Neue Therapien bei Rheumatoider Arthritis

Rheumatoide Arthritis

Alte und neue DMARDs - EULAR und ACR 2012

Vortrag in der RheumaAkademie

17. Januar 2012

Die Rheumatoide Arthritis (chronische Polyarthritis) ist die häufigste Erkrankung in der Rheumatologie. Dabei sind besonders Gelenke betroffen, die sich entzünden. Es handelt sich um eine Autoimmunerkrankung, bei der unbehandelt die betroffenen Gelenke zerstört werden. Aber die Krankheit kann außer den Gelenken auch innere Organe angreifen. Die aktuelle Forschung beschäftigt sich auch mit der Frage, ob es sich überhaupt um eine Erkrankung handelt und nicht um mehrere eines Spektrums. In diesem Vortrag soll besonders der Frage von therapeutischen Möglichkeiten, alten und neuen, aber auch zukünftigen, nachgegangen werden.

Synovialitische Schwellungen der Fingergrundgelenke bei Rheumatoider Arthritis

Röntgenbild der Hände mit Ausbildung eines Os carpale (Verschmelzung einzelner Handwurzelknochen zu einem Knochen)
Mehr Informationen zur Rheumatoiden Arthritis auch über Wikipedia: http://de.wikipedia.org/wiki/Rheumatoide_Arthritis

Zu den frühen Therapien gehört das parenterales Gold oder Goldspritzen. Weitere Medikamente kamen hinzu und haben nach wie vor ihren Stellenwert. Die meisten Patienten werden mit Methotrexat behandelt, da es ein gutes Verhältnis von Wirksamkeit zu unerwünschten Arzneimittelwirkungen hat.
Mehr Informationen zu Basistherapien auch über Wikipedia:
http://de.wikipedia.org/wiki/Basistherapie
Mehr Informationen zu Basistherapien auch über die Rheumaliga:
http://www.rheuma-liga.de/home/layout2/page_sta_204.html

Ende der 90iger Jahre kam ein neues Präparat auf den Markt, das für die Therapie der Rheumatoiden Arthritis entwickelt worden war. An der internationalen Multizenterstudie RELIEF haben auch wir uns beteiligt. Es handelt sich um das Medikament Arava (Wirkstoff Leflunomid).

Übersicht über die Wirkmechanismen der DMARDs/Basistherapeutika
    Goldsalze (unklarer Wirkmechanismus) – Aurothiomalat
    Folsäure Inhibition – Methotrexat
    Antimalariamittel – Chloroquin und Hydroxychloroquin
    Aminosalicylate – Sulfasalazin
    Purin Synthese Inhibition – Azathioprin
    Pyrimidin Synthese Inhibition – Leflunomid
    T-Zell Immunsuppression – Cyclosprin A, (Tacrolimus)

Iguratimod
• Iguratimod ist ein neues langwirksames Antirheumatikum (DMARD)
• Effekte auf die Produktion von Immunoglobulinen in B-Zellen
• Die Produktion von Zytokinen wird herabgesetzt
• Die Aktivierung des nuclear factor kappa B (NF-kB) wird herabgesetzt
Mehr unter: http://rheumatologe.blogspot.de/2012/06/iguratimod-at-eular-2012.html
• Es wurden einige Studien vorgestellt
• Kein neuen Studien auf dem ACR
• Medikament ist noch nicht zugelassen
• Wird wahrscheinlich noch dauern

Biologika
Biologika, der Ausdruck klingt harmlos, aber TGN1412 (CD28-SuperMAB) führte zu einem cytokine release syndrome auch cytokine storm genannt. Vier Probanden erlitten heftigstes Multiorgan-Versagen.
Ein  Proband scheint Krebs zu entwickeln. Mehr dazu steht unter Wikipedia, nämlich hier: http://en.wikipedia.org/wiki/TGN1412 und hier: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2964774/ (beide Texte auf Englisch).

Tuberkulose
Die Zahl der Erkrankten an Tuberkoulose ist nach Screening deutlich zurückgegangen. Die unentdeckte Tuberkulose kann unter Biologika lebensgefährlich werden. Wir testen jeden Patienten, dem ein solches Medikament verschrieben werden soll.
Wir haben jetzt eine ganze Reihe von Biologika zur Verfügung, deren Wirksamkeit wir immer besser einschätzen lernen. Selbst das bei der Rheumatoiden Arthritis wenig verwendete Präparat Anakinra wird weiter getestet.

Seit 2008 sind Rituximab, Abatacept, Tocilizumab, Golimumab und Certulizumab als wirksame Medikamente zur Therapie der Rheumatoiden Arthritis zugelassen worden. Es gibt insgesamt nur wenige Daten zum direkten Vergleich der einzelnen Therapeutika. Jasvinder A. Singh hat 2009 eine Metaanalyse vorgelegt, die diese Frage zu beantworten sucht (Jasvinder A. Singh MD: CMAJ 2009. DOI:10.1503/cmaj.091391). Die Daten dieser Metaanalyse waren eine Bestätigung für unser eignes Vorgehen in der Wahl des geeigneten Medikaments.

Übersicht über die Wirkmechanismen der aktuell zugelassenen Biologika
    TNF-alpha Inhibition – Etanercept, Infliximab, 
             Adalimumab, Golimumab, Certolizumab
    Interleukin-1 Blockade – Anakinra
    T-Zell Modulation / Kostimulationshemmung – Abatacept
    B-Zell Depletion – Rituximab
    Interleukin-6 Rezeptor Blockade – Tocilizumab

Ozoralizumab
“Ozoralizumab (ATN-103), a novel TNF-alpha inhibitor, is a trivalent, bispecific NanobodyR that potently neutralises TNF and binds to human serum albumin to increase its in vivo half-life.” Wir werden erst in den nächsten Jahren sehen, ob sich daraus ein zugelassenes Medikament entwickelt.

Abatacept
Das Medikament ist unter dem Namen Orencia zugelassen. Die subkutane Anwendung von Abatacept ist nun zugelassen, so dass man auf die Infusionen verzichten kann.

Ocaratuzumab
Ocaratuzumab is a Fc- and Fab engineered anti-CD20 antibody.
Adrienne O'Reilly and colleagues presented a study (Abstract No. 835): "Low Doses of Ocaratuzumab, a Fc- and Fab-Engineered Anti-CD20 Antibody, Result in Rapid and Sustained Depletion of Circulating B-Cells in Rheumatoid Arthritis Patients".
Wenn Ocaratuzumab es schafft, als B-Zell gerichtete Therapie subkutan zur Verfügung zu stehen, könnte es ein großer Erfolg werden, denn die Infusionen mit Rituximab dauern lange.

Tocilizumab
Für Tocilizumab stehe Studien für die Spritze unter die Haut zur Verfügung, aber die Zulassung für die subkutane Gabe wird noch dauern. Das Marketing der Firma verfolgt aktuell einen anderen Vorteil in der Werbung.

Anti-IL-6 Receptor Nanobody
(ALX-0061) Seamless "First-in-Human" Phase I/II POC Study in Patients with Active RA On Stable MTX Treatment" (Abstract No. 1307). - Völlig unklar, ob und was sich daraus für Vorteile in der Praxis ergeben könnten.

Sarilumab
Sarilumab ist ein Anti-IL-6-MAB. 2011 wurde eine Phase 2 Studie vorgelegt. Link: http://rheumatologe.blogspot.de/2011/12/sarilumab-for-treatment-of-rheumatoid.html 
Was gibt es Neues? Eine Studie schaute aufs Hämoglobin. Eine Studie erzählte etwas über akute Phase Proteine. Was ist aus der Phase 2 Studie geworden? Wo ist die Phase 3 Studie? Hier will man Zeit gewinnen, bis man sich darüber klar geworden ist, was man eigentlich will.

Olokizumab
Olokizumab targets interleukin-6 (IL-6).
R. Fleischmann and colleagues presented: "A Pilot Study Investigating the Tolerability and Pharmacodynamic Effect of Single Intravenous / Subcutaneous Doses of Olokizumab, an Anti-Interleukin-6 Monoclonal Antibody, in Patients with Rheumatoid Arthritis (Abstract No. 1339). They concluded: "These results provided the rationale for a further study to investigate the clinical efficacy of olokizumab in RA."
Das heißt also, dass es Hinweise gibt, die für weitere Studien sprechen.

Biosimilars
Biosimilars werden die Biologika genannt, die ein Zweithersteller nachahmt. Es werden jedoch auch Risiken gesehen, dass nämlich das Folgeprodukt doch nicht völlig identisch ist.
In Südkorea werden bei Celltrion Biosimlars bereits hergestellt. Studien zur Zulassung laufen. Wir sind gespannt, wann diese Präparate zur Verfügung.
    CT-P13 TNF (entspricht Infliximab / Phase III) - dieses Jahr in den USA, 2014 hier bei uns
    CT-P10 CD-20 (entspricht Rituximab / ?)
    CT-P17 TNF (wahrscheinlich Etanercept / ?)
Wir hatten wir eine internationale Diskussion zu Rituximab und mein Freund Dr. Shashank Akerker, der in Mumbai seine rheumatologische Praxis hat und auf einem der Bilder oben zu sehen ist, berichtete über ein Biosimilar, das in Indien bereits verfügbar ist und eingesetzt wird.
Reditux ist ein Biosimilar von Rituximab Reditux ist nur in Indien erhältlich / zugelassen.

Secukinumab
X. Baraliakos and colleagues tested secukinumab (IL-17A inhibition) in a proof-of-concept (PoC) trial and showed via MRI, that secukinumab may reduce spinal inflammation (Abstract No. 574). - Der Wirkstoff wird also noch bei M. Bechterew, wahrscheinlich nicht mehr bei rheumatoider Arthritis weiterverfolgt.

NNC0109-0012 NNC0109-0012 (anti-IL-20 mAb) is a novel human monoclonal IgG4 antibody.
L. SEnolt and colleagues presented: "Clinical Responses and Patient Reported Outcomes to NNC0109-0012 (anti-IL-20 mAb) in Rheumatoid Arthritis (RA) Patients Following 12-Weeks Dosing and 13 Weeks Follow up: Results From a Phase 2a Trial" (Abstract No. 836). Wird sicherlich weiterverfolgt.

NNC0114-0005
NNC0114-0005 is a recombinant anti-IL-21 monoclonal antibody. IL-21 is produced by activated T-cells.
St. Ignatenko and colleagues presented: "First in Human Study with Recombinant Anti-IL-21 Monoclonal Antibody in Healthy Subjects and Patients with Rheumatoid Arthritis" (Abstract No. 1279). Conclusions included: "The improvements in DAS28-CRP for patients with RA at the highest dose level may suggest biologic and clinical activity of NNC0114-0005." Ich bin mir nicht so sicher, ob dieser Wirkstoff eine Zukunft hat.

Small molecules
Small molecules oder kleine Moleküle sind die neueuste Entwicklung. Aber hier wird es kompliziert.
Ich versuche es mit Sprachen zu erklären. Von Zelle zu Zelle spricht man eine andere Sprache als in der Zelle. Und in der Zelle spricht man in verschiedenen Dialekten mit dem Zellkern, der wiederum in einer eigenen Sprache Anweisungen gibt.
Von Zelle zu Zelle sind es die Zytokine, wie z.B TNF-alpha oder die Interleukine. Diese Nachricht wird in der Zellwand durch Kinasen übersetzt. Daraufhin wird im Zellkern aus der Erbinformation wie aus einem Buch eine Anweisung ausgelesen und geht aus dem Zellkern wieder hinaus (mRNA). Für uns sind nun die Kinasen von Bedeutung.
Die Komplexität der Vorgänge lässt sich sehr gut an diesem Bild verfolgen: http://www.google.de/imgres?start=88&hl=de&biw=1339&bih=741&gbv=2&tbm=isch&tbnid=Q0BrIqPJmA8SpM:&imgrefurl=http://www.ask.com/wiki/Wnt_signaling_pathway&docid=rhMiIQ4y3e1e7M&imgurl=http://rpmedia.ask.com/ts%253Fu%253D/wikipedia/commons/thumb/2/29/Signal_transduction_v1.png/500px-Signal_transduction_v1.png&w=500&h=367&ei=cBlvT9ftPOmm4gSolaHAAg&zoom=1&iact=rc&dur=93&sig=111244820799203899031&page=5&tbnh=155&tbnw=211&ndsp=22&ved=1t:429,r:9,s:88&tx=94&ty=81  
Aus der Komplexität ergibt sich auch, dass Fehlschläge erst sehr viel später als bei anderen Medikamenten auffallen können.

Januskinasen
Kommen wir nun zu den Januskinasen. Hier z.B. ist eines dieser Bilder zu den Januskinasen: http://www.google.de/imgres?hl=de&biw=1339&bih=741&gbv=2&tbm=isch&tbnid=613r8cUmWWed7M:&imgrefurl=http://www.cellsignal.com/reference/pathway/Jak_Stat_IL_6.html&docid=F7WEmbTdfA9a_M&imgurl=http://www.cellsignal.com/reference/pathway/images/Jak_Stat_IL_6.jpg&w=700&h=597&ei=3RhvT5iuMPPP4QTui-W_Ag&zoom=1&iact=hc&vpx=367&vpy=135&dur=1262&hovh=207&hovw=243&tx=129&ty=122&sig=111244820799203899031&page=1&tbnh=125&tbnw=147&start=0&ndsp=26&ved=1t:429,r:1,s:0 http://oncochat.typepad.com/.a/6a00d8342ae08153ef01348768e87e970c-popup 

Baricitinib
Baricitinib (also known as INCB28050, LY3009104) is an oral JAK1 and JAK2 inhibitor. Die Studien zeigen ein Präparat, dass ein Potential hat, auf den Markt zu gelangen.
To sum it up: Baricitinib, we’re waiting for you!

GLPG0634
GLPG0634 is selective inhibitor of Janus kinase 1 (JAK-1). With JAK-inhibitors it seems that JAK-2-driven side effects limit the use of non-selective JAK-inhibitors. GLPG0634 has a 30-fold selectivity for JAK-1 over JAK-2 in human whole blood.
Dies spricht dafür, dass dieses Molekül auch eine Chance hat. Aber da der Teufel im Detail steckt, werden wir uns noch eine Weile gedulden müssen.

Dekavil
Dekavil - “F8-IL10 is a fusion protein in which the cytokine is fused with the antibody F8 specific to the alternatively-spliced EDA domain of fibronectin, a marker of angiogenesis.” Sehr geringe Fallzahl!
Dekavil ist ein guter Name, aber die Firma scheint die Studien nicht genügend schnell voranzutreiben.

Tofacitinib
Tofacitinib wurde einige Tage vor dem ACR 2012 von der FDA für die USA zugelassen und zwas unter dem Namen Xeljanz. .
Xeljanz Black kommt allerdings mit einer box warning auf den Markt: opportunistische Infektionen, Tuberkulose, Krebs, Lymphom.

MOR103
(Abstract No. L11): “First in Patient Study of Anti-GM-CSF Monoclonal Antibody (MOR103) in Active Rheumatoid Arthritis: Results of a Phase 1b/2a Randomized, Double-Blind, Placebo-Controlled Trial”. Dies war eine late breaking Studie, also eine Studie, die so interessant ist, dass man sie noch nachträglich zugelassen hat. Die Firma hatte zuvor Studien nur auf der eigenen Webseite veröffentlicht und kommt nur aus dem Nichts, so dass ich einen Marketing-Trick dahinter vermute. Das Medikament muss sowieso noch in einer größeren Studie getestet werden.

Fostamatinib
Concerning fostamatinib (a SYK inhibitor), how far have we come during the the time since EULAR 2012? Any date for launching the drug? Link: http://rheumatologe.blogspot.de/2012/07/fostamatinib-at-eular-2012.html.
I was surprised seeing a rat CIA study on fostamatinib (P. Pine et al. No. 329). Nothing more! Perhaps asking for a date when fostamatinib is to be launched was a bit premature. But is there any drug in sight?
More details are here: http://rheumatologe.blogspot.de/2012/12/fostamatinib-at-acr-2012-in-washington.html.
Hier war ich nun etwas enttäuscht. Ich hatte früher bereits Schwierigkeiten vermutet. Aber jetzt weren bestimmte Studien nicht weiter verfolgt und man kommt mit einer Tierstudie zurück. Wir werden auch sehen, wie es sich weiter entwickelt.

Zusammenfassend können wir auf eine Reihe von klassischen DMARDs, die TNF-alpha-Inhibitoren, Biologika mit weiteren Angriffspunkten sowie dem ersten "small molecule" Xeljanz zugreifen; bald wird die Palette durch Biologika von bekanntem oder neuem Angriffspunkt, Biosimilars und weiteren small molecules erweitert werden.

Targeting CD-40 – Preliminaries at the EULAR 2012

I had been interested in the question, if CD-40 could be a target for the treatment of rheumatoid arthritis as there had been a study with the title: “Common variants at CD40 and other loci confer risk of rheumatoid arthritis” in 2008; link: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2757650/.


At the EULAR 2012 there has been a study on the subject. P. Fan and colleagues reported a study on arthritic rats, blocking CD40/CD40L and NF-κB. The promising results are represented in the conclusions auf the authors, which follows.


[AB0177] SIMULTANEOUS BLOCKADE OF THE CD40/CD40L AND NF-κB PATHWAYS IMPROVING THERAPY EFFECT ON ARTHRITIC RATS
P. Fan, L. He, D. Pu, W. Zhou, Y. Sun. Department of Rheumatism, the First Affiliated Hospital Xi'an Jiaotong University, Xi'an, China
Conclusions: The expression CD40LIg and IκBα can effectively inhibit inflammatory reaction of arthritic rats. Simultaneous expression CD40LIg and IκBα can improve the therapeutic effect by synergistic effect.


Let’s see how quickly we will see further results on the way a a new target in treating rheumatoid arthritis.


PS. More on CD-40 on Wikipedia: http://en.wikipedia.org/wiki/CD40_(protein)  

Persistant Synovitis of Rheumatoid Arthritis in Remission

There has been a study on persistence of ultrasound synovitis in patients with rheumatoid arthritis fulfilling DAS and/or ACR/EULAR remission criteria presented at the EULAR 2012 meeting in Berlin. P. Zufferey and colleagues looked at patients fulfilling remission criteria with a semi-quantitative ultrasound score using the OMERACT criteria for synovitis in rheumatoid arthritis. The abstract looks a bit complicated, but the authors defined a cut-off and found that 33% of the patients still showed signs of ultrasound synovitis, which means that a state of low activity instead of a true remission would be a better description.


[OP0275] PERSISTENCE OF ULTRASOUND SYNOVITIS IN THE PATIENTS FULLFILING THE DAS AND/OR THE NEW ACR/EULAR RA REMISSION DEFINITIONS: RESULTS OF THE SONAR SCORE APPLIED TO THE PATIENTS OF THE SCQM COHORT
P. Zufferey1, B. Möller2, L. Brulhart3, G. Tamborrini4, A. Scherer5, H.R. Ziswiler2, for the Rheumatologists of SCQM. 1Dal, CHUV, Lausanne; 2Rheumatology, Inselspital, Bern; 3Rheumatology, HUG, Geneva; 4Rheumatology, Universitat Spital; 5SCQM, Zurich, Switzerland
Conclusions: This study shows that the SONAR score applied by different examinators to RA patients is not different in those fulfilling the DAS remission and the new ACR/EULAR criteria. More than a third of all RA patients in clinical remission (either DAS or ACR/EULAR) still present signs of ultrasound synovitis suggesting that they have reached a low activity instead of a true remission state.


Aiming at remission should still be our goal in treating rheumatoid arthritis, but we should be aware that this might mean for the individual patient reaching the lowest state of disease activity possible.

Sirukumab at the EULAR 2012

Sirukumab (formerly known as CNTO 136) is a human MAB that binds to the cytokine IL-6, designed for the treatment of rheumatoid arthritis. So sirukumab will be competiting with tocilizumab. Several studies have been presented at the 2012 EULAR meeting in Berlin. Actually there have been three abstracts to one study and another study using serum samples of the mentioned phase 2 study.


B. Hsu and colleagues presented a phase 2 study with proof of concept part and a dose ranging part to determine efficacious and safe sirukumab dose regimens. It doesn´t surprise that "sirukumab in combination with MTX, improved physical function as well as reduced multiple other signs and symptoms of RA." As tocilizumab marketing is stressing the point of monotherapy, this study on sirukumab comes in combination with methotrexate.


[FRI0181] SIRUKUMAB, A HUMAN ANTI-IL-6 MONOCLONAL ANTIBODY, IMPROVES PHYSICAL FUNCTION IN PATIENTS WITH ACTIVE RA DESPITE METHOTREXATE THERAPY: RESULTS FROM A 2-PART, PROOF-OF-CONCEPT, DOSE-RANGING, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, PHASE 2 STUDY
B. Hsu1, C.-F. Chiou1, S. Sheng1, J. Smolen2, M. Weinblatt3. 1Janssen R&D, Spring House, PA, United States; 2Medical U of Vienna and Hietzing Hospital, Vienna, Austria; 3Brigham & Women's Hosp, Boston, MA, United States
Conclusions: In this Phase 2 study of patients with active RA despite MTX therapy, sirukumab in combination with MTX, improved physical function as well as reduced multiple other signs and symptoms of RA.


B. Hsu and colleagues show further details of the phase 2 study in another abstract. The new provisional 2011 ACR/EULAR rheumatoid arthritis (RA) remission criteria were used to assess remission rates. The highest remission rates were achieved in the 100 mgs sirukumab SC group.


[OP0025] RESULTS FROM A MULTICENTER, INTERNATIONAL, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, PHASE 2 STUDY OF SIRUKUMAB, A HUMAN ANTI-IL-6 MONOCLONAL ANTIBODY, IN PATIENTS WITH ACTIVE RHEUMATOID ARTHRITIS DESPITE METHOTREXATE THERAPY
B. Hsu1, S. Sheng1, M.E. Weinblatt2, J.S. Smolen3. 1Janssen Research & Development, LLC, Spring House, PA; 2Brigham and Women's Hospital, Boston, MA, United States; 3Medical University of Vienna and Hietzing Hospital, Vienna, Austria
Conclusions: Higher remission rates according to both the 2011 ACR/EULAR and the DAS28 (CRP) criteria were achieved with sirukumab at SC dose regimens ranging from 25-100 mg q2w-q4w compared with placebo. After placebo crossover to sirukumab, all groups achieved increasing remission rates over time with continued sirukumab treatment. The highest sirukumab dose regimen (100 mg q2w) achieved the highest remission rates. The 2011 ACR/EULAR criteria were more stringent than the DAS28 (CRP) criteria; and the Boolean-based definition was more stringent than the SDAI-based definition.


It feels like Hollywood comes to EULAR - here´s part three of the story. B. Hsu and colleagues on efficacy and safety of SC sirukumab. " Thru wk38, AEs occurred more often w/ SRM than PBO (81 vs 67%), including minor infections/infestations (31 vs 13%), GI disorders (19 vs 10%), & injection site reactions (16 vs 3%). Leukopenia (19, 13% [1 NCI Gr 3]), neutropenia (5, 3% [3 Gr 3]), thrombocytopenia (3, 2% [1 Gr 3, 1 Gr 4]), & lymphopenia (2, 1%, [1 Gr 3, 1 Gr 4]) were reported w/ SRM." We have to see later in real life as for leukopenia and neutropenia. See my blog for these in patients treted with tocilizumab: LINK " SRM was efficacious & generally well tolerated." Look for the whole conclusion below:


[THU0100] RESULTS FROM A 2-PART, PROOF-OF-CONCEPT, DOSE-RANGING, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, PHASE 2 STUDY OF SIRUKUMAB, A HUMAN ANTI-IL-6 MONOCLONAL ANTIBODY, IN PATIENTS WITH ACTIVE RHEUMATOID ARTHRITIS DESPITE METHOTREXATE THERAPY
B. Hsu1, S. Sheng1, J.S. Smolen2, M.E. Weinblatt3. 1Janssen R&D, Spring House, PA, United States; 2Med U Vienna & Hietzing Hosp, Vienna, Austria; 3Brigham & Women's Hosp, Boston, MA, United States
Conclusions: SRM was efficacious & generally well tolerated. SRM PK were linear over SC regimens ranging from 25 to 100mg.


G. Toedter and colleagues looked at hepcidin levels and markers of anemia in patients of the phase 2 study on sirukumab. They concluded that sirukumab might be effective in reversing inlammation related anemia, but so do other drugs and tocilizumab.


[THU0105] EFFECT OF SIRUKUMAB ON HEPCIDIN LEVELS AND MARKERS OF ANEMIA: RESULTS OF A PHASE 2B TRIAL IN PATIENTS WITH ACTIVE RHEUMATOID ARTHRITIS DESPITE METHOTREXATE THERAPY
G. Toedter, S. Sague, X. Wu, M. Curran, B. Hsu. Janssen Research & Development, LLC, Spring House, PA, United States
Conclusions: Sirukumab was effective in reducing serum concentrations of hepcidin through week 12 of treatment. Serum hemoglobin levels in anemic patients increased significantly following sirukumab treatment, with half of the patients normalizing hemoglobin levels. This indicates that in addition to demonstrating efficacy, treatment of RA patients with sirukumab may be effective in reversing inflammation-related anemia.


Is there a market for sirukumab. Of course, but it´s largely a me too part of the market, if tocilizumab will be out on the market with SC preparation. Janssen would need to establish a SC sirukumab without the need of methotrexate to compete.

VX-509 and EULAR 2012

There hasn’t been much on VX-509, a JAK 3 directed small molecule. Joel Kremer just told us that VX-509 is in study phase 2. Roy Fleischmann presented a study at the ACR 2011 in Chicago: “Dose Ranging Study of VX-509, An Oral Selective JAK3 Inhibitor, As Monotherapy in Patients with Active Rheumatoid Arthritis (RA)” (late breaking poster No.3, link: https://acr.confex.com/acr/2011/webprogram/Paper24549.html). Nothing new on this study at the EULAR meeting in Berlin.


[SP0169] JAK INHIBITION IN PATIENTS WITH RHEUMATOID ARTHRITIS
J. Kremer. Albany Medical College and The Center for Rheumato, Albany, United States
JAK inhibitors are small molecules with short half lives which can be administered orally in BID (CP-690,550; half life of 3 hrs) or QD dosing (INCBO28050; half life of 6 hrs). CP-690,550 has completed several phase III trials including use as: monotherapy; use with background DMARDs; and structure. INCBO18424, INCBO28050 and VX-509 are presently in Phase II.


The second study comes from I.M. Catlett and colleagues. They looked at biomarkes assessment of VX-509. They found that VX-509 reversibly inhibits JAK 3. So the drug warrants further clinical assessment, which is under way.


[THU0141] BIOMARKER ASSESSMENT OF VX-509, AN INVESTIGATIONAL SELECTIVE JAK3 INHIBITOR, IN HEALTHY VOLUNTEERS
I.M. Catlett, X. Luo, M.S. Penney, M.E. Pray, G. Spencer-Green, M. Botfield, T. Hoock. Vertex Pharmaceuticals Incorporated, Cambridge, United States
Conclusions: The PK/PD correlations of the experimental biomarkers demonstrated that VX-509 is a selective, reversible inhibitor of JAK3 signaling in humans. VX-509 warrants further clinical investigation in patients with chronic, immune-mediated inflammatory disorders, including rheumatoid arthritis.

So we have to wait for news on VX-509 until the ACR meeting 2012 in Washington.

NKG2A / NNC141-0100 at the EULAR 2012

NNC141-0100 is a humanized anti-human NKG2A monoclonal antibody that blocks interaction between CD94/NKG2A. If you are look for the study " Safety and Tolerability of NNC0141-0000-0100 in Subjects With Rheumatoid Arthritis", I must disappoint you as this phase 1 study is still recruiting and my guess is that some data will be presented at the ACR meeting 2012 in Washington. At the EULAR meeting 2012 in Berlin we were shown in vitro studies.

I will show you the conclusions, but it comes to the point that CD94/NKG2A is expressed at sites of inflammation in rheumatoid arthritis and is targeted by NNC141-0100.

Let´s go into detail. V. Pascal and colleagues looked into the binding specificity of NNC141-0100 to CD94/NKG2A receptors in peripheral blood, synovial fluid and/or synovial tissue from RA patients and healthy donors; and more, but here I won´t get into detail. The authors come to the conclusion that NNC141-0100 may promote the elimination of activated pro-inflammatory cells and suppress inflammation in rheumatoid arthritis patients.

[AB0071] CHARACTERIZATION OF NNC141-0100, A THERAPEUTIC ANTIBODY TARGETING INHIBITORY CD94/NKG2A RECEPTORS EXPRESSED IN INFLAMED JOINTS OF RHEUMATOID ARTHRITIS PATIENTS
V. Pascal1, Y. Sundström2, A. Fasth2, V. Malmström2, L. Berg2, P.H. Kvist3, P. Spee1, E.D. Galsgaard3. 1Department of Translational Immunology, Biopharmaceutical Research Unit, Novo Nordisk A/S, Maaloev, Denmark; 2Department of Medicine, Unit of Rheumatology, Karolinska University Hospital, Stockholm, Sweden; 3Department of Histology, Biopharmaceutical Research Unit, Novo Nordisk A/S, Maaloev, Denmark
Conclusions: These data demonstrate that CD94/NKG2A and its ligand HLA-E are expressed at sites of inflammation in RA. NNC141-0100 specifically binds to CD94/NKG2A+ NK cells accumulating in inflamed joints of RA patients, thus treatment with NNC141-0100 may promote the elimination of activated pro-inflammatory cells and suppress inflammation in RA patients. NNC141-0100 is currently being developed for the treatment of RA.

The study of N. Nielsen and colleagues show that natural killer cells may play a role in the elimination of fibroblast-like synoviocytes and may be blocked via CD94/NKG2A with NNC141-0100.

[FRI0020] BLOCKING THE INHIBITORY CD94/NKG2A NK CELL RECEPTOR WITH A NOVEL ANTI-NKG2A MAB ENHANCES THE SUSCEPTIBILITY OF RHEUMATOID ARTHRITIS FIBROBLAST-LIKE SYNOVIOCYTES (FLS) TO NK CELL-MEDIATED CYTOTOXICITY
N. Nielsen1, E.D. Galsgaard2, D. Ahern3, M. Andersen1, P. Spee1, M. Feldmann3, F. Brennan3, K. Söderström1. 1Department of Translational Immunology, Biopharmaceutical Research Unit; 2Department of Histology, Biopharmaceutical Research Unit, Novo Nordisk, Maaloev, Denmark; 3Kennedy Institute of Rheumatology, University of Oxford, London, United Kingdom
Conclusions: This study is the first to suggest that NK cells may play a role in the elimination of FLS, a process that is enhanced upon blocking the ability of HLA-E to engage the inhibitory CD94/NKG2A NK cell receptor. Exploitation of the cytotoxic potential of NK cells by blocking CD94/NKG2A with the novel humanized anti-NKG2A mAb NNC141-0100 may thus yield an opportunity for therapeutic treatment of chronic inflammation. NNC141-0100 is currently being tested in a phase I clinical trial for rheumatoid arthritis.


K. Söderström and colleagues could show that NNC141-0100 "leads to suppression of osteoclast formation and subsequent bone erosion, as well as a reduction in IL-6 levels in vitro."

[OP0142] MASKING CD94/NKG2A USING A NOVEL THERAPEUTIC MAB RESULTS IN SIGNIFICANT SUPPRESSION OF IL-6 LEVELS AND REDUCED OSTEOCLAST FORMATION IN RHEUMATOID ARTHRITIS EX VIVO CULTURES
K. Söderström1, Y. Sundström2, L. Berg2, D. Schepis2, E.D. Galsgaard3, L. Klareskog2, N. Wagtmann1. 1Department of Translational Immunology, Novo Nordisk A/S, Måløv, Denmark; 2Department of Medicine, Unit of Rheumatology, Karolinska Institutet, Stockholm, Sweden; 3Department of Histology, Novo Nordisk A/S, Måløv, Denmark
Conclusions: This study shows that blocking CD94/NKG2A with anti-NKG2A mAb NNC141-0100 that is currently being developed for the treatment of RA, leads to suppression of osteoclast formation and subsequent bone erosion, as well as a reduction in IL-6 levels in vitro. Based on these findings, we propose that anti-NKG2A therapy may have a beneficial effect in vivo in RA patients.

L. Alifrangis and colleagues looked at affinity and potency of NNC141-0100 and it´s implications for dosing in the first-in-man trial in rheumatoid arthritis, which looks good to get started.

[THU0110] AFFINITY AND POTENCY OF THE ANTI-NKG2A MAB NNC141-0100: IMPLICATIONS FOR MABEL AND DOSING IN THE FIRST-IN-MAN TRIAL IN RHEUMATOID ARTHRITIS
L. Alifrangis1, P. André2, V. Pascal3, E. Bonnet2, L. Radzikowski4, M.B. Petersen1, M. Bléry2. 1Non-Clinical Development, Diabetes Research Unit, Novo Nordisk A/S, Måløv, Denmark; 2Innate Pharma, Marseille, France; 3Translational Immunology, Biopharmaceutical Research Unit; 4Dev. Bioanalysis, Diabetes Research Unit, Novo Nordisk A/S, Måløv, Denmark
Conclusions: Given the observed difference between affinity and potency, the MABEL dose for the First-In-Man trial in RA patients had a high predicted CD94/NKG2A receptor occupancy of 90%, while the expected cytotoxicity as measured by the degranulation marker CD107 was much lower (<1%).


The in vitro studies look good, now we´re eager to now if the concept proofs to be working in vivo. It would mean a novel approach to treat rheumatoid arthritis.

NNC141-0100 - please give the baby a name!

Fibromyalgia at the EULAR 2012

There have been more than 70 studies/abstracts on fibromyalgia at the EULAR 2012 in Berlin. It´s impossible to evaluate all of them.


W. Häuser and colleagues gave a very good overview on "comparative efficacy of pharmacological and non-pharmacological interventions in fibromyalgia". I have already used some of these results in treatment and shall later introduce them in detail.


[OP0192] COMPARATIVE EFFICACY OF PHARMACOLOGICAL AND NON-PHARMACOLOGICAL INTERVENTIONS IN FIBROMYALGIA
W. Häuser1, E. Nüesch2, P. Jüni2. 1Internal Medicine 1, Klinikum Saarbrücken, Saarbrücken, Germany; 2Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland
Conclusions: We deem the small advantages of GABA-analogues and SNRIs over placebo of questionable clinical relevance. Our results do not necessarily support EULAR-recommendations, which currently favour drug therapy over other treatment options. (2). We found a potentially important benefit of aerobic exercise and multicomponent therapy in the management of FMS, which is in line with the recommendations of the Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften (AWMF) in Germany (3).


Additional large scale randomised trials of high methodological quality of promising non-pharmacological interventions, such as aerobic exercise and multicomponent therapy, are warranted.


S. Metyas an colleagues looked at drug combination therapy. More drugs more effects. Nothing is said concerning adverse events or the fact that people are drugged. The authors could show a reduction in symptoms. So in their conclusion the authors ask for larger, prospective trials to test their conclusion and to assess safety and tolerability of combination therapy.


[THU0355] MONOTHERAPY VERSUS COMBINATION THERAPY IN THE TREATMENT OF FIBROMYALGIA
S. Metyas1, M. Ibrahim1, E.C. Ortiz2, S. Maher2, D. Arkfeld1. 1University of Southern California, Los Angeles, United States; 2Rheumatology, University of Southern California, Los Angeles, United States
Conclusions: Treatment with combined pharmacotherapy significantly improved fibromyalgia severity and associated symptomatology. Combination therapy is synergistic in their effects and yields greater results in multiple symptom domains compared to that of monotherapy. Larger, prospective trials should be developed to test this conclusion and to assess safety and tolerability of combination therapy.


S.L.K. Yuan and colleagues looked at shiatsu in patients with fibromyalgia. The group size is much too small (N=17 per group) and the shiatsu group received 16 sessions of shiatsu lasting 50 minutes, twice a week, while the control group simply received educational guidance through a booklet. If the authors conclude, that staitsu "is effective in improving pain, tenderness and sleep quality in fibromyalgia patients", I must disappoint them. With this kind of study design you proof anything. The control group didn´t receive as much attention as the stiatsu group. A acceptable, not good control group would have received a sham shiatsu (not double blinded!).


[THU0492-HPR] THE EFFECTIVENESS OF SHIATSU ON PAIN, SLEEP QUALITY AND BALANCE CONFIDENCE OF FIBROMYALGIA PATIENTS: A CONTROLLED CLINICAL TRIAL
S.L.K. Yuan, A.A. Berssaneti, A.P. Marques. Department of Physical Therapy, Speech Therapy and Occupational Therapy, University of Sao Paulo, Sao Paulo, Brazil+
Conclusions: The results indicate that the Shiatsu technique is effective in improving pain, tenderness and sleep quality in fibromyalgia patients.


E. Choy gave a lecture on "How to treat: fibromyalgia". I´ll comment some of his ideas. And as he is a good presenter, I´ll also attend one of his next lectures. Even if I disagree in some parts, his lectures give stimulus to test where you stand yourself.


[SP0071] HOW TO TREAT: FIBROMYALGIA
E. Choy. Department of Rheumatology, Cardiff University School of Medicine, Cardiff, United Kingdom


"These subgroups of patients with FM are likely to respond differently to different treatment strategies, ..."
But is hasn´t been shown that the proposed subgroups have an impact on treatment strategies. That is still to come.
"... treatment should be tailored to the individual, addressing their particular needs and targeting their most distressing symptoms."
I fully agreee, but wouldn´t agree if it comes to drugs.
"Patient education is a key aspect of management as for any chronic medical condition."
Yes and No. Yes, by all means patients need to be educated about their condition. No, education alone doesn´t chance anything. So, education is a needed basis, but then you have to structure other approaches on this basis.
"Explaining underlying pathophysiology reduces frustration and promote coping as well as self-management."
Yes. This is what I do in the educational part of therapy.
"FM patients are equally able to carry out exercise as healthy people, at levels tailored to each individual."
Exercise can help to overcome fear avoidance. It should be an integral part of therapy. But it needs individual tailoring as E. Choy also said. Depressive avoiders are to be addressed differently than happy endurers.
"Cognitive behavioural therapy has been shown to improve pain and function in FM either as sole therapy or in combination with exercise."
Cognitive behavioural therapy shows better results in combination with exercise.
"Tramadol has been shown to reduce pain in FM. It acts centrally and inhibits norepinephrine and serotonin re-uptake ..."
So tramadol works more in the anti-depressive region. It comes with lots of adverse events, to name the most common: nausea.
"Non-steroidal anti-inflammatory drugs, corticosteroids and opioids appear less effective in FM."
What a pharma friendly statement! NSAIDs, corticosteroids, and opiods as well as a long list of drugs have shown to be not effective in fibromyalgia.
"Pregabalin, duloxetine and milnacipran have been licensed by the Food and Drugs Administration in the US for the treatment of FM although none has been licensed in Europe."
And I hope it stays this way as F. Wolfe has shown that effect sizes of these drugs are small or even non existant. Adverse events outreach effects.
"Recent positive trial of sodium oxybate in FM suggests that impaired sleep may be of pathogenic importance in FM[3], therefore improving sleep quality in FM will be an important treatment strategy for future research."
In the ancient beginnings of fibromyalgia research Modolfky has shown that impaired sleep is important in fibromyalgia. Sodium oxybate is a drug designed for the treatment of narcolepsy. Patients with narcolepsy have other needs than patients with fibromyalgia.


B. Hamnes and colleagues looked at "effects of a one week multidisciplinary inpatient self-management programme for patients with fibromyalgia". The background for this study is that self-management programs with or without exercise showed benefits in some outcome parameters for more than 6 months. This study shows only short term effects. It refelects the educational aspect of the intervention. Education itself is important but doesn´t chance itself. We have looked at this issue in 1999-2001 [Valentin, Th., L.M. Kirsch, A. Clasen, G. Bender, B. Kahlfuß, K. Koch: Was taugt die Patientenschulung „Fibromyalgie“ in der Rheumatologie? Die Ergebnisse einer Langzeitstudie. Zeitschrift für Rheumatologie (61), Supplement 1, 2002, S. I/123.].


[OP0079-HPR] EFFECTS OF A ONE WEEK MULTIDISCIPLINARY INPATIENT SELF-MANAGEMENT PROGRAMME FOR PATIENTS WITH FIBROMYALGIA: A RANDOMISED CONTROLLED TRIAL
B. Hamnes1, I. Kjeken2, P. Mowinckel2, K.B. Hagen2,3. 1Hospital for Rheumatic Diseases, Lillehammer; 2National Resource Centre for Rehabilitation in Rheumatology, Department of Rheumatology, Diakonhjemmet Hospital; 3Department of Health Sciences, Institute of Health and Society, University of Oslo, Oslo, Norway
Conclusions: This study shows that in patients with fibromyalgia the SMP has a small short-term effect on skills and behavior that are important for managing and participating in health care (EC-17).


There are lots of other studies and I might find the time to work through these and present them here.

Gout and other crystal diseases at the EULAR 2012

Gout and other crystal diseases have been a hot topic at the EULAR meeting 2012 in Berlin.


M. Doherty has given a superb lecture on gout and other crystal diseases. Gout is well understood in pathogeneis and can even be cured. The pathogenesis of calcium pyrophosphate (CPP) or basic calcium phosphate (BCP) crystal associated diseases is less well understood. For acut gout or pseudo-gout (CPP) best practice "is to aspirate and inject the joint with corticosteroid (this is safe, quickly effective and allows confirmation of diagnosis) and then apply ice-packs." Alternatives are: " oral steroid; intramuscular injection of steroid or ACTH; oral colchicine (0.5mg 2-4 times daily); oral NSAID/coxib (with PPI); or IL-1 inhibition using a biologic (e.g. anakinra, canakinumab - though currently not licensed for gout)." I must say, I don´t use intramuscular steroids. Without constructing the prerequisites of a patient, who would be considered for intramuscular steroids, I´d say it´s obsolete. I´ll come back to it later. And I don´t see "many" patients, who would not tolerate low dose colchicine. And M. Doherty mentioned colchicine useful: "Low dose colchicine may be helpful for patients with frequently recurring acute CPP crystal synovitis, with or without OA, but there is no long-term treatment to eliminate CPP crystals." If we can lower urate levels, we can "cure" gout. We can do so with: " allopurinol, febuxostat, sulphinpyrazone and benzbromarone - each has its own advantages and disadvantages." Gout has a lower profile than other forms of arthritis, which is to be addressed. " Successful management requires full patient discussion and explanation concerning gout and its treatment". " The key challenge therefore is to raise the profile of gout and to improve training, interest and knowledge of doctors so they can impart correct information to their patients." All in all time spent on this lecture has been time well spent!



[SP0096] GOUT AND OTHER CRYSTAL DISEASES
M. Doherty. Academic Rheumatology, University of Nottingham, Nottingham, United Kingdom
Citation: Ann Rheum Dis 2012;71(Suppl3):24
Session: How to manage 5




In the next study K. Reiter and colleagues looked at "comparative effectiveness and health economic evaluation of systemic anti-inflammatory therapies for acute gout flares". See for yourself at conclusions and limitations. I see a problem for canakinumab as it is extreme expensive compared to other alternative and moreover it´s off-label.



[FRI0430] COMPARATIVE EFFECTIVENESS AND HEALTH ECONOMIC EVALUATION OF SYSTEMIC ANTI-INFLAMMATORY THERAPIES FOR ACUTE GOUT FLARES
K. Reiter1, E. Krishnan1, J. Goldhaber-Fiebert2. 1Deapartment of Medicine; 2Health Policy, Stanford University, Palo Alto, United States
Conclusions: When priced as an unbranded product, colchicine is cost effective for the treatment of acute gout flare. In the US, where colchicine is sold as a branded product, systemic corticosteroids provide a more cost effective alternative. At current prices, biologic therapy does not provide additional benefits commensurate with the cost.
Limitations: These results apply to patients with gout who do not have absolute contraindications to any of the treatment options, such as allergies to the drugs, advanced liver or renal disease, or heart failure. Our models did not take into account the drug half-life of parenteral corticosteroids. Our assessment of biologic therapy may not be applicable to non-canakinumab therapies currently in development.


The next studies all come from the same set or nearly the same set of authors. The first is by R. Alten and colleagues, who compared canakimumab to intramuscular triamcinolone. Serious adverse events occurred more often in the group of patients treated with canakinumab (8.5% vs. 3.4%). Look for yourself!


[AB1081] EFFICACY AND SAFETY OF CANAKINUMAB VS TRIAMCINOLONE ACETONIDE IN PERSISTENT OR ELDERLY GOUTY ARTHRITIS PATIENTS
R. Alten1, M. Bloch2, T. Bardin3, A. So4, A. Shpilsky5, J.M. Nebesky6, T. Kiechle6, N. Schlesinger7. 1Charité Univ Medicine, Berlin, Germany; 2Holdsworth House Medical Practice, Sydney, Australia; 3Hôpital Lariboisière, Paris, France; 4CHUV, University of Lausanne, Lausanne, Switzerland; 5Novartis Pharmaceuticals Corporation, East Hanover, NJ, United States; 6Novartis Pharma AG, Basel, Switzerland; 7Umdnj-Rwjms, NJ, United States
Conclusions: Canakinumab provided superior pain relief and reduced the risk of a new flare vs TA in this subgroup of pts with persistent GA or elderly pts with GA. Thus it may represent a treatment alternative given that these pts are at a higher risk of comorbidities and may have more limitations to currently available treatments.


In the next study N. Schlesinger and colleagues studied the "effect of canakinumab vs triamcinolone acetonide for treatment of gouty arthritis in patients who are unable to use NSAIDs and colchicine or with severe gouty arthritis". I wondered where they recruited 312 of 454 patients, who are unable to use NSAIDs and colchicine, but severity does the trick. The authors conclude that canakinumab "may represent a potential treatment alternative for this subpopulation." That would be a large subgroup if defined like the authors did.

[FRI0369] EFFECT OF CANAKINUMAB VS TRIAMCINOLONE ACETONIDE FOR TREATMENT OF GOUTY ARTHRITIS IN PATIENTS WHO ARE UNABLE TO USE NSAIDS AND COLCHICINE OR WITH SEVERE GOUTY ARTHRITIS - POSTER TOURS
N. Schlesinger1, R. Alten2, T. Bardin3, M. Bloch4, A. Shpilsky5, G. Krammer6, T. Kiechle6, A. So7. 1Umdnj-Rwjms, NJ, United States; 2Charité Univ Medicine, Berlin, Germany; 3Hôpital Lariboisière, Paris, France; 4Holdsworth House Medical Practice, Sydney, Australia; 5Novartis Pharmaceuticals Corporation, East Hanover NJ, United States; 6Novartis Pharma AG, Basel; 7CHUV, Univ of Lausanne, Lausanne, Switzerland
Conclusions: Pts unable to use NSAIDs and colchicine or with severe GA when treated with CAN had significantly reduced risk of new flare and better pain relief compared to pts treated with TA. CAN may represent a potential treatment alternative for this subpopulation.


There have been more studies:


[AB1080] EFFECT OF SERUM URATE LEVEL ON PREVENTION OF FLARE IN ACUTE GOUTY ARTHRITIS PATIENTS WITH CANAKINUMAB
P. Sunkureddi1, N. Schlesinger2, T. Kiechle3, A. Shpilsky4, A. So5. 1Clear Lake Rheumatology Center, Texas; 2Umdnj-Rwjms, New Jersey, United States; 3Novartis Pharma AG, Basel, Switzerland; 4Novartis Pharmaceuticals Corporation, East Hanover NJ, United States; 5CHUV, University of Lausanne, Lausanne, Switzerland
Conclusions: Results of this retrospective exploratory analysis show that baseline SU level was not a predictor of new flares in patients receiving anti-inflammatory therapy for acute GA, suggesting that GA severity may be more closely related to the prevention of flare than the baseline SU level.


[FRI0377] EARLY RESPONSE TO TREATMENT IS A SURROGATE MARKER OF FLARE RECURRENCE IN ACUTE GOUTY ARTHRITIS
A. So1, T. Bardin2, M. Bloch3, A. Shpilsky4, T. Kiechle5, N. Schlesinger6. 1CHUV, University of Lausanne, Lausanne, Switzerland; 2Hôpital Lariboisière, Paris, France; 3Holdsworth House Medical Practice, Sydney, Australia; 4Novartis Pharmaceuticals Corporation, New Jersey, United States; 5Novartis Pharma AG, Basel, Switzerland; 6Umdnj-Rwjms, New Jersey, United States
Conclusions: These results demonstrate that a 50% pain reduction by VAS within 7 days of treatment in acute GA pts is associated with delay of new flare and can be used as a surrogate marker of time to new flare.


[FRI0402] TOPHI SPREAD, ACUTE JOINTS AND FLARE FREQUENCY PREDICT REFLARE IN GOUTY ARTHRITIS: A SPATIO-TEMPORAL MODEL
T. Bardin1, R. Alten2, N. Schlesinger3, A. Shpilsky4, T. Kiechle5, A. So6. 1Hôpital Lariboisière, Paris, France; 2Charité Teaching Hospital–Schlosspark-Klinik, Berlin, Germany; 3Umdnj-Rwjms; 4Novartis Pharmaceuticals Corporation, NJ, United States; 5Novartis Pharma AG, Basel; 6CHUV-University of Lausanne, Lausanne, Switzerland
Conclusions: Based on this spatio-temporal model the number of tophi locations, number of joints affected by acute GA, along with the number of flares is predictive of subsequent reflaring in this population of GA patients. Thus, the phenomenon of repeated acute GA is impacted mainly by the extent of advanced GA, i.e. the degree of systemic disease and frequency of flares, and not by factors immediately preceding an inflammation (CRP, urate level, etc.) thought to be contributing to the reflaring.


[AB1077] THE SPREAD OF TOPHACEOUS DISEASE STRONGLY PREDICTS TIME TO NEW FLARE IN GOUTY ARTHRITIS
N. Schlesinger1, P. Sunkureddi2, R. Alten3, T. Bardin4, A. Shpilsky5, T. Kiechle6, A. So7. 1Umdnj-Rwjms, NJ; 2Clear Lake Rheumatology Center, Texas, United States; 3Charité Teaching Hospital–Schlosspark-Klinik, Berlin, Germany; 4Hôpital Lariboisière, Paris, France; 5Novartis Pharmaceuticals Corporation, NJ, United States; 6Novartis Pharma AG, Basel; 7CHUV, University of Lausanne, Lausanne, Switzerland
Conclusions: Our results suggest that the number of locations to which tophaceous formations have spread throughout the body leading to systemic disease is an indicator of disease severity in GA. This quantitative measure is a strong predictor of delay of new flare (the higher the number of locations the less delay in reflares).


To me it looks like a massive attack to push forward the use of canakinumab in gouty attacks. Let´s stay alerted if our definitions of intolerability of certrain drugs or disease severity change!

Comments and Abstracts from the 2012 EULAR Meeting in Berlin

Comments and Abstracts from the 2012 EULAR Meeting in Berlin. Somehow this is an inventory of blogposts:


Biosimilars
Celltrion will most probably launch an infliximab biosimilar in 2013. http://rheumatologe.blogspot.de/2012/06/biosimilars.html


Ustekinumab
Ustekinumab and other options in psoriatic arthritis. http://rheumatologe.blogspot.de/2012/07/ustekinumab-and-other-options-in.html  


Anti-CD-20 Monoclonal Antibody (like Rituximab)
Ofatumumab and ocrelizumab? have been analyzed in:
[AB0572] META-ANALYSIS OF THE KEY RHEUMATOID ARTHRITIS (RA) DISEASE ACTIVITY ENDPOINTS IN PATIENTS TREATED WITH B-CELL DEPLETING THERAPIES
S. Menon, K. Barker, E. Peeva, I. Gourley, A. Heatherington. Research and Development, Pfizer Inc, Cambridge, United States
http://rheumatologe.blogspot.de/2012/06/anti-cd-20-monoclonal-antibody.html 


Co-Stimulation-Inhibition
Subcutaneous abatacept, when will it be available?
I have an idea about this, but up to now couldn’t confirm the date.


Tocilizumab
In a head to head study tocilizumab monotherapy has been studied against humira monotherapy. http://rheumatologe.blogspot.de/2012/06/tocilizumab-monotherapy-vs-humira.html  
Concerning Tocilizumab, my most important question to solve at the EULAR 2012 has been: How about subcutaneous tocilizumab? http://rheumatologe.blogspot.de/2012/06/tocilizumab-at-eular-2012.html  


Sarilumab
Sarilumab, another anti-IL-6 monoclonal antibody, has already been in a phase 2 study last year, what’s new? http://rheumatologe.blogspot.de/2012/06/sarilumab-news-from-eular-2012.html

Sirukumab
Sirukumab (formerly known as CNTO 136) is a human MAB that binds to the cytokine IL-6
http://rheumatologe.blogspot.de/2012/07/sirukumab-at-eular-2012.htmlAtacicept
Has atacicept [works on BLys(B-lymphocyte stimulator) and APRIL (A PRoliferation Inducing Ligand)] shown new efficacy? http://rheumatologe.blogspot.de/2012/06/atacicept.html  


Pateclizumab
Pateclizumab is an anti-Lymphotoxin-alpha Monoclonal Antibody. http://rheumatologe.blogspot.de/2012/06/pateclizumab-anti-lymphotoxin-alpha.html


Secukinumab
Secukinumab (an Anti-Il17a Monoclonal Antibody). http://rheumatologe.blogspot.de/2012/06/secukinumab-anti-il17a-monoclonal.html


Small molecules / protein kinase inhibitors
Safety of different small molecules / protein kinase inhibitors
http://rheumatologe.blogspot.de/2012/06/safety-of-different-small-molecules.html


Tofacitinib
The oral jak inhibitor tofacitinib (CP-690,550) has attracted most attention. http://rheumatologe.blogspot.de/2012/07/tofacitinib-oral-jak-inhibitor-at-eular.html  


Fostamatinib
Concerning fostamatinib (a SYK inhibitor), how far have we come during the past year? http://rheumatologe.blogspot.de/2012/07/fostamatinib-at-eular-2012.html  

VX-509
VX-509, a JAK 3 directed small molecule
http://rheumatologe.blogspot.de/2012/07/vx-509-and-eular-2012.htmlAnakinra - IL-1Ra-Receptor antagonist
Anakinra and Pseudogout (calcium pyrophosphate crystal arthritis) at the EULAR 2012
http://rheumatologe.blogspot.de/2012/07/anakinra-and-pseudogout-calcium.html


SBI-087
SBI-087 is a SMIP (= small molecule immune pharmaceutical) binding to CD-20 http://rheumatologe.blogspot.de/2012/07/sbi-087-at-eular-2012.html

Mavrilimumab
Mavrilimumab is a human MAB for the treatment of rheumatoid arthritis. It targets the GMCSF receptor and alpha-chain. http://rheumatologe.blogspot.de/2012/07/mavrilimumab-at-eular-2012.html  


NKG2a
NNC141-0100 is a humanized anti-human NKG2A monoclonal antibody that blocks interaction between CD94/NKG2A.
http://rheumatologe.blogspot.com/2012/07/nkg2a-nnc141-0100-at-eular-2012.html
Cetrorelix
Cetrorelix is a gonadotropin-releasing hormone antagonist (GnRH antagonist). http://rheumatologe.blogspot.de/2012/07/cetrorelix-at-eular-2012.html  


CCX354-C
CCX354-C did better than expected. http://rheumatologe.blogspot.de/2012/07/ccx-354-c-at-eular-2012.html  


Dekavil
Dekavil - fibronectin-A-chain connected to IL-10
http://rheumatologe.blogspot.de/2012/07/dekavil-at-eular-2012.html


Baricitinib
Baricitinib (also known as INCB28050, LY3009104) is an oral JAK1 and JAK2 inhibitor.
http://rheumatologe.blogspot.de/2012/06/baricitinib-ly3009104-at-eular-2012-in.html


Iguratimod
Iguratimod is new DMARD is under way from Japan:
http://rheumatologe.blogspot.de/2012/06/iguratimod-at-eular-2012.html


Modified release prednisolone
On modified release prednisolone: http://rheumatologe.blogspot.de/2012/06/modified-release-prednisone.html  


Synavive
Synavive, a combination of 2 mgs of prednisolone and 200 mgs of dipyramidole
http://rheumatologe.blogspot.de/2012/07/synavive-crx-102-at-eular-2012.html


Acronyms of studies in rheumatology:
http://rheumatologe.blogspot.de/2012/06/acronyms-of-studies-in-rheumatoid.html


Tabalumab
Tabalumab is an anti-BAFF Monoclonal Antibody. http://rheumatologe.blogspot.de/2012/06/tabalumab-ly2127399-anti-baff.html

Rheumatoid Arthritis
Persistant Synovitis of Rheumatoid Arthritis in Remission http://rheumatologe.blogspot.de/2012/07/persistant-synovitis-of-rheumatoid.htmlAnkylosing Spondylitis
Ankylosing Spondylitis Refractory to TNF-inhibition in the light of EULAR 2012. http://rheumatologe.blogspot.de/2012/07/ankylosing-spondylitis-refractory-to.html  


Psoriatic Arthritis
Non-anti-TNF Biologics in Psoriatic Arthritis at EULAR 2011. http://rheumatologe.blogspot.de/2012/07/non-anti-tnf-biologics-in-psoriatic.html  

Gout and other crystal diseases
Gout and other crystal diseases / Canakinumab.
http://rheumatologe.blogspot.de/2012/07/gout-and-other-crystal-diseases-at.html


Fibromyalgia
Fibromyalgia and the influence of weather on symptoms. http://rheumatologe.blogspot.de/2012/06/fibromyalgia-and-influence-of-weather.html
Chronic Widespread Pain – a study presented at the EULAR 2012. http://rheumatologe.blogspot.de/2012/07/chronic-widespread-pain-study-presented.html  

Osteoarthritis
Strontium ranelate in Knee Osteoarthritis at the EULAR 2012
http://rheumatologe.blogspot.de/2012/07/strontium-ranelate-in-knee.html

CD-40
This is a very speculative subject, but who knows, maybe we're going to target CD-40 to treat rheumatoid arhtiris:
http://rheumatologe.blogspot.de/2012/08/targeting-cd-40-preliminaries-at-eular.html