Physician Productivity. Provides the full updated 2011 CDC Recommended Adult Immunization Schedule. – CDC Vaccine Schedule for the iPhone, iPod touch, and the iPad

Choose Your Poison by University of California. Pills vs candy: a game which asks players to tell the difference between pills and look-alike candy. – Choose Your Poison for iPhone, iPod touch, iPad, and Choose Your Poison for Android mobile devices

Clinical Trials Mobile by Pharmaceutical Product Development. – Clinical Trials Mobile iPhone app, and iPad app

Consumer Product Safety Commission by Consumer Product Safety Commission. Provides product warnings as well as podcasts about products. – Consumer Product Safety Commission for the iPhone, iPod touch, iPad

Control of Communicable Diseases Manual by Unbound Medicine. Provides information for identifying, managing and preventing infectious diseases. – Control of Communicable Diseases Manual for iPod touch, iPhone, iPad

CSPI Chemical Cuisine by Center for Science in the Public Interest. Lists information about commonly used food additives. – CSPI Chemical Cuisine for iPhone, iPod touch, and iPad —CSPI Chemical Cuisine for  Android

Eponyms by Pascal Pfiffner. Short description of medical eponyms. – Eponyms (for students) iPod touch, iPhone App, and  iPad, and Eponyms for Android mobile devices

iRadiology by Lieberman’s iRadiology. A Learning tool for medical students and residents. – iRadiology for iPod touch, iPhone app and iPad app

MedCalc by Mathias Tschopp and Pascal Pfiffner. A medical calculator that contains medical formulas and scores. – MedCalc for the iPad, iPhone, iPad

Medscape Mobile from WebMD is a very comprehensive app for healthcare professionals. - © rosemary

Medscape by WebMD Health. Free medical app available for healthcare professionals. – Medscape app for the iPhone, the iPod touch, and the iPad, Medscape for Android mobile devices, and Blackberry App World.

My QuitLine by National Cancer Institute. Quit smoking app. – My QuitLine for the iPhone

ORGENTEC Autoimmunity Guide by ORGENTEC Diagnostika GmbH. Our mobile app on autoimmunity, autoimmune disesease and autoimmune diagnostics. ORGENTEC Autoimmunity Guide for the iPhone, the iPod touch, and the iPad and the ORGENTEC Autoimmunity Guide for Android devices.

Outbreaks Near Me by HealthMap. Real-time disease outbreak information. – HealthMap: Outbreaks Near Me iPhone, iPod touch, iPad, and Swine Flu: Outbreaks Near Me Android

Public Health News by Harvard University. – Harward School of Public Health News for the iPod touch, iPhone, iPad

UN Aidsinfo by The United Nations. – UN AIDSinfo for the iPad

UV Index by Environmental Protection Agency. Sun-safety app. – UV Index for Android mobile devices, UV Index for Blackberry, UV Index Mobile Web

Walking Paths by American Heart Association. Create, find and track walking paths anytime. – Walking Paths app for the iPhone, and Walking Paths app for Android devices

Timely diagnosis is of critical importance to the progression of rheumatoid arthritis (RA) because the rapid implementation of intensive treatment can inhibit damage to the joints and maintain function. In conjunction with medical history, clinical examination, and imaging procedures, serological tests form the foundation for an early diagnosis.

In addition to rheumatoid factors, autoantibodies against citrullinated antigens (ACPA) have proven to be valuable tools for the serological diagnosis of early RA. They have become a critical component of the new 2010 ACR criteria for the classification of RA, and account for three of the six points required to verify a diagnosis of RA.

Anti-CCP hs (high sensitive)^® – higher sensitivity, earlier diagnosis, successful treatment

The new Anti-CCP hs (high sensitive)^® test from ORGENTEC Diagnostika is the most recent addition to the ACPA family. It combines the many advantages of the detection of autoantibodies against the native autoantigen, mutated citrullinated vimentin (MCV), which have been demonstrated in many publications, with the strengths of modern peptide synthesis. Anti-CCP hs (high sensitive)^® is based on specific optimized peptide epitopes from the body’s own MCV protein. This tailored antigen profile gives the test the highest sensitivity while maintaining high specificity. It is positioned as an effective tool for rapid and precise routine diagnosis and favours the rapid selection and implementation of treatment.

Anti-MCV – diagnosis and differentiation

The target antigen MCV, produced by the body, is found in the synovial tissues and synovial fluid of RA patients. MCV plays a central role in the pathogenesis of RA and is involved in the initiation of ACPA production. MCV antibodies correlate with an erosive course of disease with severe joint damage, extra-articular manifestations, and cardiovascular symptoms. A correlation between disease activity and stratification of RA with ACPA has thus far only been proven for Anti-MCV antibodies.

Sources:

H. Bang, K. Egerer, A. Gauliard, K. Luthke, P. E. Rudolph, G. Fredenhagen, W. Berg, E. Feist, and G. R. Burmester. Mutation and citrullination modifies vimentin to a novel autoantigen for rheumatoid arthritis. Arthritis Rheum. 56 (8):2503-2511, 2007  (Link to full text article)

D. Coenen, P. Verschueren, R. Westhovens, and X. Bossuyt. Technical and diagnostic performance of 6 assays for the measurement of citrullinated protein/peptide antibodies in the diagnosis of rheumatoid arthritis. Clin.Chem. 53 (3):498-504, 2007. (Link to full text article)

S. W. Syversen, G. L. Goll, D. van der Heijde, R. Landewe, B. A. Lie, S. Odegard, T. Uhlig, P. I. Gaarder, and T. K. Kvien. Prediction of radiographic progression in rheumatoid arthritis and the role of antibodies against mutated citrullinated vimentin: results from a ten-year prospective study. Ann. Rheum. Dis. 69 (2):345-351, 2009 (Link to abstract on journal homepage)

El-Barbary, A.M. et al. Association of Anti-Modified Citrullinated Vimentin with Subclinical Atherosclerosis in Early Rheumatoid Arthritis Compared with Anti-Cyclic Citrullinated Peptide J. Rheumatology  138 (5) 828-834 2011  (Link to abstract on journal homepage);

Read an extract of the article by El-Barbary et al.

The discovery of ACPAs and the biology of citrullination have  led to important advances in the understanding of the pathophysiology and development of RA.  Going forward, research into autoimmunity to citrullinated proteins may help identify the specific etiology of RA and provide approaches for the prediction of future risk of disease, and ultimately prevention of RA.

Without further ado I have translated Barbara’s post in order to make you this text, and especially the interesting images, available. – Here it is:

The Development of Indirect Immunofluorescence Technology (IFT)

by Barbara Fabian, MSc, Community Manager of GRÜNER CLUB AUTOIMMUN

Over the last 20 years, the detection of autoantibodies has developed into an indispensible component of autoimmune diagnostics. Along with serological and clinical data, autoimmune status has become an important building block in the formation of diagnoses.

Autoantibodies were first detected many years ago on frozen sections of mouse and rat liver. The samples were generally prepared in the laboratory, and the other required reagents, such as conjugates, were rarely available at the optimal concentrations required for the individual diagnostic test systems. Early autoimmune results were thus found to be highly variable. The use of different substrates for autoantibody detection showed that autoantibodies against nuclear components, such as those against double-stranded DNA, anti-dsDNA antibodies, which exhibited a homogeneous immunofluorescence pattern, were easily detectable on liver sections (Figure 1).

Figure 1: Indirect immunofluorescence test (IFT) on tissue sections: homogeneous immunofluorescence pattern on mouse kidney and stomach – © Barbara Fabian, www.der-gruene-club.at

The HEp-2 cell line raises new possibilities

However, not all antinuclear antibodies (ANA) exhibit a typical immunofluorescence pattern on mouse or rat organ tissue sections. For this reason, the additional detection of autoantibodies on human epithelial cells, known as HEp-2 cells, was developed after a few years. The use of this cell line has the advantage that a very broad spectrum of autoantibodies is detectable on HEp-2 cells. Antibodies against cell-cycle dependent antigens exhibit no immunofluorescence pattern on organ tissue sections. However, they are, like proliferating cell nuclear antigen (PCNA), of significance in the diagnosis of systemic lupus erythematosus (SLE), and can be detected on HEp-2 cells in the autoimmune laboratory (Figure 2).

Because both the mitotic phase and metaphase are identifiable in these cells, information regarding the patterns of the chromosomes is also available (Bayer PM, Fabian B, Hübl W: Immunofluorescence Assays (IFA) and Enzyme-Linked Immunosorbent Assays (ELISA) in Autoimmune Disease Diagnostics – Technique, Benefits, Limitations and Applications. – The link leads to the PubMed abstract). This allowed new, previously undetectable antibodies against the HEp-2 cell cytoplasm (cytoplasmic antibodies), such as the anti-SRP antibodies (SRP stands for signal recognition particle) or antibodies against PL7 or PL12 (anti-PL7, anti-PL12), to be detected as well. This led to numerous studies regarding the clinical significance of these new biomarkers. Various diagnostics companies that specialized in the development of test systems for the detection of autoimmune diseases developed tests for these “new” autoantibodies, such as the cytoplasm immunoblot test system.

Figure 2: IFT in autoimmune disease diagnostics: laboratory detection of anti-PCNA antibodies on HEp-2 cells – © Barbara Fabian, www.der-gruene-club.at

In order to establish the value of the HEp-2 cell in the diagnosis of antinuclear antibodies, these cells were initially compared to the liver. It was demonstrated that the sensitivity of antinuclear antibodies, ANA, in human cells was better than that in tissue sections. Rat kidney and rat liver demonstrated the least sensitivity in the detection of nuclear antibodies (Hahon N, Eckert HL, Stewart J: Evaluation of Cellular Substrates for Antinuclear Antibody Determinations. – The link leads to a free full-text article in the Journal of Clinical Microbiology).

To this day, antibody detection on HEp-2 cells has retained its central role. When autoimmune disease is suspected, the HEp-2 test is used for screening, which allows for the cost-effective and high-quality serological diagnosis of various autoimmune diseases (Hiemann R et al. Challenges of Automated Screening and Differentiation of Non-Organ-Specific Autoantibodies on HEp-2 Cells. – this link leads to an abstract in Autoimmunity Reviews). The sensitive detection of many clinically relevant autoantibodies is possible on HEp-2 cells. Any positive result is followed up by a step-wise diagnosis in which, depending on the evaluation of the reactivity with HEp-2 cells, other substrates may be used or other immunological tests like ELISA (enzyme-linked immunosorbent assay) or immunoblot assays carried out.

Tissue sections – indispensible for gastroenterological diagnostics

Diagnosis by means of tissue sections remains very important in gastroenterology. In cases of autoimmune hepatitis (AIH) especially, the detection of anti-smooth muscle antibodies, or: ASMA, or antibodies to liver-kidney microsomes, or: anti-LKM antibodies, are important diagnostic tools. Testing on HEp-2 cells alone would not suffice in these cases, because tests for anti-smooth muscle antibodies, the so called ASMA tests, are not always positive, and tests for anti-LKM autoantibodies are not positive. If autoimmune hepatitis is suspected, routine diagnostics call for testing for antibodies on mouse or rat tissues. If required, a positive antibody screening test can be confirmed by enzyme immunoassays (“ELISA tests”) or immunoblot tests (“blot assays”).

Autoantibodies may be detectable years before the diagnosis of an autoimmune disease. For example, the antimitochondrial antibodies (AMA) in cases of primary biliary cirrhosis (PBC), which are also detected by means of mouse or rat tissue (Beleznay Z, Regenass S. Diagnostics of Autoimmune Diseases. – The link leads to an English language abstract in PubMed, the article itself is in German). A consensus report published in 2004 included guidelines and recommendations in this regard (Vergani D et al. Liver Autoimmune Serology: a Consensus Statement from the Committee for Autoimmune Serology of the International Autoimmune Hepatitis Group. – This link leads to a free full-text article in the Journal of Hepatology). The report recommends diagnosis on a section consisting of combined kidney, stomach, and liver tissue (KSL). It also made the first steps toward standardization by establishing the optimal size and histological composition of the tissues. First attempts at analytical standardization, including incubation times, for example, were also covered in this publication.

Indirect immunofluorescence tests (IFT assays) in ANCA diagnostics

Another important area in the diagnosis of autoimmune diseases is the serological diagnosis of systemic autoimmune vasculitis, such as Wegner’s granulomatosis or microscopic polyangiitis. This is achieved through the detection of autoantibodies against cytoplasmic neutrophil granulocytes with the ANCA test (ANCA = anti-nuclear cytoplasmic antibodies). ANCA primarily involves antibodies that display perinuclear (pANCA) or cytoplasmic (cANCA) staining upon exposure to ethanol-fixed granulocytes (Figure 3). In addition to ethanol-fixed granulocytes, formalin- and methanol-fixed granulocytes are also used.

The additional use of formalin-fixed granulocytes allows for the differentiation of the antinuclear antibodies from the ANCA test. Methanol-fixed neutrophil granulocytes are rarely used in routine laboratory analysis because they deliver relatively little information. Diagnostic tests like ELISA and immunoblot assays that are directed toward myeloperoxidase (anti-MPO test systems) and proteinase 3 (anti-PR3 assays) are also available for autoantibodies against neutrophil granulocytes.

A consensus study on the subject of ANCA diagnostics was published in 1999, with an addendum issued in 2003 (Savige J et al. International Consensus Statement on Testing and Reporting of Antineutrophil Cytoplasmic Antibodies (ANCA). – This link leads to the PubMed abstract. – Savige J. et al. Addendum to the International Consensus Statement on Testing and Reporting of Antineutrophil Cytoplasmic Antibodies. Quality Control Guidelines, Comments, and Recommendations for Testing in other Autoimmune Diseases. – This link leads to the full-text article in the American Journal of Clinical Pathology.)

The emphasis of these studies is the clinical importance of tests for antibodies against neutrophil granulocytes. However, the goals of these studies also included the standardization of indirect immunofluorescence techniques for the detection of ANCA, including recommendations for the optimal dilution of the serum samples, the conjugate, and the counterstain. A diagnostic scheme for both minimal and optimal antibody detection was established.

Figure 3a: IFT detection of pANCA on ethanol-fixed neutrophil granulocytes, ANCA diagnosis with the aid of indirect immunofluorescence technology – © Barbara Fabian, www.der-gruene-club.at

The continuing issue of standardization

Over the years, many publications have discussed the analysis of autoantibodies through indirect immunofluorescence. The emphasis of a 1983 study on the problems with the standardization of immunofluorescence was on the reproducibility of the detection of antinuclear antibodies, known as ANA detection (Beutner EH, Krasny S, Kumar V, Taylor R, Chorzelski TP. Prospects and Problems in the Definition and Standardization of Immunofluorescence. Present Levels of Reproducibility and Disease Specificity of Antinuclear Antibody Tests. – This link leads directly to the article in the Annals of the New York Academy of Sciences). In addition to pointing out the fact that certain autoantibodies such an anti-centromere antibodies react with human cell lines while remaining undetectable on tissue sections or mouse fibroblast cells, this work also covers methodological studies regarding the titre of antibodies.

Figure 3b: IFT detection of pANCA on formalin-fixed neutrophil granulocytes. – © Barbara Fabian, www.der-gruene-club.at

In order to minimize variations in titre between different laboratories, the influence of the conjugate was described. At the center of the investigation were the specificity of the concentration, the dilution, and the fluorescein/protein ratio of the conjugate used. The sensitivity of the optical systems used to evaluate the sample slides was also compared. The use of optically standardized sample slides was recommended as a means to control the variation between different systems.

The quality of test products has improved sharply over time. Because diagnostics firms now offer prepared test kits for the serodiagnosis of autoimmune diseases, which contain mutually calibrated “ready-to-use” reagents, the technical aspect of work in the field of autoimmune diagnostics has been significantly simplified.

However, diagnosis by means of indirect immunofluorescence continues to demand a great deal of knowledge and experience, continuing to offer a challenge for laboratory personnel and physicians. This challenge is surely also the reason why most people working in this field exhibit great enthusiasm and intensity in tackling this problem, and why advanced training in this field is of great value.

Please note: All fotographs of immunofluorescence patterns in this article are protected by copyright law, which is ensured by watermarks. If the pictures have attracted your interest, and if you feel the interest to use one or a number of immunofluorescence pictures for a lecture, a presentation, a publication … please feel free to get into contact with Barbara Fabian via the GRÜNER CLUB AUTOIMMUN website.

References:

Bayer PM, Fabian B, Hübl W. Immunofluorescence assays (IFA) and enzyme-linked immunosorbent assays (ELISA) in autoimmune disease diagnostics–technique, benefits, limitations and applications. Scand. J. Clin. Lab. Invest. Suppl. 235, 68–76 (2001). – link leads to the abstract in PubMed: http://www.ncbi.nlm.nih.gov/pubmed?term=Bayer%20Fabian%20H%C3%BCbl

Beleznay Z, Regenass S. [Diagnostics of autoimmune diseases]. Ther Umsch 65, 529–537, doi:10.1024/0040-5930.65.9.529 (2008). – link leads to the English-language abstract in PubMed, the article itself is written in German: http://www.ncbi.nlm.nih.gov/pubmed?term=Beleznay%20Regenass

Beutner EH, Krasny S, Kumar V, Taylor R, Chorzelski TP. Prospects and problems in the definition and standardization of immunofluorescence. I. Present levels of reproducibility and disease specificity of antinuclear antibody tests. Ann. N. Y. Acad. Sci. 420, 28–54 (1983). – link leads to the full-text article in the Annals of the New York Academy of Sciences: http://onlinelibrary.wiley.com/doi/10.1111/j.1749-6632.1983.tb22186.x/abstract;jsessionid=1AC6AD5E6E4751591D0CE810B3E1E6D7.d02t02

Hahon N, Eckert HL, Stewart J. Evaluation of cellular substrates for antinuclear antibody determinations. J. Clin. Microbiol. 2, 42–45 (1975). – link to the free full-text article in the Journal of Clinical Microbiology: http://jcm.asm.org/cgi/reprint/2/1/42?view=long&pmid=818105

Hiemann R et al. Challenges of automated screening and differentiation of non-organ specific autoantibodies on HEp-2 cells. Autoimmun Rev 9, 17–22, doi:10.1016/j.autrev.2009.02.033 (2009). – link leads to the abstract in Autoimmunity Reviews: http://www.sciencedirect.com/science/article/pii/S1568997209000731

Savige J et al. International Consensus Statement on Testing and Reporting of Antineutrophil Cytoplasmic Antibodies (ANCA). Am. J. Clin. Pathol. 111, 507–513 (1999). – link leads to the PubMed abstract: http://www.ncbi.nlm.nih.gov/pubmed/10191771

Savige J. et al. Addendum to the International Consensus Statement on testing and reporting of antineutrophil cytoplasmic antibodies. Quality control guidelines, comments, and recommendations for testing in other autoimmune diseases. Am. J. Clin. Pathol. 120, 312–318, doi:10.1309/WAEP-ADW0-K4LP-UHFN (2003). – link leads to the full-text article in the American Journal of Clinical Pathology: http://ajcp.ascpjournals.org/content/120/3/312.long

Filed under: ANCA / vasculitis diagnostics, autoimmunity, lupus / SLE, rheumatology diagnostics Tagged: ANCA / vasculitis diagnostics, antinuclear antibodies (ANA), autoantibodies, autoimmune diagnostics, autoimmunity, ELISA, IFT / IFA, lupus / SLE, PR3, rheumatoid arthritis (RA), vasculitis, Wegener's granulomatosis ]]> http://autoimmunityblog.wordpress.com/2011/09/28/orgentec-autoimmune-diagnostics-history-of-indirect-immunofluorescence-technology-ift/feed/ 0 Tobias Stolzenberg ORGENTEC_immunofluorescence_homogenous IFT pattern_mouse kidney_magen ORGENTEC_immunofluorescence pattern_IFT_anti_PCNA on HEp-2 cells ORGENTEC immunofluorescence_IFT_pANCA on ethanol-fixed neutrophil granulocytes ANCA diagnosis with the aid of indirect immunofluorescence - ORGENTEC IFT tests http://autoimmunityblog.wordpress.com/2011/08/21/orgentec-autoimmunity-blog-why-are-autoimmune-diseases-more-common-in-women-than-men/ http://autoimmunityblog.wordpress.com/2011/08/21/orgentec-autoimmunity-blog-why-are-autoimmune-diseases-more-common-in-women-than-men/#comments Sat, 20 Aug 2011 22:37:12 +0000 Tobias Stolzenberg http://autoimmunityblog.wordpress.com/?p=1299 ]]> No matter if it’s rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), or multiple sclerosis (MS): most autoimmune diseases affect women significantly more often than men. It is possible that this could be at least partially explained by the occurrence of age-associated B cells (ABCs), as described in an article recently published in Blood, the journal of the American Society of Hematology.

Why autoimmune diseases are more common in women than men is actually far from fully understood. In previous years, scientists researching the cause primarily focused on the differences in hormone levels between men and women. The genetic differences between men and women are also clearly one of the reasons for the significantly higher incidence of autoimmune diseases in those of the female sex.

Aside from hormones and genetic predisposition, another possible cause has now been found by Anatoly V. Rubtsov, Kira Rubtsova, Aryeh Fischer, Richard T. Meehan, Joann Z. Gillis, John W. Kappler, and Philippa Marrack. In a current article in Blood, these scientists describe a special form of B cells known as CD11c⁺ B cells. These cells express a special integrin, the CD11c molecule, on their surface. In animal experiments with mice, the number of these special B cells increases with age – but only in females.

Age-associated B cells also in female RA patients

The researchers working with Anatoly V. Rubstov have also found such age-associated B cells, ABCs, in female patients with autoimmune diseases (Rubtsov et al., Blood 2011 online). The scientists have observed that the number of these B cells also increases with age in women with rheumatoid arthritis (RA). It is thus possible that Rubstov’s research group has now found another explanation in addition to hormonal risk factors and the sex-linked chromosomes for why women suffer from autoimmune diseases more often than men.

And there is another factor involved with ABCs: The activation of these special B cells is stimulated by means of toll-like receptor 7, TLR-7. The gene for TLR7 is located on the X chromosome. Women thus have two copies of the TLR-7 gene in their genome – which brings genetics into play with regard to the age-associated B cells as well.

A very nice overview of this topic can be found in the review article Why Are Women Predisposed to Autoimmune Rheumatic Diseases? by Jacqueline E. Oliver and Alan J. Silman, which appeared in the journal Arthritis Research & Therapy in October 2009. (Please note: This paper covers information current in 2009, the more recent work by Rubstov et. al, is thus naturally not included!) This article is available to anyone in the BioMed Central – reading tip!

Literature:

Oliver JE, Silman AJ. Why are women predisposed to autoimmune rheumatic diseases? Review. Arthritis Res Ther. 2009;11(5):252. – link opens the free full-text article

Rubtsov AV, Rubtsova K, Fischer A, Meehan RT, Gillis JZ, Kappler JW, Marrack. Toll-like receptor 7 (TLR7)-driven accumulation of a novel CD11c+ B-cell population is important for the development of autoimmunity. Blood. 2011 Aug 4;118(5):1305-15. Epub 2011 May 4. – doi:10.1182/blood-2011-01-331462 – link opens the abstract

The results of the study, which was carried out at the University of Munich Clinics, were recently published in the Annals of the Rheumatic Diseases, The EULAR Journal. At the centre of this study lies an analysis of the cell hormone interleukin-22, IL-22, and its significance as a prognostic marker for RA. The researchers examined the relationship between the serum levels of interleukin-22 and the risk of bone erosion and joint damage in RA patients.

This project in the division of rheumatology of the clinic was initially motivated by the observation that for reasons not yet understood, the onset of RA is associated with increased immunological activity and increased secretion of certain CD4 T cell cytokines. This increased immunological activity results in a CD4 T-cell-mediated persistent inflammatory reaction that leads to joint damage within a short period for two thirds of patients.

Desperately seeking: prognostic marker for RA

For researchers in the field of rheumatic diseases, the identification of molecules involved in the development of inflammation, joint erosion, and bone destruction represents a major challenge. Of particular interest are those biomarkers that allow an individualized prognosis of when a specific patient will develop joint erosion or destruction in the course of the disease. The primary goal of modern treatments is to hinder looming joint destruction with systematic treatment.

In this latest study from the research group led by Dr. med. Jan Leipe, the Munich scientists have now found that some patients with RA have significantly elevated serum levels of proinflammatory cytokine IL-22. Interestingly, these elevated IL-22 serum levels correlate significantly with the occurrence of joint erosion in the early stages of rheumatoid arthritis.

Interleukin-22 in the pathogenesis or rheumatoid arthritis

IL-22 is a cytokine produced primarily by CD4 T cells. The receptor for IL-22 is expressed in various joint tissues. Earlier studies demonstrated that IL-22 activates synovial fibroblasts. These in turn secrete cartilage-destroying proteinases that immediately participate in the destruction of cartilage. In addition, interleukin-22 promotes the formation of osteoclasts, which are substantially involved in bone erosion and joint destruction.

In the study Interleukin 22 serum levels are associated with radiographic progression in rheumatoid arthritis now published in the Annals of the Rheumatic Diseases, the significance of IL-22 in the occurrence of joint erosions was thoroughly investigated in a homogeneous, clinically well-defined cohort of RA patients. In order to ensure an unbiased analysis of IL-22 production at the beginning of the disease, only patients with an average symptom duration of less than three months were included in the study. In addition, the patients must have had no previous immunomodulator treatment. About half of the RA patients (49%) exhibited IL-22 values significantly above the norm at the beginning of the disease, while the other half had values in the normal range.

IL-22 serum levels are associated with radiographic progression in RA

Interestingly, up to 33% of the patients in the group with elevated interleukin-22 levels already exhibited joint damage at this early stage of the disease. In the group of patients with low IL-22 serum levels, this was only the case for a single patient (corresponding to 4%).

All patients were subsequently examined regularly over a period of two years. It was found that another quarter of the patients with elevated IL-22 values exhibited new joint erosion. In contrast, no damage was found in any of the patients with normal IL-22 values. The predictive value of IL-22 was independent of other parameters associated with more aggressive RA.

The measurement of IL-22 serum levels thus makes it possible to predict the risk of early joint destruction, the Munich scientists conclude. In addition, the results of this study also indicate that IL-22 plays an important role in the pathogenesis of joint destruction in rheumatoid arthritis.

Literature:

Leipe J., Schramm MA, Grunke M., Baeuerle M., Dechant C., Nigg A.P., Witt M.N., Vielhauer V., Reindl C.S., Schulze-Koops H., Skapenko A. Interleukin 22 serum levels are associated with radiographic progression in rheumatoid arthritis. Ann Rheum Dis. 2011 Aug;70(8):1453-7. Epub 2011 May 18. – link opens the abstract

Rheumatoid arthritis (RA) is associated with increased morbidity and mortality due to cardiovascular disease (CVD), especially accelerated atherosclerosis (1-3). There is evidence that this already occurs early in the disease process. Well known common CVD risk factors interact with the systemic auto-inflammatory response during the disease process and speed up the development of atherosclerosis in patients suffering from rheumatoid arthritis.

Antibodies against citrullinated protein and peptide antigens (ACPA) are highly sensitive and specific markers for early rheumatoid arthritis. Antibodies to Modified Citrullinated Vimentin (anti-MCV) predict poor outcome and appear to play a major role in the pathogenesis of rheumatoid arthritis. 

A recently published study by Amal El-Barbary and his co-workers may now shed light on the relationship between anti-MCV antibodies and cardiovascular co-morbidities in patients with rheumatoid arthritis (4). They investigated the correlation of anti-MCV antibodies in early RA with disease activity and cardiovascular risk factors compared to antibodies against cyclic citrullinated peptides (anti-CCP3).

A. M. El-Barbary, E. M. Kassem, M. A. El-Sergany, S. A. Essa, and M. A. Eltomey. Association of Anti-Modified Citrullinated Vimentin with Subclinical Atherosclerosis in Early Rheumatoid Arthritis Compared with Anti-Cyclic Citrullinated Peptide. J Rheumatol, 2011, 38(5):828-34

The Egyptian researchers measured antibody concentrations in 100 patients with early RA and 100 healthy subjects to determine sensitivity and specificity of the anti-MCV and the anti-CCP tests.

Anti-MCV, anti-CCP, rheumatoid factor (RF), disease activity score (DAS 28), lipid profile, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), insulin resistance (HOMA-IR), tumour necrosis factor alpha (TNF-alpha), interleukin 6 (Il-6) and carotid intima-media thickness (cIMT) were determined before and after 12 months of treatment with methotrexate (MTX) and prednisone.

Values of carotid intima-media thickness are closely linked to local and systemic atherosclerosis and  clinical cardiovascular endpoints (5-7). cIMT as a marker for early atherosclerotic changes can be assessed by non-invasive ultrasound methods.

Anti-MCV and anti-CCP are similarly helpful for initial diagnosis

The study demonstrated, that values for anti-MCV and anti-CCP3 correlated well, and the two assays showed comparable sensitivity and specificity for the diagnosis of early rheumatoid arthritis.

At baseline, anti-MCV titres and anti-CCP3 titres were related to CRP, Il-6, HOMA-IR, serum RF-level and cIMT. The levels of all biochemical markers were significantly higher and carotid intima-media thickness was significantly greater in RA patients than in healthy subjects, suggesting that RA patients with circulating ACPA show signs of accelerated subclinical atherosclerosis and may suffer a more aggressive disease (8).

Changes of anti-MCV levels parallel changes in clinical and laboratory parameters in response to therapy

After 12 months of treatment with MTX and prednisone a significant decrease of serum anti-MCV and anti-CCP3 was observed.

However, only alterations in anti-MCV levels correlated significantly with changes of clinical or biochemical variables related to disease activity. Variation of anti-CCP levels was not significantly linked to these parameters. Especially changes in CV risk factors, CRP, Il6, TNF-alpha, HOMA-IR and cIMT were strongly associated with changes in anti-MCV concentrations.

 These observations suggest, that changes of anti-MCV titers in response to treatment with MTX reflect an improvement in subclinical atherosclerosis. The considerable decrease of Anti-MCV in association with amelioration of clinical symptoms reveals that anti-MCV might be a more sensitive indicator for disease activity than anti-CCP.

In conclusion the results of the study evidence that anti-MCV is a highly sensitive and specific marker for diagnosing RA. Moreover, determination of anti-MCV levels indicates response to MTX therapy and may be useful for monitoring subclinical atherosclerosis in early rheumatoid arthritis.

References: 

1. T. M. Farragher, N. J. Goodson, H. Naseem, A. J. Silman, W. Thomson, D. Symmons, and A. Barton. Association of the HLA-DRB1 gene with premature death, particularly from cardiovascular disease, in patients with rheumatoid arthritis and inflammatory polyarthritis.  Arthritis Rheum 58 (2):359-369, 2008.  (link to full text)

2. Z. Szekanecz and A. E. Koch. Vascular involvement in rheumatic diseases: ‘vascular rheumatology’. Arthritis Res.Ther. 10 (5):224, 2008. (link to full text)

3. H. Pieringer and M. Pichler. Cardiovascular morbidity and mortality in patients with rheumatoid arthritis: vascular alterations and possible clinical implications. QJM. 104 (1):13-26, 2011.  (link to abstract)

4. A. M. El-Barbary, E. M. Kassem, M. A. El-Sergany, S. A. Essa, and M. A. Eltomey. Association of Anti-Modified Citrullinated Vimentin with Subclinical Atherosclerosis in Early Rheumatoid Arthritis Compared with Anti-Cyclic Citrullinated Peptide. J Rheumatol, 2011. (link to abstract)

5. M. W. Lorenz, H. S. Markus, M. L. Bots, M. Rosvall, and M. Sitzer. Prediction of clinical cardiovascular events with carotid intima-media thickness: a systematic review and meta-analysis. Circulation 115 (4):459-467, 2007. (link to full text)

6. A. Sodergren, K. Karp, K. Boman, C. Eriksson, E. Lundstrom, T. Smedby, L. Soderlund, S. Rantapaa-Dahlqvist, and S. Wallberg-Jonsson. Atherosclerosis in early rheumatoid arthritis: very early endothelial activation and rapid progression of intima media thickness. Arthritis Res Ther 12 (4):R158, 2010. (link to full text)

7. P. N. Tyrrell, J. Beyene, B. M. Feldman, B. W. McCrindle, E. D. Silverman, and T. J. Bradley. Rheumatic disease and carotid intima-media thickness: a systematic review and meta-analysis. Arterioscler.Thromb.Vasc.Biol 30 (5):1014-1026, 2010.  (link to full text)

8. T. M. Farragher, D. Plant, E. Flynn, S. Eyre, D. Bunn, W. Thomson, D. Symmons, and A. Barton. Association of a rheumatoid arthritis susceptibility variant at the CCL21 locus with premature mortality in inflammatory polyarthritis patients. Arthritis Care Res (Hoboken.) 62 (5):676-682, 2010. (link to full text)

In the past, it has only been possible to explain some of the joint damage caused by rheumatoid arthritis (RA) based on known risk factors. In order to improve treatment for RA, future approaches to treatment will increasingly need to be tailored to individual patients and individually configured.

Personalized medicine in RA treatment

The goal is to develop individual treatments tailored to the needs of the individual patient, “personalized medicine” for rheumatoid arthritis diagnosis and treament (for more on the subject of personalized medicine, refer to the background article Early Detection and Personalised Medicine – What Biomarkers Tell Us on our rheumachec homepage).

The use of individual and personalized medicine should make it possible to accurately predict whether early, undifferentiated arthritis (UA) will actually develop into rheumatoid arthritis. If RA has already manifested itself, it should be possible to make an individual estimation regarding the progression of RA in the patient based on defined and evaluated risk factors. In either case, adequate (and individual) treatment could be prescribed.

Defined and evaluated RA risk factors

This type of risk factor, about which little was previously known, has now been described by scientists in the Netherlands at the Leiden University Medical Center in their article Predicting Arthritis Outcome – What Can Be Learned from the Leiden Early Arthritis Clinic? Their results were published earlier this year in the journal Rheumatology.

In their study, the group led by Diederik P. C. de Rooy and Michael P. M. van der Linden, evaluated data from over 1,200 patients. The data were obtained from the Leiden Early Arthritis Clinic Cohort and included the individual results from 676 patients with rheumatoid arthritis (RA patients) as well as 570 patients with early, undifferentiated arthritis (UA patients).

Risk factors for joint damage with RA

The parameters used for the estimation of disease progression included fulfilment of the ACR 1987 Criteria for the Classification of Rheumatoid Arthritis, the duration of the Arthritis symptoms in the patients with undifferentiated arthritis, and the degree of joint damage detectable by radiology. Achievement of persistant DMARD-free remission in the RA patients was also considered in the prognoses made by the scientists.

The results of the study by de Rooy et al.: The Leiden scientists discovered that the markers for meeting the ACR 1987 RA classification criteria (the diagnosis of rheumatoid arthritis) and the markers for the duration of arthritis in patients with undifferentiated arthritis (the manifestation of RA) are largely similar.

(At this point I feel I had to add a remark in parantheses and should clarify the terms “RA Classification Criteria” and “RA Diagnostic Criteria”: In current practice, the “Classification of arthritis according to the ACR 1987 RA criteria” is largely equivalent to the “Diagnosis of rheumatoid arthritis” by an experienced rheumatologist, because such an experienced specialist will de facto rely on the classification criteria as his or her diagnostic criteria in daily clinical practice – an approach that is uncontroversial in this field. It is thus also to be expected that the 2010 ACR/EULAR Rheumatoid Arthritis Classification Criteria will likewise be implemented not only for the Classification of RA, but also as a diagnostic tool for the Diagnosis upon suspicion of rheumatoid arthritis. It goes without saying that the doctor performing the examination must be experienced with rheumatism, ideally an experienced rheumatologist. I also refer you to my article, New ACR/EULAR 2010 Classification Criteria for Rheumatoid Arthritis (RA) on ORGENTEC’s Autoimmunity Blog, posted 24/08/2010. The section entitled Why the differentiation between classification and diagnosis? discusses the ways in which formal and rigid criteria can hinder the highly individual diagnostic process for individual patients.)

Risk factors for severe joint damage from RA

According the study, the risk factors for the manifestation of rheumatoid arthritis and the occurrence of severe joint damage are very similar to the predictors of the persistence of RA. The risk factors for severe damage to the joints, as determined by the group led by de Rooy and van der Linden, include:

• presence of ACPA in the blood (ACPA stands for antibodies against citrullinated protein antigens) – specifically the detection of anti-MCV (anti-MCV stands for antibodies against mutated citrullinated vimentin) and anti-CCP antibodies (anti-CCP stands for antibodies against cyclic citrullinated peptides) (on this subject, please refer to Section B, Serology, in The 2010 ACR/EULAR Classification Criteria for RA in tabular form)
• the age of the patient
• the sex of the patient (male is at higher risk)
• symptoms present for a long time before the first examination
• involvement of the lower extremities
• Body Mass Index (BMI): high BMI is tied to a low rate of joint destruction, but a higher risk for progression of RA
• high titre of acute-phase proteins
• detection of IgM rheumatoid factors (RF IgM)
• presence of the Shared Epitope Allele HLA-DRB1

In any case, only a portion of the progression of joint destruction in cases of rheumatoid arthritis can be accounted for by the risk factors known to date, according to the authors of the Predicting Arthritis Outcomes article from the Leiden University Medical Center. In order to improve medical intervention for individual RA patients on a completely individual level, more risk factors must be identified, the researchers state.

Recommended Literature (accessed 06/05/2011):

• Aletaha D, Neogi T, Silman AJ, Funovits J, Felson DT, Bingham CO 3rd, Birnbaum NS, Burmester GR, Bykerk VP, Cohen MD, Combe B, Costenbader KH, Dougados M, Emery P, Ferraccioli G, Hazes JM, Hobbs K, Huizinga TW, Kavanaugh A, Kay J, Kvien TK, Laing T, Mease P, Ménard HA, Moreland LW, Naden RL, Pincus T, Smolen JS, Stanislawska-Biernat E, Symmons D, Tak PP, Upchurch KS, Vencovsky J, Wolfe F, Hawker G. The 2010 ACR-EULAR classification criteria for rheumatoid arthritis. Arthritis Rheum 2010 Sep;69(9):1580-8 – the link will open the full text article!
• Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF, Cooper NS, Healey LA, Kaplan SR, Liang MH, Luthra HS. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arth Rheum. 1988 Mar;31(3):315-24 – the link will open to the article’s abstract!
• Egerer K, Feist E, Burmester G. The Serological Diagnosis of Rheumatoid Arthritis –Antibodies to citrullinated Antigens [Serologische Diagnostik der rheumatoiden Arthritis: Antikörper gegen citrullinierte Antigene]. Dtsch Arztebl Int 2009; 106(10):159-63. Review – doi:10.3238/arztebl.2009.0159 – link will open the full text article!
• de Rooy DP, van der Linden MP, Knevel R, Huizinga TW, van der Helm-van Mil AH. Predicting arthritis outcomes – what can be learned from the Leiden Early Arthritis Clinic? Rheumatology (Oxford). 2011 Jan;50(1):93-100. – link will open to the abstract of this article!

The detection of anti-nuclear antibodies, the ANA test, is a clear (laboratory-) diagnostic indicator of rheumatic autoimmune disease. One of the standard laboratory tests for the detection of these antinuclear antibodies is IIF, the indirect immunofluorescence assay, on human HEp-2 cells (ANA-HEp-2 test).

ANA-HEp-2 indirect immunofluorescence test (IIF): antibodies against RNP (ribonucleoproteins) – interphase nucleoli: coarse granular positive, nucleoli neglected; mitotic cells: negative (400x) - © ORGENTEC Diagnostika, Mainz

However, for up to 13% of healthy individuals, indirect immunofluorescence may detect anti-nuclear antibodies. Most of these healthy people will not develop an autoimmune disease – despite the positive ANA test. It is thus a challenge for the physician to differentiate these healthy, false-positive patients from those ANA-positive patients who already have an inflammatory rheumatic disease or who truly have an increased risk of developing such an autoimmune disease.

Several very specific IIF patterns

In a large study, Brazilian IIF experts have now worked out the fundamental differences between the ANA-HEp-2 test results on serum samples from healthy individuals and the immunofluorescence patterns from serum samples of patients with rheumatic disease; they have described various IIF patterns that can be used to differentiate between the two patient groups (Mariz et al. 2011). This study was published a few weeks ago in the January issue of Arthritis & Rheumatism, the journal of the American College of Rheumatology (ACR). In their article, the scientists from the Universidade Federal de São Paulo, Brazil, explain in detail that there are several very specific immunofluorescence patterns in the ANA-HEp-2 assay with which the autoimmune rheumatic diseases (ARD) are truly associated.

The investigations of Henrique A. Mariz, Emilia I. Sato, Silvia H. Barbosa, Silvia H. Rodrigues, Alessandra Dellavance, and Luis E. C. Andrade included 918 healthy people with ages ranging from 18 to 66 years. The results of the ANA-HEp-2 immunofluorescence tests (ANA-HEp-2 IIF assays) carried out on serum samples from these healthy participants were compared with those from a control group. The control group consisted of 153 patients who all suffered from an autoimmune rheumatic disease. They included 87 SLE patients (systemic lupus erythematodes), 45 patients with systemic sclerosis, 11 people with confirmed Sjögren’s syndrome, and 10 individuals suffering from idiopathic inflammatory myopathy (autoimmune myopathy).

Indirect immunofluorescence assays on ANA-HEp-2 cells were carried out on serum samples from all of these people. The result was evaluated as positive if the typical fluorescence pattern of indirect immunofluorescence was observed.

The results in brief: Well-defined IIF patterns, and thus a positive ANA-HEp-2 test result, were found for 12.9% of the healthy people. The ANA were observed at low to intermediate titres, and the nuclear fine speckled pattern (NFS) was particularly commonly observed – in nearly half of the ANA-positive healthy individuals (45.8%). The nuclear dense fine speckled pattern (NDFS) was found in nearly one third of the healthy people (33.1%), primarily in conjunction with a high ANA antibody titre. It is noteworthy that none of the healthy patients’ samples demonstrated the nuclear coarse speckled pattern (NCS) or a nuclear homogenous pattern (Ho).

ANA-HEp-2 immunofluorescence pattern: antibodies against CENP-B (centromere) – interphase nuclei: the 46 dots are positive; mitotic cells are positive (400x) - © ORGENTEC Diagnostika, Mainz

In contrast, the serum samples from the autoimmune patients gave positive IIF results at intermediate to high ANA titres. The control group samples were also distinguishable by their completely typical fluorescence patterns. The serum samples from autoimmune patients were the only ones that demonstrated the nuclear coarse speckled (26% of samples), nuclear homogenous (7% of samples), nuclear centromeric (8%), and cytoplasmic dense fine speckled (3%) patterns. At 42%, the nuclear fine speckled pattern was also quite common in this group of patient serum samples; however, the antibodies were present at significantly higher titres than in the sample from healthy individuals. In a follow up after four years, 72.5% of the ANA-positive healthy people still had a positive ANA-HEp-2 test result. As before, they had no symptoms of autoimmune rheumatic disease!

ANA-HEp-2 pattern “is critical in properly diagnosing autoimmune disorders”

In a press release from Wiley-Blackwell (publisher of Arthritis & Rheumatism), Dr. Luis E. C. Andrade drew the following conclusion from his research group’s results: “The ANA-HEp-2 test is positive in a sizeable portion of the general population and our findings established distinguishing characteristics between healthy individuals and patients with autoimmune disease, which is essential to accurately interpret the test results.” In addition, “Our study confirms that the ANA-HEp-2 pattern is critical in properly diagnosing autoimmune disorders and future research should attempt to reproduce the interpretation of test results among different ANA experts and ANA-HEp-2 slide brands.”

[ ... ] the ANA-HEp-2 pattern is critical in properly diagnosing autoimmune disorders and future research should attempt to reproduce the interpretation of test results among different ANA experts and ANA-HEp-2 slide brands.            

IIF pattern on the HEp-2 cells: antibodies against SRP (signal recognition particle) – cytoplasm: diffuse fine speckled positive; mitotic cells: negative (400x) - © ORGENTEC Diagnostika, Mainz

For many studies in autoimmune diagnostics and rheumatism diagnostics, the ANA test for HEp-2 cells is the method of choice; in fact, the ANA HEp-2 test system is often considered the gold standard of diagnosis. A few weeks ago, an Austrian colleague gave me basic instruction in the correct way to carry out indirect immunofluorescence tests and how to evaluate IIF patterns. I was amazed at how easy it is (in principle!) to carry out this technique. I was fascinated by the brilliance of the images I saw under the immunofluorescence microscope – and I was simultaneously humbled intimidated by the tremendous challenge involved in recognizing and evaluating the highly complex immunofluorecence patterns!

The analyst in an ordinary clinical laboratory should be able to recognize the ANA patterns that are clinically relevant and those that are the most probably observed in individuals with no apparent autoimmune disease.

As Dr. Andrade also points out in his article, careful and regular training, as well as a great deal of experience, are a requirement. In any case, he argues for basic knowledge of this highly complex topic: “The analyst in an ordinary clinical laboratory should be able to recognize the ANA patterns that are clinically relevant and those that are the most probably observed in individuals with no apparent autoimmune disease.” – I highly recommend you read the original text, it is worth it!

Re©ognise ©opyright law!!! — Please note that all immunofluorescence pictures used in this blog post are copyrighted material! All these IIF pattern fotos are taken and kindly left by Barbara Fabian, Austria. If you’re interested in using the pictures, please ask for permission: pr@orgentec.com 

References:
Mariz HA, Sato EI, Barbosa SH, Rodrigues SH, Dellavance A, Andrade LE. Pattern on the antinuclear antibody-HEp-2 test is a critical parameter for discriminating antinuclear antibody-positive healthy individuals and patients with autoimmune rheumatic diseases. Arthritis Rheum. 2011 Jan;63(1):191-200. – doi: 10.1002/art.30084.

Duroux-Richard I, Jorgensen C, Apparailly F. miRNAs and rheumatoid arthritis – promising novel biomarkers. Swiss Med Wkly. 2011 Mar 18;141:w13175 – doi: 10.4414/smw.2011.13175 – Free full text available! – Today, the most challenging issue in the field of rheumatoid arthritis is the identification of biomarkers for early disease diagnosis and for prediction drug response. micro(mi)-RNAs certainly represent an realistic option for optimal diagnosis an disease treatment.

Roux CH, Breuil V, Valerio L, Amoretti N, Brocq O, Albert C, Grisot C, Allam Y, Chevalier P, Pradier C, Euller-Ziegler L. Etanercept Compared to Intraarticular Corticosteroid Injection in Rheumatoid Arthritis: Double-blind, Randomized Pilot Study.  J Rheumatol. 2011 Mar 16. [Epub ahead of print]. – Patients with rheumatoid arthritis who had persistent monoarthritis received etanercept or intraarticular corticosteroid injections. Half a year later there was no significant difference in outcome between the two groups.

Klareskog L, Malmström V, Lundberg K, Padyukov L, Alfredsson L. Smoking, citrullination and genetic variability in the immunopathogenesis of rheumatoid arthritis. Semin Immunol. 2011 Mar 2. [Epub ahead of print] PubMed PMID: 21376627. – This review describes how studies on interactions between genetic variants, and environmental factors, mainly smoking, contribute to the understanding of how autoimmunity to post-translationally (citrullinated) proteins/peptides may occur and potentially contribute to certain subsets of rheumatoid arthritis.

Furst DE, Keystone EC, Braun J, Breedveld FC, Burmester GR, De Benedetti F, Dörner T, Emery P, Fleischmann R, Gibofsky A, Kalden JR, Kavanaugh A, Kirkham B, Mease P, Sieper J, Singer NG, Smolen JS, Van Riel PL, Weisman MH, Winthrop K. Updated consensus statement on biological agents for the treatment of rheumatic diseases, 2010. Ann Rheum Dis. 2011 Mar;70 Suppl 1:i2-36. PubMed PMID: 21339216

El-Barbary AM, Kassem EM, El-Sergany MA, Essa SA, Eltomey MA. Association of Anti-Modified Citrullinated Vimentin with Subclinical Atherosclerosis in Early Rheumatoid Arthritis Compared with Anti-Cyclic Citrullinated Peptide. J Rheumatol. 2011 Mar 1. [Epub ahead of print] – For diagnosing early rheumatoid arthritis detection of anti-MCV (anti-mutated citrullinated vimentin) is as sensitive as anti-CCP. Additionally, the anti-MCV assay appears to be a useful test for monitoring associated subclinical atherosclerosis in case of early rheumatoid arthritis, the findings of this clinical study from the Tanta-Univerity Faculty of Medicine, Gharbeia, Egypt, found.

Besada E, Nikolaisen C, Nossent H. Diagnostic value of antibodies against mutated citrullinated vimentin for rheumatoid arthritis. Clin Exp Rheumatol. 2011 Jan-Feb;29(1):85-8. Epub 2011 Feb 23. PubMed PMID: 21269572. – The authors from University Hospital North Norway in Tromsø compared the diagnostic efficiency of anti-MCV assay, anti-CCP2 tests and RF detection for rheumatoid arthritis (RA) diagnostics. According to their findings in this cross-sectional study with 144 patients with established rheumatid diseases (rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, connective tissue disease) the anti-MCV test system “could be a better test for diagnosing RA than anti-CCP2”.

Klareskog L, Gregersen PK, Huizinga TW. Prevention of autoimmune rheumatic disease: state of the art and future perspectives. Ann Rheum Dis. 2010 Dec;69(12):2062-6. Review. PubMed PMID: 21097657. – This review article discusses the new avenues for individualised and biology-based prevention of autoimmune diseases. The authors describe today’s understanding of how genes, environment and immunity interact and they describe how prevention can be improved.

You can also view my article collection on PubMed, where you’ll find links to the articles’ abstracts: View my collection, “Found on the Internet, part 1″ from NCIB.