Ernährung bei Rheumatoider Arthritis

Eure Nahrung sei Eure Medizin und Eure Medizin sei Eure Nahrung.
Hippokrates

Ich habe hier auf dem Blog häufiger über „Rheuma und Ernährung“ geschrieben und auch Vorträge dazu gehalten [1], aber in den letzten Jahren habe ich es beim Lesen von Studien belassen und nicht darüber geschrieben; ich hatte allerdings über Diäten, Ernährung und Kochexperimente berichtet. Jetzt aber las ich einerseits Studien, die auf dem letzten EULAR Kongress in Barcelona [2] diskutiert worden sind, und andererseits einen Übersichtsartikel von Dipl.-Chem. Michael van den Heuvel [3], was mich dazu motivierte, einmal wieder über das Thema zu schreiben.

Ernährung ist in der Medizin und besonders in der Rheumatologie ein Reizthema. Wie kommt das? Warum nimmt die Frage nach Ernährungsmaßnahmen bei Betroffenen einen größeren Stellenwert ein als bei Ärzten? Zum einen kann man die immer noch schlechte Studienlage anführen, denn es wird nur wenig geforscht. Warum wird wenig geforscht? Weil Ernährungsstudien wegen der vielen Einflußfaktoren schwierig sind, weil man sie lange genug durchhalten muß, dann aber werden sie teuer, und weil die Pharmaindustrie nicht daran verdienen kann, denn sie ist der wesentliche Geldgeber für wissenschaftliche Studien. Ein befreundeter irischer Rheumatologe erzählte mir einmal vor einer Studie zu Ernährung, die er durchgeführt hatte; er faßte es so zusammen: ein Albtraum. Der Albtraum bestand darin, genügend Probanden zu bekommen, die bereit waren, sich genügend lange auf eine gewisse Weise zu ernähren. Da sind wir schon mitten im Thema: Einfluß auf Erkrankung oder Gewicht über Ernährung nehmen bedeutet eine dauerhafte Umstellung. Wir sind als Patienten und Ärzte zu ungeduldig, denn eine möglich Wirkung setzt erst spät ein. Wir wissen zu wenig über die Wirkmechanismen und wissen auch wenig über die Wirksamkeit. Ärzte haben in der Regel ein schlechte Ausbildung in Ökotrophologie. Wer sie hat, hat sie kaum über das Medizinstudium erhalten.

Bei Nahrungsergänzungsmitteln findet man immer wieder etwas, das als Revolution angekündigt wird. Vitamine, Farbstoffe, Mikronährstoffe nimmt man besser über die Nahrung als über Nahrungsergänzungsmittel auf. Man überdosiert nicht und man hat die richtige Mischung. Natürliche Antioxidantien finden sich in vielen Lebensmitteln. So finden sich z.B. Karotinoide, wie Betakarotin oder Lykopin, besonders in orangenem und roten Obst und und Gemüse. Polyphenolische Verbindungen, wie Resveratrol oder Flavonoide, finden sich in Granatapfel, Kaffee, Kakao, Obst, Rotwein, Tee, Zimt und weiteren. Vitamin C ist in Obst und Gemüse enthalten. Vitamin E in Pflanzenölen sowie Ölsaaten und Nüssen. Aber: viel hilft nicht viel. Der Körper stellt Fließgleichgewichte her, die ein Optimum haben und das verhält sich nach der Normalverteilung.
Zu viel kann durchaus zur Verschlechterung führen, da das Gleichgewicht mit anderen Stoffen nicht mehr stimmt. Wir kennen z.B. mittlerweile hunderte von Karotinoiden, so daß es möglich ist, daß verschiedene Karotinoide ganz unterschiedlich wirken, das Nahrungsergänzungsmittel aber überflutet uns nur mit einem Karotinoid.

Bei der Rheumatoiden Arthritis handelt es sich um eine chronisch-entzündliche Autoimmunerkrankung mit dem Potential, Gelenke und innere Organe zu  zerstören, so daß im Akutstadium auf Medikamente nicht verzichtet werden kann. Da entzündungshemmende (antiinflammatorische) Medikamente aber mehr oder minder starke Nebenwirkungen mit sich bringen, sucht man nach Alternativen und die Ernährung ist eine davon.

Van den Heuvel wies auf eine dänische Metaanalyse hin [4], die sieben randomisierte, kontrollierte Studien aus den Jahren 1979 bis 2023 zusammengefaßt hat. In diesem Zeitraum hat sich die Wissenschaft erheblich geändert, aber es gab nicht mehr Studien, die man hätte verwenden können! „Es gab bei den eingeschlossenen Studien zu wenige Teilnehmer, zu heterogene Studiendesigns und methodische Schwächen.“ Die Autoren der Metaanalyse sehen in einer mediterranen Kost einen „Hoffnungsträger mit Grenzen“.
 
Als mediterrane Diät bezeichnet man Ernährungsformen des Mittelmeerraumes, die mehr Gemüse, Hülsenfrüchte, Fisch, Nüsse und Olivenöl enthalten und auch eine moderate Menge an Rotwein. Außerdem kann man zu mehr Vollkornprodukten bei dieser Art der Ernährung raten. Diese Lebensmittel  liefern entzündungshemmende Fettsäuren, Polyphenole und Antioxidantien. Van den Heuvel führt den MEDRA-Trial (randomisierte, kontrollierte Studie mit 44 RA-Patienten über zwölf Wochen, d.h. 2x22 Pat. [5a]) und eine griechische Studie mit 210 RA-Patienten an [5b]. Diese modernen Studien zeigen eine verbesserte Lebensqualität auf, aber eine Therapie ergab sich daraus nicht. Und schon gar nicht ist eine magische Substanz in dieser Ernährungsform zu finden. 

Eine Studie aus Großbritannien fand bei RA-Patienten, bei denen die Diagnose gerade gestellt worden war, im Rahmen der DESIGNA Studie (Dietary Signatures In Arthritis) vermehrt kurzkettige Fettsäuren, wie sie von Bakterien im Dickdarm aus Ballaststoffen synthetisiert werden, bei Patienten mit geringerer Krankheitsaktivität, so daß sie daraus folgern, daß ein erhöhter Anteil von Ballaststoffen in der Ernährung die Krankheitsaktivität senken kann [6]. Die SUPERFIBRES Studie in Montpellier (Frankreich) untersuchte die Zugabe von 12 g Ballaststoffen in Form von Inulin-Pulver bei RA-Patienten (26 vs. 23) und fand eine verminderte Krankheitsaktivität sowie eine verminderte Zahl von (pro-inflammatorischen) Th17-Zellen in der Verumgruppe [7]. Zusammenfassend zeigen diese beiden Studien, daß es sinnvoll sein kann, die Menge an Ballaststoffen in der Ernährung zu erhöhen, um die Krankheitsaktivität zu senken.

Gerade Hülsenfrüchte, Vollkorn und Gemüse sind reich an Ballaststoffen, aber es gibt weitere Stoffe, die möglicherweise positive Effekte haben. Omega-3-Fettsäuren oder Polyphenole könnten das sein. In der Mittelmeerdiät können Polyphenole aus Olivenöl stammen, aber auch aus Obst und Gemüse; man könnte sich auch Beeren und Tee, wie grünen Tee. in anderen Ernährungsformen überlegen. Fetter Seefisch ist reich an Omega-3-Fettsäuren, aber auch Leinöl. 
Lausitzer Leinöl schmeckt gut, wird allerdings in einer Weißglasflasche ausgeliefert, die das Öl nicht vor Licht schützt, so wird es schneller ranzig. Also sind u.U. Leinölsorten in Metallbehältern oder dunklen Flaschen vorzuziehen. Geöffnetes Leinöl gehört in den Kühlschrank und sollte schnell verbraucht werden. 
Verschiedene Gewürze wirken entzündungshemmend, wobei der Effekt üblicher Verzehrmengen wahrscheinlich nur einen geringen Teil der Entzündung hemmen kann. Bitte würzen Sie nach Ihrem Geschmack. Ingwer (Ginger) dürfte bekannt sein, Gelbwurz (Turmeric) ist in Currypulver, Galgant ist wenig bekannt, wird aber in der thailändischen Küche viel verwendet (Rhizom wie Gelbwurz und Ingwer), Nelken / Nelkenöl oder Kreuzkümmel (Cumin).
Das Curcumin im Gelbwurz hemmt z.B. die Bildung von entzündungsfödernen Zytokinen [darauf wirken Biologika] wie auch auf den NF-kappa B Signalweg in den Zellen. Aber man muss auch wissen, daß Curcumin vom Verdauungstrakt schlecht aufgenommen wird.
Für Koriander gibt es Berichte, aber auch eine experimentelle Studie an Ratten, daß es gegen Rheuma wirksam sei [8]. Mittlerweile gibt es eine Metaanalyse [9], die zu folgendem Ergebnis kommt: „Diese Ergebnisse zeigten das Potenzial von C. sativum bei der Reduzierung von IL-1β, IL-6 und TNF-α“.
Besonders Grüner Tee hat durch verschiedene Inhaltsstoffe eine entzündungshemmende Wirkung, die wiederum durch Unterdrückung des NF-kappa B Signalwegs oder auch durch die Förderung einer vermehrten Produktion von einem Zytokin IL-10 (entzündungshemmend!) entsteht [10]. 

Leider haben spezifische Diäten (z. B. vegan, vegetarisch oder glutenfrei) keinen nachweisbaren Einfluß auf Krankheitsaktivität oder Gelenkzerstörung nachweisen können. Die EULAR-Leitlinien behandeln mehr den sequentiellen Einsatz von Medikamenten, aber auch sie äußern sich zum Thema Ernährung [11]. Hier steht: „Es ist unwahrscheinlich, dass spezielle Ernährungsweisen bzw. Diäten große, spezifische Effekte für Rheumapatienten bewirken.“ Allerdings weisen sie auch hierauf hin: „Eine gesunde, ausgewogene Ernährung ist ein wesentlicher Bestandteil der Verbesserung des Lebensstils von Rheumapatienten.“ 

Zusammenfassend ist Diät bei Rheumatoide Arthritis nur zusätzlich sinnvoll. Ein Diätterror ist völlig unangebracht. Das Essen soll schmecken. Empfehlenswert sind jedoch viel Obst, Gemüse, Vollkorn, Hülsenfrüchte, eher Fisch als Fleisch, wenig Zucker, Vermeidung von Trans- und gesättigten Fetten [12], wobei es sich bei den Empfehlungen ab Fleisch um generelle Empfehlungen der WHO handelt. Eine mediterran ausgerichte Ernährungsform kann diese Empfehlungen gut erfüllen.

Links und Anmerkungen:
[1] Rheuma und Ernährung
https://rheumatologe.blogspot.com/2012/11/rheuma-und-ernahrung.html 
[2] EULAR 2025 Congress in Barcelona, 11-14 June 2025
https://www.drfz.de/veranstaltungen/eular/ 
[3] Dipl.-Chem. Michael van den Heuvel: Rheuma: Mit Ernährung umgelenkt?
https://www.doccheck.com/de/detail/articles/52037-rheuma-mit-ernaehrung-umgelenkt/ 
[4] Jensen et al.: Effects of vegetarian and vegan diets on disease activity, pain, fatigue, and physical function in patients with rheumatoid arthritis: A systematic review and meta-analysis. Joint Bone Spine. doi: 10.1016/j.jbspin.2025.105 (zitiert nach [3])
[5a] Raad et al.: Effects of a telehealth-delivered Mediterranean diet intervention in adults with rheumatoid arthritis (MEDRA): a randomised controlled trial. BMC Musculoskeletal Disorders, 2024. doi: 10.1186/s12891-024-07742-1 (zitiert nach [3])
[5b] Virvili et al.: Mediterranean Diet and Rheumatoid Arthritis: A Controlled Trial. Annals of the Rheumatic Diseases, 2025. doi: 10.1016/j.ard.2025.05.928 (zitiert nach [3])
[6] G. Le Gall1, M. Defernez1, A. Mcdonald2, J. Dainty1, M. Yates1, P. Saha1,
K. Kemsley2, A. MacGregor1: POS0704 LIPIDOMICS AND INFLAMMATION FOLLOWING DISEASE ONSET IN NEWLY DIAGNOSED RHEUMATOID ARTHRITIS: INSIGHTS FROM THE DESIGNA (DIETARY SIGNATURES IN ARTHRITIS) STUDY. DOI: 10.1136/annrheumdis-2025-eular.A1999 
[7] C. Immediato Daien1,2,3, J. P. Hellier1, Z. Salis2,3, J. Morel1,2,3, L. Macia4, R. Audo1,3: ABS0692 DOES FIBER SUPPLEMENTATION IMPROVE DISEASE ACTIVITY IN RHEUMATOID ARTHRITIS INSIGHTS FROM SUPERFIBRES, A RANDOMIZED, DOUBLEBLIND, PLACEBO-CONTROLLED TRIAL DOI: 10.1136/annrheumdis-2025-eular.B2609
[8] Nair, Vinod; Singh, Surender; Gupta, Y.K.. Evaluation of disease modifying activity of Coriandrum sativum in experimental models. The Indian Journal of Medical Research 135(2):p 240-245, February 2012. 
https://journals.lww.com/ijmr/fulltext/2012/35020/evaluation_of_disease_modifying_activity_of.17.aspx  
[9] Malek Mahdavi, A., Javadivala, Z. Systematic review of preclinical studies about effects of Coriandrum sativum L. on inflammatory mediators. Inflammopharmacol 30, 1131–1141 (2022). https://doi.org/10.1007/s10787-022-01000-3  
[10a] Inhaltsstoffe im Tee – ein Überblick 
https://rheumatologe.blogspot.com/2023/12/inhaltsstoffe-im-tee-ein-uberblick.html 
[10b] Superfood Macha 
https://rheumatologe.blogspot.com/2017/03/superfood-macha.html  
[11] https://www.rheuma-liga.de/unser-einsatz/rheumaforschung/aktuelles-aus-der-rheumaforschung/detailansicht/lebensstil-ernaehrung-arbeit-neue-eular-Empfehlungen 
[12] „Transfette sind toxische Substanzen, die töten“, sagte WHO-Chef Tedros Adhanom Ghebreyesus. […] Zu den Lebensmitteln, die nennenswerte Mengen an Transfettsäuren enthalten können, gehören nach DGE-Angaben Back- und Süßwaren sowie frittierte Kartoffelprodukte und Fertiggerichte.“
https://www.aerzteblatt.de/news/who-milliarden-menschen-nicht-vor-gefaehrlichen-transfetten-geschuetzt-d6040071-2f7a-4e60-806e-f305b6035a37 

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Fibromyalgia in patients with rheumatoid arthritis and PROs (patient related outcomes)

I’ve just written on the 12^th TNF-alpha-Forum in Munich. Prof. Schulze-Koops talked about patient related outcomes. The gist is: PROs are indispensable tools to capture the functional experience of the patient. PROs capture parameters that are not directly related to inflammation. The scores recorded in disease activity scores with visual analogue scales are not suitable for sensitively and adequately providing information about functionality limitations. PROs are not sufficient to escalate immune-suppressive therapy.

SA Provan and colleagues just published: “Fibromyalgia in patients with rheumatoid arthritis. A 10-year follow-up study, results from the Oslo Rheumatoid Arthritis Register.” The authors concluded: “RA-FM was associated with significantly higher levels of cross-sectional and longitudinal RA disease activity. FM should be considered in patients with RA not reaching remission.”

On the same TNF-alpha-Forum the CAPEA study has been quoted, which shows a constant DAS28 above 3.2 in a little less than 40% of RA patients. After six months nothing changes for the next 18 months.

It means that we have to find tools besides the current disease activity scores to monitor activity, which means to separate pain, inflammation, immunologic parameters, disability and more to come to safer conclusions concerning the escalation or de-escalation of immune-suppressive therapies. The fibromyalgia group could easily receive a more intensive immune-suppression, which would result in a higher risk for infections for instance. By the way, obese women share also this risk as they have elevated inflammation markers.

Links:

http://rheumatologe.blogspot.com/2019/01/12-tnf-alpha-forum-in-munchen_14.html

https://www.ncbi.nlm.nih.gov/pubmed/30620293

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Etanercept Biosimilars at the ACR 2015 Meeting in San Francisco

There has been one publication on SB4, an etanercept biosimilar, at the ACR 2015 Annual Meeting in San Francisco. SB4 has been developed by Samsung Bioepis. However, Hanwha Chemical’s HD203, also a biosimilar of etanercept, didn’t appear at the ACR 2015 Annual Meeting, which I think is strange as HD203 appeared at the ACR 2014 Annual Meeting with a phase 3 study.

Jiri Vencovsky and colleagues presented: “A Phase III, Randomized, Double-Blind Clinical Study Comparing SB4, an Etanercept Biosimilar, with Etanercept Reference Product (Enbrel®) in Patients with Moderate to Severe Rheumatoid Arthritis Despite Methotrexate Therapy (52-week Results)”. Conclusion: “Efficacy including radiographic progression and safety were comparable between SB4 and ETN [Enbrel] up to Week 52. The immunogenicity profile was lower in SB4 compared to ETN.”

SB4 will be marketed under the name of Benepali. What’s in a word: bene – good and the Tripitaka has been written in Pali. After the meeting the Committee for Medicinal Products for Human Use (CMPH) has recommended the European Medicines Agency (EMA) to approve Benepali. So, Samsung Bioepis now has the apply for approval. Benepali might be available in Europe in 2016. I did’t find anything on the status with the FDA.

References:

Vencovsky J, Sylwestrzak A, Leszczyñski P, Porawska W, Baranauskaite A, Tseluyko V, Zhdan V, Stasiuk B, Milasiene R, Barrera Rodriguez AA, Cheong SY, Ghil J, Emery P. A Phase III, Randomized, Double-Blind Clinical Study Comparing SB4, an Etanercept Biosimilar, with Etanercept Reference Product (Enbrel®) in Patients with Moderate to Severe Rheumatoid Arthritis Despite Methotrexate Therapy (52-week Results) [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). http://acrabstracts.org/abstract/a-phase-iii-randomized-double-blind-clinical-study-comparing-sb4-an-etanercept-biosimilar-with-etanercept-reference-product-enbrel-in-patients-with-moderate-to-severe-rheumatoid/. Accessed December 1, 2015.

Benepali and the Committee for Medicinal Products for Human Use - http://www.ema.europa.eu/docs/en_GB/document_library/Summary_of_opinion_-_Initial_authorisation/human/004007/WC500196736.pdf

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Rheumatoid arthritis and falls

The study of C. Boehler and colleagues tried to correlate disease activity of rheumatoid arthritis and falls (Abstract: http://www.ncbi.nlm.nih.gov/pubmed/22879462). “Conclusion: The strongest correlation with falls was evident for patient-reported outcomes. Pain seems to be the common ground of these parameters.”
As falls should be avoided, this study suggests an increased attention towards the risk of falling. Patients with a higher level of disease activity are at a higher risk of falling. Pain seems to play a pivotal role. So control of pain and disease activity may reduce the risk. Concomitant osteoporosis is also of interest, but this issue hasn’t been addressed in the study. Also physiotherapy and especially muscle building exercise may be helpful in preventing falls.

More on new drug candidates against rheumatoi arthritis

There has been a comment to my blog at:

http://rheumatologe.blogspot.de/2012/07/fighting-rheumatoid-arthritis.html


Ville7 has written on 31st August 2012 12:58

Hallo Rheumatologe,
es ist Wahnsinn, wieviel Antikörper Medikamente derzeit gegen RA untersucht werden, man könnte die Liste fortführen mit

ACZ885 (Canakinumab), Target IL-1 beta
MDX-1100, Target CXCL10
MOR103, Target GM-CSF
KB-003, Target GM-CSF
Sirukumab, Target IL-6
BT061, Target CD4
Belimumab, Target BAFF
Veltuzumab, Target CD20
Golimumab, Target TNF-alpha
Mavrilimumab, Target GM-CSF

und wäre damit noch lange nicht vollständig.

Auf Clinicaltrials findet man unter dem Stichwort "rheumatoid arthritis" allein 231 Studien der Phasen 1 bis 3.


ACZ885 (Canakinumab), Target IL-1 beta, has been developed for the treatment of rheumatoid arthritis, but this indication has been abandoned. IL-1 beta isn’t a successful target in rheumatoid arthritis. Novartis tries desperately to find indications for its’ drug like gout as cryopyrin-associated periodic syndromes (CAPS) are orphan diseases.


MDX-1100, Target CXCL10, but doesn’t seem to be very effective: “The ACR50 and ACR70 response rates on day 85 did not differ between the groups.” http://www.ncbi.nlm.nih.gov/pubmed/22147649  The ACR20 response rate, however, was significantly higher among MDX-1100-treated patients. Lets wait for further results!


MOR103, Target GM-CSF, there is some interesting data, but only published by MorphoSys: http://www.morphosys.com/pressrelease/morphosyss-mor103-antibody-demonstrates-excellent-safety-and-efficacy-rheumatoid-arthritis-patients . Lets wait for the discussions at the ACR2012 next month!


KB-003, Target GM-CSF, “The study was terminated upon completion of safety run-in due to program refocus.” http://clinicaltrials.gov/ct2/show/results/NCT00995449  


Sirukumab, Target IL-6, please look at: http://rheumatologe.blogspot.de/2012/07/sirukumab-at-eular-2012.html (it’s a me too drug).


BT061, Target CD4, “Dose-finding of Multiple Dose of BT061 in Patients With Active Rheumatoid Arthritis Incompletely Controlled on Stable Methotrexate (MTX)”, Estimated Study Completion Date: December 2013. http://clinicaltrials.gov/ct2/show/NCT01481493


Belimumab, Target BAFF, “Belimumab has also undergone phase II clinical trials for rheumatoid arthritis.[6] Preliminary results in November 2005 were encouraging,[7] but no clinical trials are ongoing as of April 2012” - http://en.wikipedia.org/wiki/Belimumab.


Veltuzumab, Target CD20, VELVET, a Dose Range Finding Trial of Veltuzumab in Subjects With Moderate to Severe Rheumatoid Arthritis – the study is ongoing. Let’s wait for results! And please check: http://rheumatologe.blogspot.de/2012/06/anti-cd-20-monoclonal-antibody.html  

Golimumab, Target TNF-alpha, is already on the market!

Mavrilimumab, Target GM-CSF – please check: http://rheumatologe.blogspot.de/2012/07/mavrilimumab-at-eular-2012.html  


All in all I like the efforts for new drugs, but we have to wait for stable results!


Please check also: http://rheumatologe.blogspot.de/2012/05/some-small-molecules-in-pipeline.html

Safety of different small molecules / protein kinase inhibitors

Salgado and colleagues looked at the safety profiles of 18 protein kinase inhibitors (AMG-548, ARRY-371797, BMS-582949, dilmapimod, doramapimod, pamapimod, PH-797804, SCIO-323, talmapimod, VX-702, VX-745, LY3009104, tofacitinib, ruxolitinib, fostamatinib disodium, imatinib mesylate, masitinib and ARRY-438162) in clinical trials in rheumatoid arthritis. Most interesting for the being are tofacitinib and fostamatinib, of course. Tofacitinib is closer to being launched than fostamatinib. Tofacitinib shows higher rates of adverse events concerning cholesterol, headaches, and renal impairment. LY3009104, another Jak inhibitor also has higher rates of adverse events for cholesterol and headaches. Fostmatinib showed higher rates af adverse events for mild increase of transaminases, hypertension, and diarrhea. I’ll come back to this excellent review, when other small molecules mentioned here surface with relevant studies in rheumatoid arthritis.

[THU0097] SYSTEMATIC REVIEW OF THE SAFETY OF PROTEIN KINASE INHIBITORS IN CLINICAL TRIALS IN RHEUMATOID ARTHRITIS - POSTER TOURS
E. Salgado1, J.R. Maneiro1, L. Carmona1,2, J.J. Gomez-Reino1,3. 1Hospital Clinico Universitario De Santiago, Santiago de Compostela; 2Universidad Camilo José Cela, Madrid; 3Universidad de Santiago de Compostela, Santiago de Compostela, Spain
Conclusions: In RA, a unique safety profile seems related to the different PK inhibitors. Dizziness, rash and neutrophilia are related with p38 inhibition; cholesterol increase with JAK inhibition; mild transaminases increase, hypertension and diarrhea with Syk inhibition; and headache, rash, peripheral edema, nausea, vomiting and diarrhea with cKit inhibition.

Back from EULAR 2012 in Berlin – refocussing

I’m back from the 2012 EULAR Meeting in Berlin. Here is some information on the topics I had been looking for:


1. Biosimilars
How far have we come? What will be on the market as alternative to existing products?
Celltrion will most probably launch an infliximab biosimilar in 2013.

http://rheumatologe.blogspot.de/2012/06/biosimilars.html

2. Anti-CD-20 Monoclonal Antibody (like Rituximab)
Is ofatumumab still in the race? Unclear, I’ve seen no poster.

How about ocrelizumab? Unclear, I’ve seen no poster.

Both 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

And veltuzumab? Unclear, I’ve seen no poster.

http://rheumatologe.blogspot.de/2012/06/anti-cd-20-monoclonal-antibody.html 

3. Co-Stimulation-Inhibition
Subcutaneous abatacept, when will it be available?
I have an idea about this.


4. Anti-Interleukin-6 Monoclonal Antibody (like Tocilizumab)
How far has BMS-945429 (ALD518), an anti-IL-6 monoclonal antibody, come? An alternative to tocilizumab? Can’t find an abstract!


And CDP6038, another anti-IL-6 monoclonal antibody? Can’t find an abstract!


Sarilumab, another anti-IL-6 monoclonal antibody, has already been in a phase 2 study last year, what’s new?
There are two studies:
[OP0023] SARILUMAB FOR THE TREATMENT OF MODERATE-TO-SEVERE RHEUMATOID ARTHRITIS: RESULTS OF A PHASE 2, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, INTERNATIONAL STUDY
[OP0169] SARILUMAB FOR THE TREATMENT OF ANKYLOSING SPONDYLITIS: RESULTS OF A PHASE 2, RANDOMIZED. DOUBLE-BLIND, PLACEBO-CONTROLLED, INTERNATIONAL STUDY (ALIGN)
http://rheumatologe.blogspot.de/2012/06/sarilumab-news-from-eular-2012.html



Will still take a while. Here’s one of the studies:
[FRI0180] THE MUSASHI STUDY: COMPARISON OF SUBCUTANEOUS TOCILIZUMAB MONOTHERAPY VERSUS INTRAVENOUS TOCILIZUMAB MONOTHERAPY: RESULTS FROM A DOUBLE-BLIND, PARALLEL-GROUP, COMPARATIVE PHASE III NON-INFERIORITY STUDY IN JAPANESE PATIENTS WITH RHEUMATOID ARTHRITIS
http://rheumatologe.blogspot.de/2012/06/tocilizumab-at-eular-2012.html



Has LY2127399 (an anti-BAFF monoclonal antibody) been studied further? Didn’t find an abstract.
I did so later:

Has atacicept [works on BLys(B-lymphocyte stimulator) and APRIL (A PRoliferation Inducing Ligand)] shown new efficacy? There is a study on atacicept:
[THU0090] SAFETY AND EFFICACY OF ATACICEPT IN COMBINATION WITH RITUXIMAB IN PATIENTS WITH RHEUMATOID ARTHRITIS: RESULTS FROM THE ATACICEPT FOR REDUCTION OF SIGNS AND SYMPTOMS IN RHEUMATOID ARTHRITIS TRIAL (III)

http://rheumatologe.blogspot.de/2012/06/atacicept.html

6. Anti-Lymphotoxin-alpha Monoclonal Antibody
Is MLTA3698A, an anti-lymphotoxin-alpha monoclonal antibody, still studied? Didn’t find an abstract.
I did so later.


7. Secukinumab (an Anti-Il17a Monoclonal Antibody)
Is secukinumab (AIN457), an anti-IL17A monoclonal antibody, still under study? There are 8 abstracts, here is one:
[THU0111] SECUKINUMAB TREATMENT IMPROVES ACR50, HAQ-DI AND EULAR REMISSION RATES IN PATIENTS WITH RHEUMATOID ARTHRITIS

http://rheumatologe.blogspot.de/2012/06/secukinumab-anti-il17a-monoclonal.html

8. Oral JAK-Inhibitor, “small molecules”, SYK-Inhibitor and others
The oral jak inhibitor tofacitinib (CP-690,550) will most probably attract most attention. When will the drug be available? There are 16 studies like:
[THU0152] HOW SHOULD THE PRIMARY ENDPOINT BE ANALYSED IN RHEUMATOID ARTHRITIS TRIALS WHICH MANDATE RESCUE PRIOR TO THE CLINICAL ENDPOINT? ANALYSIS OF THREE PHASE 3 TRIALS OF TOFACITINIB


GLPG0259, a MAPKAPK5 inhibitor, should be abandoned. Didn’t find an abstract.
Has AMAP102, an orally available 5-HT2 receptor antagonist been studied further in a phase 2 study as planned? Didn’t find an abstract.




Concerning fostamatinib (a SYK inhibitor), how far have we come during the past year?, pain, fatigue, and overall physical health status. There are three abstracts:
[THU0139] PHARMACOKINETICS OF FOSTAMATINIB IN PATIENTS WITH IMPAIRED HEPATIC FUNCTION: A PHASE I STUDY


Do we have new data on the oral S1P lyase inhibitor LX3305 (LX2931)? Didn’t find an abstract.

A study small molecules / protein kinase inhibitors (PKI)

http://rheumatologe.blogspot.de/2012/06/safety-of-different-small-molecules.html

9. IL-1Ra-Receptor antagonist
New developments concerning anakinra?
There are 40 abstracts – I haven’t read one, yet!


10. Some further ideas after today's preliminary session (06.06.2012)
* SBI-087 is a SMIP (= small molecule immune pharmaceutical) binding to CD-20 – here is one study
[OP0024] SAFETY AND EFFICACY OF SBI-087 IN SUBJECTS WITH ACTIVE RHEUMATOID ARTHRITIS IN A PHASE 2 RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY

* Sirukumab MAB against IL-6 – has 4 abstracts:
[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


* Mavrilimumab MAB against GM-CSF has four abstracts:
[FRI0182] PHARMACOKINETICS AND IMMUNOGENICITY OF MAVRILIMUMAB
ADMINISTERED SUBCUTANEOUSLY IN SUBJECTS WITH RHEUMATOID ARTHRITIS


* NKG2a - negative regulator of cell activation has seven abstracts:
[AB0071] CHARACTERIZATION OF NNC141-0100, A THERAPEUTIC ANTIBODY TARGETING INHIBITORY CD94/NKG2A RECEPTORS EXPRESSED IN INFLAMED JOINTS OF RHEUMATOID ARTHRITIS PATIENTS


* Cetrorelix - GnRH-antagonist one abstract:
[OP0202] CETRORELIX, A GONADOTROPIN-RELEASING HORMONE ANTAGONIST, SIGNIFICANTLY REDUCES TNF-ALPHA AND DEMONSTRATES EFFICACY IN PATIENTS WITH ACTIVE RHEUMATOID ARTHRITIS: A PROOF-OF-CONCEPT, DOUBLE-BLIND RANDOMISED TRIAL


* CCX354-C and CCX168, which are chemokin-inhibitors. CCX354-C better than expected, one abstract:
[OP0203] ORALLY-ADMINISTERED CCR1 ANTAGONIST CCX354-C IN A PHASE 2 RHEUMATOID ARTHRITIS STUDY
Also something on CCX168, one abstract:
[OP0204] CHARACTERIZATION OF THE NOVEL C5AR ANTAGONIST CCX168, A POTENTIAL THERAPEUTIC FOR ANCA-VASCULITIS, RHEUMATOID ARTHRITIS, AND OTHER AUTOIMMUNE DISORDERS


* Dekavil - fibronectin-A-chain connected to IL-10
One abstract:
[FRI0194] A PHASE IB CLINICAL TRIAL WITH DEKAVIL (F8-IL10), AN ANTI-INFLAMMATORY IMMUNOCYTOKINE FOR THE TREATMENT OF RHEUMATOID ARTHRITIS, USED IN COMBINATION WITH METHOTREXATE


* GLPG0634 - JAK1 inhibitor also one study:
[OP0263] EFFICACY AND SAFETY OF GLPG0634, A SELECTIVE JAK1 INHIBITOR, AFTER SHORT-TERM TREATMENT OF RHEUMATOID ARTHRITIS; RESULTS OF A PHASE IIA TRIAL


* A new DMARD is under way from Japan:

http://rheumatologe.blogspot.de/2012/06/iguratimod-at-eular-2012.html

* On modified release prednisolone:

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

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



I hope you liked this teaser – it will take a couple of weeks to work through this.

http://rheumatologe.blogspot.de/2012/06/pateclizumab-anti-lymphotoxin-alpha.html

http://rheumatologe.blogspot.de/2012/06/tabalumab-ly2127399-anti-baff.html

5. Anti-BAFF Monoclonal AntibodyHow about subcutaneous tocilizumab?

Rheumatoid Arthritis - Radiographic Progression

Today I dictated the findings in our patient's x-rays and I saw two women with rapid progression.

Here are the x-rays of one patient, who showed up for the first time two weeks ago, is now at our day clinic. She was born in 1983 and suffers from rheumatoid arthritis for at least seven years, but didn't look for professional help. She just go prescription pain killers by her GP.

The carpalia are destructed and fused into an os carpale.

Also the heads of the metatarsalia show erosive disease.

The second woman was born in 1958. We treated her until 2010, when she wanted to frequent a rheumatologist closer to her home. We gave the advice to chance therapy to Enbrel as she already suffered from erosive disease. Here are the two x-rays of March 2010.

And now two years after these pictures, we have made these x-rays today.

I think one can easily see the dramatic changes and the rapid progression of the disease.

The second metacarpalia must have been broken and healed during the past two years.

These two examples demonstrate, how important it might be to act within a small limit of time.

Rheumatoid Arthritis / Old and New DMARDs / EULAR and ACR 2011

This is basically the translation of a talk into English, I have held on 22 March 2012 in the Rheumatoid Academy. I cannot display all the slides because of copyright reasons. For the talk I had collected data from posters, session, and abstracts,

Here I have collected some information and other materials, which are been presented on the two major conferences in the world. The first Congress was the eular in London 2011 (June). The second Congress was the ACR 2011 in Chicago (November).

Rheumatoid arthritis

Rheumatoid arthritis (chronic polyarthritis) is the most common disease in rheumatology. Especially joints become inflamed are affected thereby. It is an autoimmune disease, which, if left untreated, destroys affected joints. But the disease can also attack internal organs besides the joints. Current research deals with the question of whether it is just one disease and not more properly called a range of similar diseases, which some already call by a broader term as rheumatic autoimmune disease.

Synovialitic swelling of finger joints in rheumatoid arthritis

X-ray of hands with os carpale (fusion of wrist bones to one bone)

More information on rheumatoid arthritis also on Wikipedia: http://en.wikipedia.org/wiki/Rheumatoid_arthritis

Basic therapeutics / classic DMARDs

Basic therapeutics or DMARDs (disease-modifying antirheumatic drugs) are drugs that change the long term course and prognosis of rheumatoid arthritis. Among the early therapeutics were oral and injected gold salts. Other drugs, most already being used in other fields of medicine, were added and still have their place. Most patients are treated with methotrexate because it has a good balance between effectiveness to adverse events.

Learn more about basic therapeutics / DMARDs on Wikipedia:

http://en.wikipedia.org/wiki/Rheumatoid_arthritis

http://en.wikipedia.org/wiki/Disease-modifying_antirheumatic_drug

The end of the 90s saw a new drug on the market: leflunomide (Arava). And leflunomide had been specifically developed for the treatment of rheumatoid arthritis. We also joined the international multi-centre study RELIEF to test leflunomide (Arava) before marketing.

Overview of the mechanisms of action of DMARDs/anti-rheumatic:

Gold salts (unclear mechanism) - aurothiomalat

Folic acid inhibition - methotrexate

Antimalarials - chloroquine and hydroxychloroquine

Aminosalicylate - sulfasalazine

Purine synthesis inhibition - azathioprine

Pyrimidine synthesis inhibition - leflunomide

T Cell immune suppression - cyclosprin A, (tacrolimus)

Biologics

Shortly afterwards we moved in the treatment of rheumatoid arthritis to new era: the era of biologics.

But stop - Biologics also have their problems:

Problems with a biologic drug in a phase I study
Biologics - the expression might sound harmless - but: TGN1412 (CD28-SuperMAB) lead to a cytokine release syndrome, also known as cytokine storm, which affected all healthy individuals being tested, four suffered a severe multi organ failure and one seems to develop cancer

Now, we already have a range of biologics being available for treatment, more and more we appreciate the effectiveness of these drugs and also the problems. Even a drug being sparingly used in rheumatoid arthritis, anakinra, is further tested.

Since 2008 rituximab, abatacept, tocilizumab, golimumab, and certulizumab heave been approved for the treatment of rheumatoid arthritis as effective drugs. There is only few data on direct comparison of different treatments. Jasvinder A. Singh presented a meta-analysis in 2009, which addresses this question (Jasvinder A. Singh MD: CMAJ 2009. DOI:10.1503/cmaj.091391). The data of this meta-analysis confirmed of our own approach in the choice of an appropriate drug.

Anakinra

The study by P. Sfriso et al. showed a lower response rate of anakinra, when compared to etanercept or adalimumab, but also found, that anakinra achieves a remission in some patients.

[eular 2011 / SAT0283] CLINICAL REMISSION IN RHEUMATOID ARTHRITIS ADULT PATIENTS TREATED WITH ANAKINRA AS FIRST-LINE BIOLOGIC THERAPY. RESULTS FROM THE GISEA REGISTRYP.

Sfriso et al.

Conclusions: The study shows that anakinra in clinical practice could lead to remission in some patients even if the frequency of remission is lower when compared to other biologic therapies (adalimumab/etanercept).

Abatacept

The study by Rike Alten and others showed, that abatacept subcutaneously is as effective as intravenously injected. The reactions at the injection site were mild.

[eular 2011 / SAT0292] SAFETY OF SUBCUTANEOUS ABATACEPT IN PATIENTS WITH RHEUMATOID ARTHRITIS (RA): INTEGRATED ANALYSIS OF FIVE CLINICAL TRIALS UP TO 4.5 YEARS

R. Alten 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 medicine. The safety profile which generally consistent with that of IV abatacept. 1 few SC injection site reactions were observed, which were mostly mild in intensity.

B cell depletion
For other biologics, which act by B cell depletion (destruction of certain white blood cells), the important studies are here on this blog: http://rheumatologe.blogspot.de/2011/12/b-cell-depletion-and-other-b-cell.html


Ofatumumab was presented at the eular in 2011, but any news was absend at the subsequent Congress, the ACR 2011. It may well be that the study had detected too many adverse effects.
The poster about Ocrelizumab was withdrawn at the ACR 2011. It may be that Ocrelizumab is studied further in cancer therapy, but for rheumatoid arthritis and systemic lupus erythematodes there won’t be further research.
Veltuzumab, an another B cell depleting agent, wasn’t introduced at the ACR 2011. Perhaps, something will come out next year.
Overall, it seems to be more difficult than thought to develop a product, which is comparable to rituximab.


Atacicept
Atacicept aims at BLyS (B lymphocyte stimulator) and APRIL (A PRoliferation inducing ligand); Atacicept prevents the binding of BLyS and APRIL on B cells. The study by van Vollenhoven shows, that the required response at ACR-20 level has not been reached. Therefore, it is unlikely that atacicept will be a new therapy principle in rheumatoid arthritis.
R.f. van Vollenhoven and colleagues: Arthritis rheum 2011 Jul;63(7):1782-92.
The phase II, randomized, placebo-controlled trial of Atacicept has been done in patients with rheumatoid arthritis and an inadequate response to methotrexate. Conclusion: "the primary end point (ACR20 CRP response) what not met despite significant biologic effects of atacicept that were consistent with its proposed mechanism of action." Modest effects of atacicept were seen for some secondary efficacy end points. "Treatment with atacicept raises no new safety concerns."


Tocilizumab and more products with Interleukin-6 inhibition
A. Sagawa presented a study about tocilizumab versus infliximab at the eular 2011. However, this study wasn’t a double blind study.
[eular 2011 / FRI0341] EVALUATION OF TOCILIZUMAB COMPARED WITH INFLIXIMAB IN TERMS OF DISEASE ACTIVITY AND SYNOVITIS IN RHEUMATOID ARTHRITIS PATIENTSA.
Sagawa
Methods: ... Evaluation of disease activity was performed using DAS28-ESR. Synovitis in the symptomatic joints of hands, wrists, elbows and knees were measured using ultrasonography.
Conclusions: Improvement of synovitis after 6 months was the same or better in the TCZ group when compared with the IFX group.


More were presented: BMS-945429 (ALD518), CDP6038, and Sarilumab. These will be competitive to tocilizumab. But the question remains whether there is a benefit in these developments for patients or whether only another company wants to make money as well.
[eular 2011 / 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
V. Strand 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.
[eular 2011 / FRI0378] SAFETY AND PHARMACOKINETICS OF CDP6038, AN ANTI-IL-6 MONOCLONAL ANTIBODY, ADMINISTERED BY SUBCUTANEOUS INJECTION AND INTRAVENOUS INFUSION TO HEALTHY MALE VOLUNTEERS: A PHASE 1 STUDYM.
Hickling et al.
Conclusions: CDP6038 was tolerated at single doses of up to 3 mg/kg s.c. and 10 mg/kg i.v. exhibiting a median half-life of 31.1 days, absolute bioavailability of 84–92% and no apparent target-mediated clearance. These findings support the ongoing clinical evaluation of CDP6038 for the treatment of RA.
[eular 2011 / TUE L2]
Sarilumab for the Treatment of Moderate-to-Severe Rheumatoid Arthritis: Results of a Phase 2, Randomized, Double-Blind, Placebo-Controlled, International Study
Mark C. Genovese, Stanford University Medical Center, Palo Alto, CA, Alan J. Kivitz, Altoona Center for Clinical Research, Duncansville, PA, J. Abraham Simon Campos, Centro De Especialidades Médicas, Merida, Mexico, Maria Rell-Bakalarska, Rheumatology and Osteoporosis Outpatient Clinic, Warsaw, Poland, Roy M. Fleischmann, Metroplex Clinical Research Center, Dallas, TX, Martine Jasson, Sanofi, Paris, France, Allen R. Radin, Regeneron Pharmaceuticals Inc, Tarrytown, NY, Xiaohong Huang, Sanofi, Bridgewater, NJ and Tom W. J. Huizinga, Leiden University Medical Centre, Leiden, Netherlands
Conclusions: In this phase 2 study, sarilumab in combination with methotrexate demonstrated efficacy in patients with active, moderate-to-severe rheumatoid arthritis. The types and incidence of adverse events were consistent with those previously reported with IL-6 inhibition. Part B, the phase 3 portion of the MOBILITY seamless study, will assess long-term efficacy of sarilumab in rheumatoid arthritis.



More, biologics with novel mode of action
About LY2127399 (an anti-BAFF monoclonal antibody), MLTA3698A (a lymphotoxin-alpha monoclonal antibody), and AIN457 / Secukinumab (an anti-IL17A monoclonal antibody) there isn’t yet much to say.
[eular 2011 / OP0017] A PHASE 2 STUDY OF MONTHLY SUBCUTANEOUS LY2127399 (AN ANTI-BAFF MONOCLONAL ANTIBODY) IN PATIENTS WITH ACTIVE RHEUMATOID ARTHRITISM.
Genovese 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
[eular 2011 / OP0018] ANTI-LYMPHOTOXIN-ALPHA MONOCLONAL ANTIBODY: RESULTS FROM A PHASE I RANDOMIZED, PLACEBO-CONTROLLED CLINICAL TRIAL IN PATIENTS WITH ACTIVE RHEUMATOID ARTHRITISB.
Emu 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.
Interestingly, etanercept has also activity against lymphotoxin-alpha.


The importance of screening for tuberculosis
The relative risk of a tuberculosis reactivation could be reduced through appropriate screening from 37 to 13 (Askling et al. arthritis rheum 2005; 52: 1986-1992).


Overview of the currently approved Biologics mechanisms:
TNF-alpha inhibition - etanercept, infliximab, adalimumab, certolizumab, and golimumab
Interleukin-1 inhibition - anakinra
T-cell modulation - abatacept
B cell depletion - rituximab
Interleukin-6 inhibition - tocilizumab






Biosimilars
Biosimilars are biologics that a second manufacturer produces after the initial company patent rights have expired. It has been discussed that the subsequent product might not be totally identical, at least these concerns have arisen with biologics.
[eular 2011 / SP0062] ADVANTAGES AND DISADVANTAGES OF BIOSIMILARS – ARE THEY GENERIC BIOLOGIC AGENTS?
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.

Celltrion will produce biosimilars in South Korea. Studies are still under way for approval. We are looking forward to look at these preparations, when they are available.
Just a few days before I’ve held the talk we had an international discussion on rituximab and my friend Dr. Shashank Akerker, who practices rheumatology in Mumbai, reported about a aiosimilar that is already available and is used in India.

Reditux, a biosimilar to rituximab, is already used in India 

Small molecules

Small molecules are the newest development. But here it becomes complicated.


I´ll try to explain it with languages. Inside the cell an other language is spoken than outside from cell to cell. And inside the cell there are various dialects to talk to the nucleus, which in return gives instructions in its own language.


Communicating between cells, there are the cytokines such as TNF-alpha or the interleukins. This message is translated by kinases in the cell wall. Then, an instruction is read out in the nucleus of the genetic information as from a book and goes out of the nucleus as messsenger RNA (mRNA). For us, the kinases are important now.


The complexity of the operations can be traced very well on this image: http://upload.wikimedia.org/wikipedia/commons/2/29/Signal_transduction_v1.png


This complexity also means, that failures may happen much later than in other drugs.


GLPG0259, a so-called MAPKAP kinase 5 inhibitor looked very well in the first trials. According to the studies of Vanhoutte and Andrews onecould hope for a new drug.
[eular 2011 / SAT0249] SAFETY AND PHARMACOKINETIC PROFILE IN HEALTHY VOLUNTEERS OF GLPG0259, A SMALL MOLECULE MAPKAPK5 INHIBITOR CURRENTLY IN A PHASE II RA STUDY
F. Vanhoutte
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.
[eular 2011 / OP0292] IDENTIFICATION OF GLPG0259, AN ORALLY BIOAVAILABLE INHIBITOR OF MAPKAPK5, AS A CLINICAL CANDIDATE FOR THE TREATMENT OF RHEUMATOID ARTHRITIS
M. Andrews 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.

At his second lecture Andrews himself had to admit that the phase 2 study, after submission of the abstract, had to be canceled due to lack of efficacy.
[eular 2011 / OP0292] IDENTIFICATION OF GLPG0259, AN ORALLY BIOAVAILABLE INHIBITOR OF MAPKAPK5, AS A CLINICAL CANDIDATE FOR THE TREATMENT OF RHEUMATOID ARTHRITIS
M. Andrews 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.

Now we come to the Janus kinases. Here for example is one of these images to the Janus kinases: http://oncochat.typepad.com/.a/6a00d8342ae08153ef01348768e87e970c-popup
Tofacitinib is a Janus kinase inhibitor.


Y. Tanaka and colleagues compared efficacy, safety and tolerability of five doses of Tofacitinib as monotherapy against placebo in the treatment of rheumatoid arthritis in Japanese patients with inadequate DMARDS of response to. The primary endpoint was ACR20 response rate in the 12th week. All doses of Tofacitinib were superior when compared to placebo and a clear dose response function was observed. ACR50 and ACR70 response rates also showed this. The most common adverse effects were nasopharyngitis, Hyperlipidemia, and elevated LDL; these were considered mild in severity.
[ACR 2011 / TUE2192]
Tofacitinib (CP-690,550), An Oral Janus Kinase Inhibitor, As Monotherapy in Japanese Patients with Active Rheumatoid Arthritis: A 12-Week Phase 2b Study.
Y. Tanaka1, T. Takeuchi2, H. Yamanaka3, M. Suzuki4, H. Nakamura4, S. Toyoizumi4, J. D. Bradley5 and S. H. Zwillich5. 1University of Occupational & Environmental Health, Kitakyushu, Fukuoka, Japan, 2Keio University School of Medicine, Tokyo, Japan, 3Institute of Rheumatology, Tokyo Women’s Medical University, Tokyo, Japan, 4Pfizer Inc., Tokyo, Japan, 5Pfizer Inc., Groton, CT
Conclusion: When used as monotherapy, tofacitinib dosed 1 mg BID demonstrated superior ACR20 response rates compared with placebo at week 12. Doses of tofacitinib 5, 10, and 15 mg BID demonstrated superiority to placebo in DAS28-4(ESR) 2.6. The safety profile of tofacitinib monotherapy was manageable in Japanese patients with longstanding active rheumatoid arthritis.

Other studies show the following results: Tofacitinib significantly reduced the progression of structural damage compared to placebo in patients with active RA who were treated with methotrexate. A study showed a statistically significant and clinically relevant improvements in several "outcomes reported by patients". Tofacitinib showed a safety profile of good compatibility and sustainable, long-term efficacy over a period of 36 months.
[ACR 20111 / WED2592]
Tofacitinib (CP-690,550), An Oral Janus Kinase Inhibitor, in Combination with Methotrexate Reduced the Progression of Structural Damage in Patients with Rheumatoid Arthritis: a 24-Month Phase 3 Study.
Désirée van der Heijde1, Y. Tanaka2, Roy Fleischmann3, Edward C. Keystone4, et al.
1Department of Rheumatology, Leiden University Medical Center, Leiden, Netherlands, 2University of Occupational & Environmental Health, Kitakyushu, Fukuoka, Japan, 3University of Texas Southwestern Medical Center, etc.
Conclusion: In this P3 study, tofacitinib significantly reduced progression of structural damage vs PBO in pts with active RA on MTX. Consistent with other studies, tofacitinib demonstrated significant and clinically meaningful reductions in signs and symptoms of RA and physical function. No new safety signals were detected.
[ACR 2011 / TUE2627]
Tofacitinib (CP-690,550) in Combination with Traditional Disease-Modifying Anti-Rheumatic Drugs: Phase 3 Study Patient-Reported Outcomes in Patients with Active Rheumatoid Arthritis and An Inadequate Response to Disease-Modifying Anti-Rheumatic Drugs.
V. Strand1, J. M. Kremer2, Z. G. Li3, S. Hall4, Roy M. Fleischmann5, M. C. Genovese6, et al.
1Stanford University, Palo Alto, CA, 2Albany Medical College and The Center for Rheumatology, Albany, NY, 3Peking University People’s Hospital, etc.
Conclusion: In this Phase 3 study of tofacitinib in combination with traditional DMARDs, treatment with 5 and 10 mg BID resulted in consistent statistically significant and clinically meaningful improvements in multiple patient-reported outcomes vs placebo at month 3.
[ACR 2011 / SUN407]
Tofacitinib (CP-690,550), An Oral Janus Kinase Inhibitor, in the Treatment of Rheumatoid Arthritis: Open-Label, Long-Term Extension Studies up to 36 Months.
J. Wollenhaupt1, J. C Silverfield2, E. B. Lee3, S. Wood4, K. Soma5, L. Wang5, H. Nakamura6, Y. Komuro6, C. I. Nduaka5, D. Gruben5, S. H. Zwillich5 and J. D. Bradley5.
1Teaching Hospital of the University of Hamburg, Hamburg, Germany, 2Tampa Medical Group, P.A., Tampa, FL, 3Hanyang University Hospital, Seoul, 4Pfizer Inc., Groton, NJ, 5Pfizer Inc., Groton, CT, 6Pfizer Inc., Tokyo, Japan
Conclusion: Treatment with tofacitinib at doses of 5 or 10 mg BID in pts with RA demonstrated a well-tolerated safety profile and sustained long-term efficacy over a 36-mo period.
An another candidate who could be successful, is fostamatinib, a SYK inhibitor. At eular 2011 Baluom pointed out at the OSKIRA study.
[eular 2011 / SAT0247] PHARMACOKINETICS OF FOSTAMATINIB, A NOVEL SYK INHIBITOR, IN HEALTHY HUMAN SUBJECTS FOLLOWING SINGLE AND MULTIPLE ORAL DOSING
M. Baluom et al.
Conclusions: … and is currently being evaluated in phase 3 clinical studies (OSKIRA trials) in RA.

Further studies were presented at the ACR 2011. Also noteworthy is a short B cell depletion which was seen under fostamatinib.
[ACR 2011 / SUN420]
Effects of the Oral SYK Inhibitor, Fostamatinib (R788), on Health-related Quality of Life in a Phase II Study of Active Rheumatoid Arthritis.
Michael E. Weinblatt1, Arthur Kavanaugh2, Mark C. Genovese3, David A. Jones4, Theresa K. Musser5, Elliott B. Grossbard5 and Daniel B. Magilavy5.
1Brigham and Women’s Hospital, Boston, MA, 2University of California San Diego, San Diego, CA, 3Stanford University, Palo Alto, CA, 4AstraZeneca, Macclesfield, United Kingdom, 5Rigel Pharmaceuticals, SouthSan Francisco, CA
Conclusion: In this phase II study, 100 mg bid fostamatinib significantly improved HRQL outcomes including physical function, pain, fatigue, and overall physical health status. Phase III clinical trials of fostamatinib in RA are in progress.
[ACR 2011 / TUE1744]
Syk Inhibition with Fostamatinib Leads to Transitional B Lymphocyte Depletion.
Chungwen Wei, Paul M. Barr, Julia Schaefer-Cutillo, John Jung,
James Roger, Jennifer L. Kelly, Alex Rosenberg, Jonathan W. Friedberg and In˜aki Sanz. University of Rochester, Rochester, NY
[ACR 2011 / WED2594]
Longer-Term Safety of Fostamatinib (R788) in Patients with Rheumatoid Arthritis—Analysis of Clinical Trial Data From up to 2 Years of Exposure.
Arthur Kavanaugh1, Michael E. Weinblatt2, Mark C. Genovese3,Theresa K. Musser4, Elliott B. Grossbard4, Daniel B. Magilavy4, SallyHollis5, Eveline Wesby van-Sway5 and David Millson5.
1University of California San Diego, San Diego, CA, 2Brigham and Women’s Hospital, Boston, MA, 3Stanford University, Palo Alto, CA, 4Rigel Pharmaceuticals, South San Francisco, CA, 5AstraZeneca, Macclesfield, United Kingdom
Conclusion: No new significant safety signals were identified with longer-term dosing of fostamatinib. Biologic refractory pts on a background of mixed DMARDs had a higher incidence rate of AEs, SAEs, and SIEs compared to MTX inadequate responders on background MTX; further confounding factors may play a role.3 This will be explored in ongoing phase III studies.

Summary

To sum up, we can rely on a number of classic DMARDs, TNF-alpha inhibitors, biologics with other modes of action; soon, the range will be expanded by other biologics (without new modes of action), biosimilars, and the small molecules.