Logistics at the EULAR 2015 Meeting in Rome

As I had attended the EULAR 2010 Meeting in Rome, I should have expected some problems this year, too. Maybe I blanked out out the logistic shortcomings. But let me already make it clear at this point, I don't think that the fault lies at EULAR.

I was staying at a small hotel in Fiumicino. Airport and the Fiera di Roma Congress Center are reasonable close by. The hotel was about 100 m away from the riviera. Molto bene! If it didn't turn out to a logistic nightmare. The sleepy, little town isn't well connected by public transport; maybe that's the reason I liked Fiumicino, not overcrowded by tourists. If I I took a late  start to go to the meeting I used a shuttle service. I only did this once. Otherwise I took the shuttle to the airport, the train from there and then another shuttle bus. The railway station is about 1.5 km from the congress center; if you missed the shuttle, you had to walk. If you didn't have a ticket, you found out that there is no vending machine at the station.

To add to my personal logistic nightmare, my airline had changed my departure from Fiumicino to Ciampino airport, only 24 hours before the start. To go from Fiumicino to Ciampino is a logistic challenge, if you do it the way I did, as the people I asked didn't know that there is a shuttle bus in between the airports.

Lets come back to transportation. There have been improvements to 2010, but still the shuttles were not frequent enough. And the stuttles to and from the airport were very insufficient. Even if I would have left from Fiumicino, I wouldn't have made it with the shuttle.

The toilet facilities were underdimensioned, which meant long lines after the sessions; the women's waiting line had been discouraging. Some doors didn't close. The sanitary conditions were bad, not always, but at peak times.

I found the logistics of catering very good, even for vegetarians!

Sessions were well advertized and it was easy to find the locations.

Would I come back to Rome, if in let's say five years the EULAR Annual Meeting would be there again? By all means yes!

EULAR Annual Meeting 2015 in Rome Opening Session

The Opening Session for the Annual Meeting of EULAR has already a history and is quite predictable, but this time we were greeted in Latin. So Prof. Cutolo, the current president of EULAR, started in an unusual way: „Salvete, medici totius Europae totiusque orbis terrarum!“ (Welcome doctors from Europe and all the world!)

The short history of EULAR and what it is today showed some new insights. EULAR spans across 47 nations and keeps contacts with other organizations like ACR, PANLAR, ILAR, APLAR, WHO, EMA etc., as well as patients' organizations.

EULAR has a vision for:

-        Research (EULAR will be the central platform for basic and clinical in rheumatology)

-        Education (EULAR will offer high level education for physicians, health professionals, and the people with the diseases)

-        Meeting (EULAR will broaden the reach of the meeting)

-        Advocacy (EULAR will have significant influence on EU level, assist actions on national levels towards improving research funding, social policy legislation, quality of care)

-        Standards of care (EULAR recommendations and criteria for rheumatic diseases)

-        Profile (EULAR will raise its profile to be more visible to patients and health care providers)

-        National Relations (EULAR will engage even more in national societies).

High set, but reachable goals.

Prof. Cutolo looked first at the numbers of abstracts – in 2000 (Nice) 850 abstracts and now over 4300. He then looked at the quality of the abstracts and found out that the quality was improving, too.

The cultural program has been predictable – Italian opera. How come, I was thinking of „Friends of the Italian Opera“ (Some like it hot – by Billy Wilder)? Nevertheless the program was well received and the selection had been standards that most people would know. Really enjoyable.

And there had been space for awards. One award (Abstract Basic Science) was going to a twitter friend: Philip Robinson (@philipcrobinson) from Australia. Congratultions!

The rest of the evening was dedicated to a social gathering in the EULAR garden. I talked with some German rheumatologists, whom I don't see regularly.

Antirheumatic drugs and foods

Some food and beverages may interact with drugs being prescribend in rheumatology against rheumatic diseases as well as concomitant diseases like osteoporosis. Some foods and beverages block the drug's absorption, so one gets less benefit ore even none at all. On the other hand foods and beverages may increase absorption or free plasma levels and so render them more powerful. Apart from acting on the drug itself, foods and beverages might increase toxicity. Neutriceuticals / dietary supplements might also interact.

Fruit
Fruits with lots of fruit acid like citrus fruits and apples may intereact with your medication. Especially grapefruit acts with cyclosporine A, it increases plasma levels of the drug (cyclosporine A and other drugs carry a warning about grapefruit juice on their labels). These fruits might also interact with methotrexate, but we use more subcutaneous methotreaxate and clinically see no interaction. Alendronate and other oral biphosphonates might also interact, but the stomach should be empty taking the drug and you should only take it with non-sparkling water.

Coffee
Coffee might interact with alendronate and other oral biphosphonates, but the stomach should be empty taking the drug and you should only take it with non-sparkling water.

Milk and milk products
Milk and milk products like yogurt, icecream, cheeses might block quite a lot of drugs, but in rheumatology only penicillamine, and though the drug still is on the list of DMARDs, I haven't seen a patient on this drug during the past 17 years, and before I have only seen patients to come off this drug.

Alcohol
If you are taking drugs that go with the risk of liver toxicity, like methotrexate of leflunomide, it's highly recommended avoiding alcohol.

St. John's Wort
St. John's Wort might increase liver toxicity of other drugs. Some people have to take sildenafil because of vasculitis, St. John's Wort might reduce plasma levels.

Vitamin E and Ginseng
Vitamin E and Ginseng might enhance the bleeding effects of nonsteroidal anti-inflammatory drugs like low-dose aspirin, ibuprofen, and others.

This list is far from complete and if you read something on the topic, please notify me, that I add other interactions. I´ll look myself for addional information.

Abbreviations of DMARDs in Rheumatology

We all use abbreviations for drugs that are in use in rheumatology. We should use equal abbreviations to be understood. I have a list, which still isn’t 100%, but please tell me about abbreviations that I should include.

ABA = Abatacept
ADA = Adalimumab
AZA = Azathioprine
CQ = Chloroquine
CSA = Cyclosporine A also CyA
CTX = Cyclophophamide
CZP = Certolizumab
DPA = d-Penicillamin
ETN = Etanercept
GOL = Golimumab
HCQ = Hydroxychloroquine
INF = Infliximab also IFX
MMF = Mycophenolate mofetil
MTX = Methotrexate
LEF = Leflunomide
RTX = Rituximab
SSZ = Sulfasalazine
SZP = Salazopyrin
TAC = Tacrolimus
TOC = Tocilizumab
UST = Ustekinumab

Parenteral gold - sodium aurothiomalate is inconclusive as there are at least six abbreviations like: SAT, ATM, GST - all abbreviations that have other meanings in everyday life. As gold isn't that important nowadays ...

To my great surprise the "Zeitschrift für Rheumatologie", the official German journal on rheumatology, uses different abbreviations for some biologics/DMARDs:

ABC = Abatacept

ADM = Adalimumab
CiA = Ciclosporin A (oh, the CIA)
CEZ = Certolizumab
ETC = Etanercept
GOM = Golimumab
INX = Infliximab (looks like INXS to me)
RIX = Rituximab
SSZ = Sulfasalazine
TOZ = Tocilizumab

I think that it's an absurd idea that different countries use different abbreviations. I'll ask K. Krüger for the reasons next time I'll meet him.

19.10.2012

Erythema of unclear etiology

A young woman, born 1989, came for a routine control visit. Her disease had been classified as an undifferentiatiated autoimmune connective tissue disorder. She had been treated with azathioprin and mycophenolate mofetil. She developed a primarily toxic liver cell damage and had to be taken off medication.


Lab findings:
25-OH D3 6 ng/ml, CRP 14 (9.8) mg/l, Gamma-GT 61 (21), GOT 487, GPT 600 (100)U/l, IgG 4.114 mg/dl, C4-Komplement 8, Rheumafaktor 65 IU/ml, ANA >1:1.280, granular, nucleolar, ds-DNA-Ab 17 IU/ml, ENA-Blot: Ro(SSA), Ro52(SSA), CENP B positiv; p-/c-ANCA, SMA, LKM-AK und AMA negative . negativ bestimmten Werte für)


Liver histology:
Portal and intralobular lymphocytic and granulocytic hepatitis with single cell necrosis and gruoped cell necrosis, focal granulomatous hepatitis and focal proliferation of biliary as well as portal, incomplete sept creating fibrosis and pericellularr fibrosis (activity level II-III, Fibrosisstadium II according to DeSmet). No fat accumulation in liver cells, no cholestasis or siderosis.
Assessment: primarily toxic liver cell damage. In view of the increased values for antinuclear antibodies one should laso consider a combination of toxic liver cell damage with an autoimmune hepatitis. The histologic image is not typical for primary sclerosing cholangitis or a primary biliary cirrhosis.


She has been put on low dose morphine by a pain specialist and is doing fine in all aspects. All but one: she has developed a new erythema that doesn’t itch, which surrounds hypo pigmented, confluent circle lesions. Here’s a picture:

Any ideas, what it is? No, it isn’t pityriasis versicolor, not lichen sclerosus et atriphicus (Csillag’s disease), nor morphea. The dermatologist, which our patient had consulted already, didn’t have any idea of what this erythema could be.

Someone just told me the solution to this puzzle. I will put the solution on the blog in about 24 hours, just in case s.o. wants to research further. 24.05.2012/15:50 MEZ

And here is the solution; Beez has sent the following two tweets concerning the problem:
@beezknez hi was looking at the pic on blog re unclear etiology she isn't perhaps having an opioid reaction to the morphine ..?

@beezknez just her skin looks similar to what i have seen with ppl who have used oxy co & long use of opioid drugs esp morphine ..
And this is what had happened: She has been put on low dose morphine by a pain specialist

Some Ideas on Gout

As I was taking part in the 3e National Expert Meeting on gout, I´ve prepared myself for the talks and sub meetings with rereading old material and looking for some new research on gout. 3e stands for evidence, experts, exchange. The topics have been diagnosis and management of gout. The following text is by no way a summary of the 3e meeting – after the national meetings have been conducted, the iniative meets on international level and after that meeting we shall see the final results on gout, and these results will be published by 3e.
The 3e meeting has been a good stimulus for me to put together some of the material I had collected over the past years and of which I already had published some here on this blog or on twitpic:
An expedition into the world of gout http://rheumatologe.blogspot.de/2012/04/expedition-into-world-of-gout_27.html
Tophi http://twitpic.com/4q61mh
Hyperuricemia and Gout ACR2011 http://rheumatologe.blogspot.com/2011/11/hyperuricemia-and-gout.html

Gout is a systemic disease
New research found that gout dos not only affect joint. Uric acid may be found even in the eyes. Most prominent and known for a long time are the deposits under the skin, the tophi. I have already shown a very drastic example on twicpic. Uric acid has been found in the pancreas, which may sound exotic, but as no one has researched the question of deposits of uric acid in the different tissues of inner organs systemically, it might turn out that this is a frequent finding with people suffering from hyperuricemia. One can find these deposits with a newly developed technique in CT, the dual energy CT.
Cardiovascular mortality rises 9% in men and 26% in woman with each increase by 1 mg/ml of uric acid level in a study of 6000 people over 16 years.
Reducing elevated uric acid leads to a reduction of hypertension.
High uric acid levels are also associated with a high incidence of kidney failure as shown in an Austrian study with 21.000 healthy people.
High uric acid levels seem to promote osteoarthritis.


Interleukin 1ß
Interleukin 1ß plays a role in gouty inflammation in activating the inflammasom complex. Therefore IL-1-inhibitors try to get approval for gout. On May the 8th 2012 FDA's Arthritis Advisory Committee voted 11-0 against approval of rilonacept (Arcalyst) to prevent gout flares in adults initiating uric acid-lowering therapy. Rilonacept showed a treatment effect to prevent gout flares in adults initiating uric acid-lowering therapy (0.3 flares vs.1.0 flares in the placebo group), but was also associated with an increased risk of malignancy (6 in the verum group and none in the placebo group!). It's more than debatable if 16-week safety studies are adequate to say anything on long term safety.
Canakinumab has been tested in different dosages for the same purpose, but it is unclear why one should use such a high risk and tigh end cost therapy other than to make the pharmaceutical firm happy.


Reducing elevated uric acid levels after a gout attack
Why start reducing high, even very high uric acid levels right with the gout attack? Lots of GPs do, but there is no good reason behind this strategy. Uric acid has accumulated during years, if you abruptly reduce the blood level of uric acid you might induce repeated gout attacks. First control the attack and then slowly and continuously reduce the elevated uric acid level. Even starting with low dose allopurinol warrants a low dose colchicine therapy to prevent a gout attack in the wake of normalizing uric acid levels. The cartilage has a slow metabolism and stores uric acid which could be released into the joint space and fall out as crystals there.




Hyperuricemia and diet
Gout is a disease of hyperalimentation and a diet being rich in purines. Your diet might overload the body with purines or reduce the capacity to eliminate them.
A very high risk is associated with alcohol, which reduces elimination, that means vodka, whiskey, brandy etc., but also beer as it contains purines from the yeast. Wine is exonerated, in little quantities. Most people know that meat, red meat, organ meats, fish and shellfish increase uric acid levels. Another risk factor is high intake of fructose, which is used to to sweeten soft drinks, and also fruits juices and fruits high in fructose might add. There migh be niche for diet drinks (artificial sweeteners) after all. Asparagus and other vegetables containing containing purines don't increase the risk of gout attacks.
Reduction of uric acid levels: low fat milk products, coffee (to a lesser degree decaffinated coffee, but not tea), vitamin C. [source Medical Tribune, Germany]

Rheumatoid nodules

Rheumatoid nodules accompany rheumatoid arthritis. Textbooks mention a rheumatoid nodulosis without arthritis, but my colleagues here and I have never seen someone with such a diagnosis. These nodules appear under the skin, often at extension sides of joints like elbow or finger knuckles. Sometimes these nodules are also seen in the lung. The Diagnosis can be confirmed by histological examination. It is unclear how the nodules develop. Methotrexate is associated with growth of nodules. With Rituximab sporadically one might see a reduction of nodules. Though most patients test positive for rheumatoid factor (M05.xx), rheumatoid nodules are classified like seronegative arthritis – M06.3x).



Here I show you some rheumatoid nodules of a patient, who recently appeared for a routine visit. Rheumatoid arthritis (ICD M05.80) started in 2003 and is currently treated with a combination of Leflunomide and Golimumab. Methotrexate can’t be used as he suffered from MTX induced pneumopathy. Last RF was 224 IU/ml. ESR 33 mm, CRP 26 mg/l.

Trophic disturbance in nail growth

Yesterday one of my long term patients (a woman aged 76) showed up for a routine visit. We diagnosed a p-ANCA associated vasculitis in 2002. Histologic work-up of the skin showed vaculitis with lots eosinophiles. Lab tests 2002: p-ANCA 1:2560, ESR 61/>100 mm, CRP 73 mg/l.
She also complained about some new lines on her nails. One could see a trophic disturbance in nail growth.

She has been in remission for long time, still takes methotrexate. Last p-ANCA has been 54.8 RU/ml. CRP 12.9 mg/l, ESR 49 mm. Complement C3 and C4 normal.


Capillary microscopy: elongated capillaries, “avascular” segments, signs post bleeding.

It looks like the term remission won’t stand the test, but otherwise she’s doing fine, so I most probably won’t change therapy.


Did someone see such trophic changes before? My guess is, that a short termed flare 6-8 weeks ago caused the nail changes.

B cell depletion – how it works

I have done some talks on B cell depletion and especially on rituximab, but I’ve never found an illustrative model to explain how B cell depletion works, so far.


Rituximab or an other monoclonal anti CD20 antibody binds to CD20, which is widely expressed on the surface of B cells. Already early pre-B cells carry CD20. All B cells do with the exception of plasma cells. And also stem cells and pro B cells don’t express CD20. Plasma cells produce antibodies. The exact mode of action of rituximab still is unclear.


Stem cell / pro B cell / pre B cell / immature B cell / mature B cell / activated B cell / memory cell / plasma cell
The marked cells carry CD20.


Imagine there’s a big company, stem cell and pro B cell represent the CEO, pre B to memory cells represent the research and development (R&D) department, plasma cells stand for production. Plasma cells still produce known antibodies. But there’s no development of new antibodies. That’s the reason why you have to get vaccinated [pneumococcal conjugate vaccine (PCV 7) (e.g.Prevena)] before receiving rituximab.

Infusion Reactions to Rituximab

Kim Byrne’s (@stmprkb) reaction to an infusion with Rituxan stimulated me to write a few thoughts on infusion reactions with rituximab.


If I read papers I see a higher rate of infusion reactions than I see in our practice. Maybe in studies one looks more accurately than we do or maybe the authors couldn’t exclude obvious non causal events. I wouldn’t like to yield up Rituxan (rituximab) as it is a helpful drug.
The majority of reactions during infusion of rituximab are due to a cytokine release syndrome, which might be clinically indistinguishable from a (type 1) hypersensitivity reaction. As cytokines have a short half life, stopping the infusion might already be sufficient, but I must admit, I’d give at least an additional antihistamine. Additional glucocorticoids might also be helpful, but would take some time to work. And that’s the reason 100 mg prednisolone*, cetirizine* , and paracetamol* are given half an hour before the infusion starts (* - or other drugs of the same category or equivalent dose). Most patients are able to be rechallenged with Rituxan. Maybe one has to adjust the speed of the infusion, which means the duration increases, which might be a problem with an already long duration of the infusion. As I have a clinic in the background, I will always have a nurse and also an assisting physician to watch over the patient when the rheumatology nurse and/or I already have left the hospital.
What might be signs of an infusion reaction? Cough, dyspnea and/or tachypnea, rhinitis, sneezing, dizziness, confusion, rash, pruritis, urticaria, nausea, vomiting, abdominal cramping, myalgias, fatigue, anxiety, and many more.

How to avoid adverse events?
1. Tell the patient that adverse events might happen, how these events might look, but that these aren’t a must. The statistics are on the side of the patient!
2. Have infusion newcomers take their first infusion together with patients, who know the routine and might ease anxiety.
3. Give 100 mg prednisolone i.v., cetirizine orally, and paracetamol orally half an hour before the infusion starts – and insist on waiting half an hour.
4. Don’t exceed infusion speed, keep to the protocol.
5. Patients need an alarm device, if the nurse is out of sight.
6. Have the physician regularly check the patients.


If a reaction happens stay calm. Infusion reactions can be managed well.
Most patients, even with moderate reactions can be rechallenged, maybe under additional co medication and/or prolonged infusion time.


There’s a good article for nurses, but about the use of rituximab in oncology patients:
http://www.ons.org/Publications/VJC/media/ons/docs/publications/VJC/vjc-apr10cjon.pdf 

An expedition into the world of gout

Gout is a disease that remains undiscovered for a long time and suddenly it starts with a bang, namely an acute gout attack. Usually, the base joint of the big toe is inflammated. In the bible you find the famouspericope of the sick of the palsy, who was taken down on his bed into the house to Jesus, after his bearers had taken off a part of the roof. It is thought that the palsy was due to gout.

Gout is the result of a metabolic disorder. Humans excrete uric acid only much worse than birds for instance. A genetic metabolic disorder, which even leads more to a degradation uric acid excretion, often worsens the situation. If it comes to an increased intake of purines, the raw material for uric acid, then there will be an increase of uric acid in the blood (hyperuricemia) and afterwards in the tissues is due to first.

The cartilage of the joints stores uric acid; because of the concentration gradient uric acid crystals will be released into the synovial fluid later, causing infklammation. High inflammation is associated with very strong pain. A gout patient once said in an interview: "I´d rather go to hell, than enduring this pain any longer."
Gout is acute, the attack comes out of a sudden. Reduced fluid intake combined with physical effort often precede an attack. The pain is described as burning, pungent, throbbing. Hyperthermia and redness of the joint are common. It is reported that the Blanket on the toe can not be tolerated because of pain.
You can secure the diagnosis by a few drops of synovial fluid, because under the polarized light microscope, you can clearly see the gout crystals.
Apart from the joints uric acid can also accumulate under the skin and so called tophus which can be seenparticularly well at the ears.
An elevated uric acid levels endangers not only the joints but also internal organs such as the kidneys and the heart. Chronic uric acid increase also leads to a faster development of arthritis.
Gout can and must be treated with a great emphasis on the change of lifestyle.

(may be be continued)

More on gout:
Gicht / Gout / monströse Harnsäure-Depots / subcutaneous depots of uric acid http://twitpic.com/4q61mh 

http://rheumatologe.blogspot.com/2011/11/hyperuricemia-and-gout.html 

And a newer one, in fact the most recent one: http://rheumatologe.blogspot.de/2014/02/a-new-venture-into-world-of-gout.html

Ankylosing spondylitis – another Diet to abandon

In an article called: “Ankylosing Spondylitis Diet – What Should Be Included?” the authors display a peculiar view of the treatment of ankylosing spondylitis. Link: http://www.healtharticles101.com/ankylosing-spondylitis-diet-what-should-be-included/.  


According to this article Humira is the acme of drugs used against ankylosing spondylitis and Remicade ist a drug that “has not been officially approved as treatment for AS, it shows promising results” – Remicade had already been approved, when Abbott was still researching the properties of Humira.


The authors maintain the view, that diet is a key factor in the treatment of ankylosing spondylitis and they think of diet in which starches (carbohydrates) are eliminated. “Dairy products, fruits, vegetables, eggs, and meats should be part of an ankylosing spondylitis diet.” This diet is also called the London AS Diet and has failed to show benefit as you can look up at; http://www.spondylitis.org/about/diet_lowstarch.aspx. When you increase eggs and meats in your diet you also increase the amount of arachidonic acid, which is used to produce inflammatory prostaglandins. NSAIDs work in blocking the enzyme cyclooxygenase (COX), which converts arachidonic acid – more to be read here: http://en.wikipedia.org/wiki/Cyclooxygenase.


Summing up, I don’t recommend this animal produce burdened diet in treating ankylosing spondylitis.

Acute Gout

Today, a man aged 52 was admitted to our hospital. He had been to several hospitals before. We suspected that his sufferings were due to acute gout. In his history he had been tested only once with an elevated count for uric acid. The aspiration from the MCP 5 joint of the right hand looked like white toothpaste.

X-ray of the left great toe shows bone erosion suggestive of gout

Before microscopy – the toothpaste like substance

Polarized light microscopy showing uric acid crystals, which are spike rod shaped and are “negatively birefringent”

Chondrocalcinosis

Chondrocalcinosis is a disorder we see quite often in rheumatology. It is classified according to ICD-10 as M 11.1/2. The higher the age, the higher the percentage of people being affected, you might see 50% of the age group 85 years and more, though most people will be asymptomatic. The disease might come with painful attacks like in gout. As the disease is also due to crystals, which are called calcium pyrophosphate dihydrate crystals (CPPD), it is very close to gout, we also call the disease pseudo-gout and the attacks might be called pseudo-gout attacks.

The term chondrocalcinosis has been coined after the radiographic findings, which I’ll show later in this short communication. Especially the knee joints are often affected and we also see it on X-ray charts of the wrists. The diagnosis can be verified by looking at the synovial fluid with a microscope that has a function of polarized light (crossed polarizing filters). The CPPD crystals are rhombus shaped and are “positively birefringent” (you better leave this to the expert :-) ). There are quite a lot of conditions that are associated with chondrocalcinosis and you might look these up in the good article on Wikipedia: http://en.wikipedia.org/wiki/Chondrocalcinosis.

So here is your X-ray. It was done in the right knee of an elderly lady. The red arrows show distinctive parts of osteoarthritis, the green arrow point at the calcifications of the menisci.

The next picture I have taken of an X-ray chart in Switzerland. It is the X-ray of a mummy, which is shown at the museum of Yverdon. The mummy has been a priest by the name of Nesshu. If you are at Yverdon I can recommend visiting the Musée d’Yverdon (http://www.musee-yverdon-region.ch/musee.php?include=vocation&lng=en). More on the Archeology part of the museum at http://www.musee-yverdon-region.ch/musee.php?include=collections&lng=en#egypte . And check, if the mummy is at the center for evolutionary medicine in Zürich instead: http://evolutionäremedizin.ch/2011/09/nes-shou-the-mummy-from-yverdon/.

Treatment is like in gout attacks, mostly NSAIDs, sometimes colchicine [one of my colleagues here likes colchicine, but I think it also may have lots of side effects], but other medications might also be considered. Reducing uric acid doesn’t have an effect on acute pseudogout.

Capillary Microscopy - some comments on an actual patient of today

The picture of the capillary microscopy I’m going to put up here shows megacapillaries, elongations, slight torquations, and moreover capillary bleedings. Quite a lot of autoimmune diseases can show these alteration. I have some colleagues from the dermatology department a couple of kilometres west of our hospital, who think it’s scleroderma. But I don’t think so. Our patient is 66 years old and I could be friends with a diagnosis like “oligosymptomatic CREST syndrome”, but I still prefer undifferentiated connective tissue disease. ESR, CRP. C3, C4, etc. normal. Antinuclear autoantibodies 1:5120 nuclear, and the only findings in the immunoblot are Ro-52 and M2-PDH. AMA, however are negative. Hopefully for the lady, we have to wait for a couple of years more to make sure, which diagnosis is appropriate.

Diagnosis Chronic Polyarthritis / rheumatoid arthritis

Regardless whether you call the disease chronic polyarthritis or rheumatoid arthritis, the diagnosis is somehow incomplete and summarizes too many different entities. The revenue relevant ICD classification doesn’t do justice to these differences; at this point one could argue that the ICD hasn’t been made for this purpose. Let’s go through some points regarding differences in the diagnosis rheumatoid arthritis.

An old classification is that into seropositive (with rheumatoid factor) and seronegative (without rheumatoid factor) chronic polyarthritis; the level of importance for rheumatoid factor is unclear, but this point isn’t found in the diagnosis (look at rheumatoid factor on this blog: http://rheumatologe.blogspot.com/2012/02/rheumatoid-factor.html). An acute form is unknown, rheumatoid arthritis is a chronic disease. Of course, there are also forms of acute polyarticular arthritis, but these are other diseases and not an acute form of rheumatoid arthritis. In Germany you can still see rheumatoid arthritis being labeled as chronic polyarthritis or even “primary chronic polyarthritis”, which creates the problem clearify, why you distinguish a mon- or oligo forms of rheumatoid arthritis and then choose a new name for the a form of more joints. Well, the Inuit language has a great variety of word for which we call snow, but that’s a different story.


The pattern of affected joints may be symmetric, asymmetric, small or large joints, or only the wrists, but this fact isn’t considered so far at all in ICD or common usage of diagnosis.

ACPA are used now in the classification criteria of ACR/EULAR. Studies on the predictive value of the amount of ACPA would be useful. Currently the diagnosis of rheumatoid arthritis according to ICD leaves ACPA status open. There’s evidence, especially from a certain level of ACPA, showing an association with an increased risk for the development of joint destructions, so that the inclusion in the diagnosis is warranted.


Radiological (or other imaging) findings are also inadequately represented, on average, you could install easily non erosive, erosive or mutilating in the diagnosis.


The disease may be accompanied by other autoimmune phenomena, so you should also consider representing this fact in your diagnosis. After all it saves us from creations such as rhupus.

Disease activity is unimportant for a classification, but not for the users of the diagnosis. At this point, regarding the treatment, the diagnosis may be of significant difference, if disease activity between the extremes remission and highly active is communicated.


And we also should indicate the duration of the disease, because it allows to draw conclusions about the aggressiveness of the disease,


The last part shows the individual diagnoses and their classification according to ICD. Why the diagnosis of rheumatoid nodules falls under the seronegative rheumatoid arthritis is unclear, because most of the patients with rheumatoid nodules are seropositive.


All in all, the ICD classification already offers a more sophisticated look, but still is completely inadequate in my view.

(This text has been translated and adapted from a preexisting German version, so around the world there might be differences in the usage of certain words.)

New kids on the block – Emerging therapies in rheumatology

New kids on the block – Emerging therapies in rheumatology
EULAR 2011 Meeting in London

There are new therapies, new strategies, but also new drugs based on existing strategies. The following gives an overview based on the abstracts of the EULAR 2011 Meeting in London.


1. Biosimilars

[SP0062] ADVANTAGES AND DISADVANTAGES OF BIOSIMILARS – ARE THEY GENERIC BIOLOGIC AGENTS? by V. Strand: Targets for ''biosimilars'' include etanercept (ETN), infliximab and rituximab. Disadvantages include that relatively small changes in manufacturing, characterization and/or formulation can significantly alter the efficacy, safety and/or immunogenicity of the biosimilar product.

South Korean based Cetlltrion has at least three products in its pipeline:
CT-P13 TNF (like Infliximab / Phase III)CT-P10 CD-20 (like Rituximab / ?)CT-P17 TNF (probably like Etanercept / ?)


2. Anti-CD-20 Monoclonal Antibody (like Rituximab)

[OP0019] OFATUMUMAB, A FULLY HUMAN ANTI-CD20 MAB, IN THE TREATMENT OF BIOLOGIC-NAÏVE RHEUMATOID ARTHRITIS PATIENTS: A RANDOMISED, DOUBLE-BLIND, PLACEBO-CONTROLLED CLINICAL TRIAL by P.C. Taylor1 et al.A phase I/II study1 of OFA at doses of 300mg, 700mg and1000 mg administered as 2 infusions 2 weeks apart, …Conclusions: In this study, OFA treatment significantly improved all clinical outcomes in biologic-naïve, active RA pts without inducing immunogenicity. No unexpected safety findings were identified.

[SAT0288] TOLERABILITY, PHARMACOKINETICS AND PHARMACODYNAMICS OF SUBCUTANEOUSLY ADMINISTERED OFATUMUMAB IN RHEUMATOID ARTHRITIS PATIENTS ON STABLE BACKGROUND METHOTREXATE: A PHASE I/II STUDY by R. Kurrasch1 et al.Conclusions: In this study of RA pts on stable MTX doses, SC OFA doses of 30, 60 or 100mg resulted in profound and sustained peripheral B-cell depletion. Single doses up to 60mg were tolerated. OFA SC may provide a method of achieving B-cell depletion without additional CS premedication.


3. Co-Stimulation-Inhibition goes subcuaneously

[SAT0292] SAFETY OF SUBCUTANEOUS ABATACEPT IN PATIENTS WITH RHEUMATOID ARTHRITIS (RA): INTEGRATED ANALYSIS OF FIVE CLINICAL TRIALS UP TO 4.5 YEARS by R. Alten1 et al.Conclusions: These pooled safety data, from 1879 patients with up to 4.5 years and 3086 p–y of exposure, demonstrate that SC abatacept has acceptable safety and tolerability. The safety profile was generally consistent with that of IV abatacept.1 Few SC injection site reactions were observed, which were mostly mild in intensity.


4. Anti-Interleukin-6 Monoclonal Antibody (like Tocilizumab)

[SAT0304] BMS-945429 (ALD518), A HIGH-AFFINITY ANTI-INTERLEUKIN-6 MONOCLONAL ANTIBODY, IS ASSOCIATED WITH IMPROVEMENTS IN HEALTH-RELATED QUALITY OF LIFE IN PATIENTS WITH RHEUMATOID ARTHRITIS AND AN INADEQUATE RESPONSE TO METHOTREXATE by V. Strand1 et al.Objectives: Here, we report health-related quality of life (HRQoL) outcomes from a Phase II randomized controlled trial of intravenous BMS945429 in patients ...Conclusions: Treatment with the IL-6 inhibitor BMS945429 resulted in statistically significant and clinically meaningful improvements in physical and mental aspects of HRQoL.


5. Anti-BAFF Monoclonal Antibody

[OP0017] A PHASE 2 STUDY OF MONTHLY SUBCUTANEOUS LY2127399 (AN ANTI-BAFF MONOCLONAL ANTIBODY) IN PATIENTS WITH ACTIVE RHEUMATOID ARTHRITIS by M. Genovese1, et al.Conclusions: The LY safety profile in this study was similar to available RA therapies and no unexpected safety signals were seen. The 120mg dose group demonstrated significant reductions in the signs and symptoms of RA, and this was not contingent on complete B cell depletion. These results support further exploration of LY to treat RA


6. Anti-Lymphotoxin-alpha Monoclonal Antibody
Etanercept also works against Lymphotoxin-alpha.

[OP0018] ANTI-LYMPHOTOXIN-ALPHA MONOCLONAL ANTIBODY: RESULTS FROM A PHASE I RANDOMIZED, PLACEBO-CONTROLLED CLINICAL TRIAL IN PATIENTS WITH ACTIVE RHEUMATOID ARTHRITIS by B. Emu1 et al.Conclusions: MLTA3698A was generally well tolerated across SD and MD phases in patients with RA. Preliminary evidence of clinical activity was seen in patients with active RA.


7. Secukinumab (an Anti-Il17a Monoclonal Antibody)

FRI0380] SECUKINUMAB (AIN457) SHOWED A RAPID DECREASE OF DISEASE ACTIVITY IN PATIENTS WITH ACTIVE RHEUMATOID ARTHRITIS INCLUDING THOSE WITH HIGH INFLAMMATORY BURDEN by M. Genovese1 et al.Background: Secukinumab has been shown to improve signs and symptoms of patients with active RA in an ongoing phase II trial1 Conclusions: The results indicate that secukinumab provides a rapid reduction of disease activity with the greatest improvements seen in those patients on 150mg or 300mg who had evidence of high inflammatory burden as evidenced by baseline hsCRP levels.

[FRI0174] THE ANTI-IL17A MONOCLONAL ANTIBODY SECUKINUMAB (AIN457) SHOWED GOOD SAFETY AND EFFICACY IN THE TREATMENT OF ACTIVE ANKYLOSING SPONDYLITIS by D. Baeten1 et al.Conclusions: The primary endpoint of this study was met, as AIN457 induced significantly higher ASAS20 responses than placebo at w6. No early safety signals were noted in this study population. Interim data presented here suggest that AIN457 may be useful for the treatment of active ankylosing spondylitis and thereby warrant larger long term studies on safety and efficacy.


8. Oral JAK-Inhibitor, “small molecules”, SYK-Inhibitor and others

[SAT0243] ORAL SOLO (A3921045): A PHASE 3 STUDY OF ORAL JAK INHIBITOR TOFACITINIB (CP-690,550) MONOTHERAPY IN PATIENTS WITH ACTIVE RHEUMATOID ARTHRITIS: SUBGROUP ANALYSIS OF EFFICACY - POSTER TOURS by R. Fleischmann1 et al.Results: The Mo 3 ACR20 response rate was 59.8% (CP 5 mg) and 65.7% (CP 10 mg) vs 26.7% (PBO), p<0.0001. Conclusions: In this first Phase 3 study in pts with RA, clinically significant efficacy and acceptable safety vs PBO was demonstrated with CP 5 and 10 mg BID monotherapy at Mo 3 and in the majority of major demographic subgroups investigated.


[SAT0240] TASOCITINIB MONOTHERAPY CAN PREVENT RADIOGRAPHIC PROGRESSION IN RHEUMATOID ARTHRITIS by J.W. Kim et al.Conclusions: In this pilot study, we found that a novel JAK inhibitor, tasocitinib can prevent structural damage of RA in respect of joint erosion and JSN. A large-scale randomized prospective study is warranted to confirm our result.
Tasocitinib is the older name for Tofacitinib.

[SAT0249] SAFETY AND PHARMACOKINETIC PROFILE IN HEALTHY VOLUNTEERS OF GLPG0259, A SMALL MOLECULE MAPKAPK5 INHIBITOR CURRENTLY IN A PHASE II RA STUDY by F. Vanhoutte1 Conclusions: GLPG0259 showed good safety and a PK profile supporting once daily dosing. Based on these promising results, a randomized, placebo-controlled multi-center Phase II dose-finding study was initiated in October 2010, where three dose levels of GLPG0259 will be evaluated in 180 active RA patients with an inadequate response to MTX.

[OP0292] IDENTIFICATION OF GLPG0259, AN ORALLY BIOAVAILABLE INHIBITOR OF MAPKAPK5, AS A CLINICAL CANDIDATE FOR THE TREATMENT OF RHEUMATOID ARTHRITIS by M. Andrews1 et al.Conclusions: Compound screening and rational drug design were applied to generate a series of potent inhibitors of the novel RA target MAPKAPK5. Of these promising molecules, ... GLPG0259 is currently being evaluated in a Phase II trial in RA patients.

[OP0292] IDENTIFICATION OF GLPG0259, AN ORALLY BIOAVAILABLE INHIBITOR OF MAPKAPK5, AS A CLINICAL CANDIDATE FOR THE TREATMENT OF RHEUMATOID ARTHRITIS by M. Andrews1 et al.Conclusions: Compound screening and rational drug design were applied to generate a series of potent inhibitors of the novel RA target MAPKAPK5. Of these promising molecules, ... GLPG0259 is currently being evaluated in a Phase II trial in RA patients.
These Phase II Study has already been stopped because of lack of efficacy.

[SAT0246] AMAP102, AN ORALLY AVAILABLE 5-HT2 RECEPTOR ANTAGONIST DEVELOPED FOR THE TREATMENT OF RA, IS SAFE AND WELL TOLERATED IN HEALTHY SUBJECTS by A.-C. Ryde1Background: The 5-HT2 antagonism leads to a reduction of IL-6 and TNF-α, two important mediators of joint inflammation and cartilage/bone destruction. Conclusions: In this single and multiple oral dose Phase I study, AMAP102 was safe and well tolerated. The safety and pharmacokinetic profile of AMAP102 supports its further development. A Phase II study in patients with RA is planned.

[OP0057] IMPROVED HEALTH-RELATED QUALITY OF LIFE IN PATIENTS WITH ACTIVE RHEUMATOID ARTHRITIS RECEIVING FOSTAMATINIB (R788) by M.E. Weinblatt1 et al.Conclusions: In this phase II study involving RA patients, 100 mg bid fostamatinib was associated with significant improvements in HRQoL outcomes including physical functioning, pain, fatigue, and overall physical health status.

[SAT0247] PHARMACOKINETICS OF FOSTAMATINIB, A NOVEL SYK INHIBITOR, IN HEALTHY HUMAN SUBJECTS FOLLOWING SINGLE AND MULTIPLE ORAL DOSING by M. Baluom1 et al.Conclusions: … and is currently being evaluated in phase 3 clinical studies (OSKIRA trials) in RA.


The oral JAK-Inhibitor Tofacitinib seems to be the most promising agent. And also the one, which might be available soon.

Let’s see, what new developments will be shown at the ACR 2011 Meeting in Chicago during November. As for rheumatology we’re living in a very interesting time.