Wie viel Methotrexat ist am besten?

Methotrexat [MTX] ist in der Regel gut verträglich, aber jeder Rheumatologe kennt eine Gruppe Patienten, die nach einer Weile nur die Packung, Spritze oder Tablette sehen müssen, um eine nennenswerte Übelkeit zu bekommen. Deshalb ist es umso wichtiger, die niedrigste sinnvolle Dosierung anzuwenden, um eine bessere Verträglichkeit auch bei dieser Patientengruppe zu erreichen. Darüber hinaus gibt es auch andere Tricks, um die Verträglichkeit zu bessern, wie z.B. die Gabe von Folsäure und hier im Blog beschriebene Maßnahmen [1].

S.A. Bergstra und Kollegen legten eine Metaanalyse vor [2]: „ Meta-regression of a dose-response relationship of methotrexate in mono- and combination therapy in DMARD naive early rheumatoid arthritis patients” [Meta-Regression einer Dosis-Wirkungs-Beziehung von Methotrexat in Mono- und Kombinationstherapie bei DMARD naiven Patienten mit früher rheumatoider Arthritis“]. Die Metaanalyse basiert auf 31 Studien mit insgesamt 5589 Patienten. Hier ist jedoch schon ein Unterschied zu deutscher Praxis anzumerken – international wird häufiger Methotrexat als Tablette eingesetzt. In Deutschland wird die subkutane Injektion vorgezogen. Die Studie deutet darauf hin, dass es nur wenig kurzfristigen Nutzen bringt, mit einer hohen im Vergleich zu einer niedrigen Methotrexat-Dosis zu beginnen. Als hoch würde man eine Dosis von 20-30 mg ansehen.

Interessant ist nun eine Studie vom M. Schiff und Kollegen, die auf dem ACR Kongress im Jahr 2015 vorgestellt wurde [3]: „Oral to Subcutaneous Methotrexate Dose-Conversion Strategies in the Treatment of Rheumatoid Arthritis“ [Perorale und subkutane Methotrexat-Dosis-Konversions-Strategien bei der Behandlung von Rheumatoider Arthritis]. Die Studie zeigte zunächst etwas wenig Aufregendes, nämlich dass die Aufnahme nach der Injektion unter die Haut höher ist als die Aufnahme über den Magen-Darm-Trakt durch die Tablette. Das Aufregende war die Aufnahme über 15 mg hinaus. Bis 15 mg waren die Kurven zu den verschiedenen parallel, danach aber kippt die Kurve für die orale Aufnahme von MTX – ob die Studienpatienten 15 oder 25 mg geschluckt hatten, war völlig unerheblich. Die Kurve für die subkutane Gabe steigt mit der Dosis weiter an, flacht aber über 20 mg langsam ab. Am besten schauen Sie sich die Kurve in der Originalveröffentlichung an [3].

Was heißt das für uns? Man kann erfolgreich eine Therapie mit niedrig dosiertem MTX durchführen. Die Dosis ist allerdings eine individuelle Entscheidung. Die muss der Rheumatologe mit Ihnen absprechen. Am Rheinischen Rheuma Zentrum (wahrscheinlich wie an anderen Zentren und Praxen auch) ist eine Dosis von 15 mg Methotrexat s.c. die häufigste Dosierung

Links:

[1] http://rheumatologe.blogspot.de/2016/07/methotrexate-und-wasserung.html

[2] https://www.ncbi.nlm.nih.gov/pubmed/27992656

[3] http://acrabstracts.org/abstract/oral-to-subcutaneous-methotrexate-dose-conversion-strategies-in-the-treatment-of-rheumatoid-arthritis/

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WIN Olokizumab

I’ve just noticed that people have been interested in my article from 2013 “Olokizumab – any new developments?” I therefore adopted the WIN (=what is new?) from the ACR meeting sessions.

To tell the story in short, let me begin a little bit earlier than at “what is new?”. As nothing on olokizumab appeared at the EULAR meeting in Madrid in June 2013, I wondered: “Nothing! / Very strange as olokizumab targets interleukin-6 (IL-6). … Postponed or abandoned?” In July 2013 there had been an announcement by UCB: “UCB out-licenses RA drug olokizumab to Russia's R-Pharm”.

In 2014 I thought that olokizumab had been abandoned as nothing had been published at the EULAR 2014 Meeting in Paris.

MC Genovese and colleagues published: “Efficacy and safety of olokizumab in patients with rheumatoid arthritis with an inadequate response to TNF inhibitor therapy: outcomes of a randomised Phase IIb study” in Annals of the Rheumatic Diseases (2014).

MC Genovese and colleagues (other group of researchers) published at the ACR 2015 Meeting in San Francisco: “Long-Term Safety and Efficacy of Olokizumab in Patients with Moderate-to-Severe Rheumatoid Arthritis Who Have Previously Failed Anti-TNF Treatment“. The researchers looked at data from Western and Asian patients. Conclusion: “OKZ [OLOKIZUMAB] was well-tolerated, with an expected safety profile for this class of agent. Reductions in disease activity were sustained to Wk48. These results support the development of OKZ for the treatment of moderate-to-severe RA in Western and Asian pts.”

These recent studies aren’t so interesting in the results, but still there is a story being told. UCB still hasn’t given up and keeps a low fire burning. I doubt that olokizumab will be approved as a drug against rheumatoid arthritis.

References:

Olokizumab – any new developments?

http://rheumatologe.blogspot.de/2013/09/olokizumab-any-new-developments.html

UCB out-licenses RA drug olokizumab to Russia's R-Pharm

http://www.pharmatimes.com/article/13-07-08/UCB_out-licenses_RA_drug_olokizumab_to_Russia_s_R-Pharm.aspx

Newer Biologics at the EULAR 2014 Meeting in Paris

http://rheumatologe.blogspot.de/2014/06/newer-biologics-at-eular-2014-meeting.html

Genovese MC, Fleischmann R, Furst D , Janssen N , Carter J, Dasgupta B , Bryson J , Duncan B, Zhu W, Pitzalis C, Durez P, Kretsos K. Efficacy and safety of olokizumab in patients with rheumatoid arthritis with an inadequate response to TNF inhibitor therapy: outcomes of a randomised Phase IIb study. Ann Rheum Dis. 2014 Sep;73(9):1607-15. doi: 10.1136/annrheumdis-2013-204760. Epub 2014 Mar 18. http://www.ncbi.nlm.nih.gov/pubmed/24641941

Genovese MC, Fleischmann R, Tanaka Y, Furst DE, Yamanaka H, Joshi R, Zhu W, Shao J, Mashimo H, Takeuchi T. Long-Term Safety and Efficacy of Olokizumab in Patients with Moderate-to-Severe Rheumatoid Arthritis Who Have Previously Failed Anti-TNF Treatment [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). http://acrabstracts.org/abstract/long-term-safety-and-efficacy-of-olokizumab-in-patients-with-moderate-to-severe-rheumatoid-arthritis-who-have-previously-failed-anti-tnf-treatment/. Accessed February 17, 2016.

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BI 655066 (a humanized IgG1 monoclonal antibody) at the ACR 2015 meeting in San Francisco

P.J. Mease mentioned IL-23 as a target in psoriatic arthritis in an article in Current Opinion in Rheumatology (Curr. Opin. Rheumatol) and he stressed the importance of “having effective medicines with an alternative mechanism of action [, which] will improve our ability to diminish disease activity impact on patient lives.”

And recently I’ve read an article, titled: “Boehringer says anti-IL-23 drug beats Stelara [Ustekinumab] in psoriasis trial”, in which we’re told: “New data from a phase II trial of Boehringer Ingelheim's psoriasis candidate BI 655066 back up earlier results showing it is more effective than a rival drug from Johnson & Johnson.” Well, this article talks about psoriasis and not of psoriatic arthritis.

But I guess, you’re also interested in hearing more about this potential drug.

Kim Papp and colleagues presented a phase 2 study at the ACR 2015 Annual Meeting in San Francisco [abract No. 2144]: “Efficacy and Safety of Different Dose Regimens of a Selective IL-23p19 Inhibitor (BI 655066) Compared with Ustekinumab in Patients with Moderate-to-Severe Plaque Psoriasis with and without Psoriatic Arthritis [PsA]”. (With and without!) BI 655066 is a humanizedIgG1 MAB, which selectively inhibits IL-23p19. “166 patients were randomly assigned (1:1:1:1 ratio) to receive subcutaneous injections of one of three dosage regimens of BI 655066 (18 mg single dose at Week 0; 90 or 180 mg at Weeks 0, 4, and 16), or ustekinumab (45 or 90 mg, based on weight, at Weeks 0, 4, and 16).” The primary endpoint of PASI 90 response at Week 12 was achieved by up to 81.0 of BI 655066 patients and 40.0% of ustekinumab patients. There were only 46 (27.7%) patients with PsA “(either previously diagnosed by rheumatologist [n=13] or suspected by investigator [n=33])”, who nevertheless showed a good pain reduction (VAS). Conclusion: “Selective blockade of IL-23p19 with BI 655066, in the 90 mg and 180 mg arms, were associated with PASI responses superior to ustekinumab in patients with moderate-to-severe plaque psoriasis. Treatment with BI 655066 or ustekinumab was associated with numeric improvement in pain-VAS in patients with diagnosed or suspected PsA. Further studies are needed to assess long-term efficacy and safety of BI 655066 in both psoriasis and PsA.”

I think in treating skin psoriasis dermatologist are beyond PASI90, so I’d call 81% achieving PASI90 good, but not outstanding. There were only 28% of patients with psoriatic arthritis in the study and furthermore only a very small number of the patient (N=13) of the whole cohort (N=166), which amount to a meagre 8% of patients, were properly diagnosed by a rheumatologist. There has been a pain reduction, but that isn’t enough to judge the efficacy of BI 655066 against signs and symptoms of psoriatic arthritis. As the authors stated: “Further studies are needed”. So, we have to wait for Boehringer to sponsor a proper study on psoriatic arthritis.

References:

Mease PJ Inhibition of interleukin-17, interleukin-23 and the TH17 cell pathway in the treatment of psoriatic arthritis and psoriasis [abstract]. Curr Opin Rheumatol. 2015 Mar;27(2):127-33. doi: 10.1097/BOR.0000000000000147. http://www.ncbi.nlm.nih.gov/pubmed/25599143

Boehringer says anti-IL-23 drug beats Stelara in psoriasis trial - http://www.pmlive.com/pharma_news/boehringer_says_anti-il-23_drug_beats_stelara_in_psoriasis_trial_837989.

Papp K, Menter A, Sofen H, Tyring S, Lacour JP, Berner B, Bennett N, Aslanyan S, Flack M, Scholl P. Efficacy and Safety of Different Dose Regimens of a Selective IL-23p19 Inhibitor (BI 655066) Compared with Ustekinumab in Patients with Moderate-to-Severe Plaque Psoriasis with and without Psoriatic Arthritis [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). http://acrabstracts.org/abstract/efficacy-and-safety-of-different-dose-regimens-of-a-selective-il-23p19-inhibitor-bi-655066-compared-with-ustekinumab-in-patients-with-moderate-to-severe-plaque-psoriasis-with-and-without-psoriatic-a/. Accessed February 11, 2016.

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Monoklonale Antikörper nach dem Kongress der amerikanischen Gesellschaft für Rheumatologie (ACR) in San Francisco (2015)

Ich habe in den letzten Wochen bereits ausführlich in Englisch über die wissenschaftlichen Erkenntnisse beim Jahreskongress des American College of Rheumatology 2015 in San Francisco berichtet. Der ACR 2015 der europäische Kongress EULAR 2015 sind die großen Kongresse in der Welt der Rheumatologie gewesen. Auf diesen Kongressen werden die neuesten Studien vorgestellt und mindestens als Zusammenfassung zugänglich gemacht.

Im folgenden Text sind die Links Verweise auf diesen Blog, aber auf die Artikel in Englisch.

Monoklonale Antikörper

Monoklonale Antikörper sind Biologika, d.h. sie werden in Zellkulturen hergestellt. Sie tragen die Enddung  „…mab“ im Substanznamen (also nicht im Namen des Präparates) und das steht für „monoclonal antibody“. Am Substanznamen kann man erkennen, welcher Herkunft das Protein ist, gegen das sich der Antikörper richtet: Antikörper von der Maus tragen die Endung –omab, von Primaten die Endung –imab, chimäre Antikörper (ein Teil des Antikörpers ist Mausprotein) die Endung –ximab, humanisierte Antikörper die Endung, humane Antikörper die Endung –umab. Beispiele aus der Rheumatologie sind: Adalimumab, Belimumab, Certolizumab, Golimumab, Infliximab, Rituximab, Tocilizumab, Secukinumab, Ustekinumab.  In der Entwicklung sind: Brodaluma, Mavrilimumab, Sirukumab und weitere mehr.

Mavrilimumab

Auf dem ACR 2015 wurden zwei Studien zu Mavrilimumab vorgestellt. Was fehlt noch für eine Zulassung? Es gibt noch keine Phase-3-Studie und noch keine Daten zur Hemmung der radiologischen Progression. Meine Vermutung ist, dass wir warten müssen, bis 104 Wochen Daten veröffentlicht werden. Aber ich war bereits skeptisch und im Laufe der Zeit bin ich noch skeptischer geworden. Wir haben auch nichts mehr von MOR103, einem anderen humanen, monoklonalen Antikörper gegen Granulozyten-Makrophagen-Kolonie-stimulierender Faktor-Rezeptor-α (GM-CSFR-α) gehört. Ich hoffe allerdings immer noch, dass dieses Konzept aufgeht, da wir einen Mangel an Biologika mit alternativen Wirkweisen haben, aber überzeugt bin ich immer noch nicht. Ich hoffe, dass dies im nächsten Jahr ändern wird. Link zum Artikel auf Englisch: http://rheumatologe.blogspot.de/2015/11/mavrilimumab-at-acr-2015-meeting-in-san.html

Secukinumab

Es wurden mehr als 10 Publikationen über Secukinumab auf der Jahrestagung ACR 2015 in San Francisco vorgestellt. Secukinumab richtet sich gegen den Interleukin-17A-Rezeptor. Secukinumab stand bereits unter dem Namen Cosentyx in Deutschland für die Indikation von mittelschwerer bis schwerer Plaque-Psoriasis zur Verfügung. Nach dem Kongress und zwar seit dem 26.11.2015 ist Cosentyx in Deutschland auch in den Indikationen Psoriasis-Arthritis und Morbus Bechterew zugelassen. Link: http://rheumatologe.blogspot.de/2015/11/secukinumab-at-acr-2015-meeting-in-san.html.

Sarilumab

Es gab einige Veröffentlichungen zu Sarilumab auf dem ACR 2015 in San Francisco. Sarilumab ist ein monoklonaler Antikörper gegen IL-6, einem Botenstoff (Zytokin). Ich denke, dass die Anzahl der Studien darauf hindeutet, dass Sanofi Sarilumab auf den Markt bringen will; aber es ist noch zu früh, um für eine Zulassung der FDA zu beantragen. Ich verfolge die Entwicklung rund um Sarilumab seit ein paar Jahren. Ich hoffe immer noch, dass das Medikament auf den Markt kommt. Aber ... brauchen wir Sarilumab? Was könnte Sarilumab uns geben, das wir nicht von Tocilizumab bekommen? Werde ich meine IL-6-Inhibitor-Patienten in zwei Gruppen aufteilen? Im Moment kann ich diese Fragen nicht beantworten. Und wir benötigen immer noch Daten über die radiologische Progression. Link: http://rheumatologe.blogspot.de/2015/11/sarilumab-at-acr-2015-meeting-in-san.html.

Tregalizumab

Es hat war eine Veröffentlichung zu Tregalizumab auf dem ACR 2015 in San Francisco gegeben. Tregalizumab (BT-061) ist ein humanisierter, anti-CD4-mAb und induziert selektiv Treg-Aktivierung in vitro.  Es scheint ein interessantes Konzept zu sein; die Autoren der Studie weisen darauf hin: "In früheren Studien wurde vorgeschlagen, die Wirksamkeit bei RA in Dosen ≥25 mg subkutan (SC).“ Aber lassen Sie uns zu den düsteren Wahrheiten der Studie kommen. Die Autoren schlussfolgerten aus ihren Daten: "Keine der getesteten Dosen von Tregalizumab zeigte eine signifikante Wirksamkeit in Hinsicht auf die Verbesserung von Zeichen und Symptomen einer aktiven rheumatoiden Arthritis in Woche 12 und 24 (basierend auf ACR20) ...“. Bedeutet das nun, dass Tregalizumab aufgegeben werden sollte? Ich meine nicht. Wahrscheinlich wird das Team um Ronald van Vollenhoven eine neue Idee vorstellen, wie das Konzept doch funktionieren kann; vielleicht in Form einer Kombination.

Link: http://rheumatologe.blogspot.de/2015/11/tregalizumab-at-acr-2015-meeting-in-san.html.

Sirukumab

Es hat eine Veröffentlichung zu Sirukumab auf dem ACR 2015 in San Francisco gegeben. Sirukumab ist ein humaner MAB, der IL-6 bindet und für die Behandlung der rheumatoiden Arthritis entwickelt wurde. Also würde Sirukumab sich mit Tocilizumab und Sarilumab sich messen müssen. Dem Sponsor scheint aufgefallen zu sein, dass er der dritte Hersteller sein würde, der einen Anteil vom Tortenstück IL-6 bekommen will. Ich sehe einen Mangel an Engagement. Und tatsächlich sehe ich auch keinen medizinischen Grund, einen weiteren IL-6-Hemmer zu bekommen. Link: http://rheumatologe.blogspot.de/2015/11/sirukumab-at-acr-2015-meeting-in-san.html.

Brodalumab

Es hat eine Veröffentlichung zu Brodalumab auf dem ACR 2015 gegeben. Brodalumab ist ein anti-IL-17-Rezeptor MAB, ein viel versprechendes neues Prinzip am Horizont gegen Psoriasisarthritis wird der MAB schön geredet. Aber dann nur eine Studie! Die Auswertung der klinischen Daten der Phase-2-Studie ist nicht sehr überzeugend. Wo ist Daten über die radiologische Progression nach zwei Jahren? Der Sponsor scheint nicht die Agenda voranzutreiben. Ich sehe keinen Grund, warum nicht für eine Phase-3-Studie Patienten rekrutiert werden. Es sei denn, man wartet darauf, wie erfolgreich Secukinumab ist. Link: http://rheumatologe.blogspot.de/2015/11/brodalumab-at-acr-2015-meeting-in-san.html.

Certolizumab

Es gab 14 Publikationen zu Certolizumab auf der Jahrestagung ACR 2015 in San Francisco. Ich zitiere im englischen Text zwei Studien. Am 20. November bekam UCB eine positive Stellungnahme vom CHMP (Ausschuss für Humanarzneimittel) der EMA (European Medicines Agency) für Certolizumab Pegol (Cimzia) bei schwerer, aktiver und progressiver rheumatoider Arthritis DMARD-naive Patienten zu behandeln. D.h. man kann das Präparat sehr viel früher einsetzen. Link: http://rheumatologe.blogspot.de/2015/12/certolizumab-part-1-at-acr-2015-meeting.html.

Tanezumab

Es hat eine Veröffentlichung zu Tanezumab bei Arthrose(!!!) auf der Jahrestagung ACR 2015 in San Francisco gegeben. Nach 2013 haben wir nicht viel über Tanezumab gehört, weil die FDA einen teilweisen klinischen Stopp der Studien außerhalb von Krebserkrankungen aufgrund von unerwarteten Nebenwirkungen dem Hersteller auferlegt hatte. Pfizer kündigte Anfang dieses Jahres an, die Phase 3 Studien zu chronischen Schmerzen für Tanezumab wieder aufzunehmen. Tanezumab ist ein humanisierter monoklonaler Antikörper, der selektiv auf den Nervenwachstumsfaktor (NGF), einem Regulator der Schmerzverarbeitung und Empfindlichkeit, gerichtet ist. Ich habe meine Probleme mit dem Wiedererscheinen von Tanezumab in der Behandlung von Arthrose-Schmerzen. Die Studien dauerten nicht lange genug an, um die langfristige Sicherheit zu bewerten. Die Auswertung der alten Daten sagt uns nicht, ob Tanezumab besser als Naproxen, Celecoxib oder Oxycodon ist. Sie sagt uns, dass Tanezumab besser als Placebo ist. Hurra! Aber mal sehen, ob das Phase-3-Programm belastbare Daten bringt. Link: http://rheumatologe.blogspot.de/2015/12/tanezumab-in-osteoarthritis-at-acr-2015.html.

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CGEN-15001 at the ACR 2015 Meeting in San Francisco

There has been one publication on CGEN-15001 at the ACR 2015 Annual Meeting in San Francisco. “CGEN-15001 is an Fc fusion protein composed of the extracellular domain of a novel B7-like protein.” The B7 proteins are found on activated APCs (antigen presenting cells). Interestingly B7 may act coinhibitory and costimulatory. CGEN-15001 has already appeared with mouse model studies at the ACR meetings in 2012 and 2014; please look under references. CGEN-15001 haa shown efficacy in these mouse models of rheumatoid arthritis and psoriasis.

Iris Hecht and colleagues presented: “CGEN-15001, a Novel B7-like Protein, Controls Inflammation in a Translational Rheumatoid Arthritis (RA) Assay and Induces Treg Driven Long-Term Remission in an Autoimmune Disease Model”. In “Background” we read: “The therapeutic potential of CGEN-15001 for RA was studied in co-cultures of cytokine activated T cells (TcK) and macrophages (Mϕ) from RA patients and healthy donors. Such co-cultures mimic the interaction of cells in RA synovium that lead to aberrant cytokine production and provide a translational tool to evaluate potential therapies.” Methods: “CD4+ T cells and monocytes were isolated from healthy donors or RA patients’ blood and cultured for 6 days with TNFα, IL-6 and IL-15 to induce TcK or with M-CSF to induce Mϕ differentiation, respectively. Autologous TcK and Mϕ were co-cultured in the presence of CGEN-15001 or controls for 24hrs. Cytokines were evaluated by luminex. […]” Results: “In synovial-like Mϕ: TcK co-cultures, CGEN-15001 abrogated secretion of pro-inflammatory cytokines including TNFα, IL-17, IFNγ, GM-CSF, RANTES and MIP-1α. Similarly, inhibition in TNFα secretion was observed in co-cultures from RA patients’ cells. […]” I’ve omitted the parts on an experimental autoimmune encephalomyelitis. Conclusion: “The anti-inflammatory activity of CGEN-15001 in a translational assay mimicking RA synovium supports its therapeutic potential in RA. The long remission maintained by active Tregs in the EAE model supports a novel mechanism of re-establishing tolerance to autoantigens. Therefore, these results support the therapeutic potential of CGEN-15001 to reduce inflammation and maintain long-term remission in autoimmune diseases and RA in particular.”

These results are complicated, but as activated t-cells and macrophages play a crucial role in synovial inflammation, CGEN-15001 is a promising drug candidate for rheumatoid arthritis but also other autoimmune diseases. I hope that Compugen will start phase 1 studies soon.

References:

https://en.wikipedia.org/wiki/B7_(protein)

Iris Hecht, Kay McNamee, Ilan Vaknin, Anat Oren, Joseph R. Podojil, Galit Rotman, Eyal Neria, Stephen D. Miller and Richard O. Williams: CGEN-15001, a Novel Negative Costimulatory Fusion Protein Is Effective in the Collagen-Induced Arthritis Mouse Model of Rheumatoid Arthritis. 2012 ACR/ARHP Annual Meeting: http://acrabstracts.org/abstract/cgen-15001-a-novel-negative-costimulatory-fusion-protein-is-effective-in-the-collagen-induced-arthritis-mouse-model-of-rheumatoid-arthritis/.

Iris Hecht, Kay McNamee, Aviad Keren, Joseph R. Podojil, Ilan Vaknin, Anat Oren, Galit Rotman, Eyal Neria, Stephen D. Miller, Amos Gilhar and Richard O. Williams: CGEN-15001, a Novel Immunomodulatory Fusion Protein of the B7 Family Induces Immune Tolerance and Shows Efficacy in Mouse Models of Rheumatoid Arthritis and Psoriasis. 2014 ACR/ARHP Annual Meeting: http://acrabstracts.org/abstract/cgen-15001-a-novel-immunomodulatory-fusion-protein-of-the-b7-family-induces-immune-tolerance-and-shows-efficacy-in-mouse-models-of-rheumatoid-arthritis-and-psoriasis/.

Hecht I, Gilmour A, Tange C, McIntyre D, Podojil JR, McNamee K, Rotman G, Neria E, Kurowska-Stolarska M, Williams RO, Miller SD, McInnes IB. CGEN-15001, a Novel B7-like Protein, Controls Inflammation in a Translational Rheumatoid Arthritis (RA) Assay and Induces Treg Driven Long-Term Remission in an Autoimmune Disease Model [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). http://acrabstracts.org/abstract/cgen-15001-a-novel-b7-like-protein-controls-inflammation-in-a-translational-rheumatoid-arthritis-ra-assay-and-induces-treg-driven-long-term-remission-in-an-autoimmune-disease-model/. Accessed December 11, 2015.

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Netrin-1 at the ACR 2015 Meeting in San Francisco

There have been three publications on Netrin-1 at the ACR 2015 Annual Meeting in San Francisco. Netrin-1 plays a role in leukocyte function and inflammation or: “Netrin-1 is a laminin-like matrix protein that acts as a chemorepulsant and which is expressed during and required for osteoclast differentiation. In other settings Netrin1 has been reported to play a pathogenic role during inflammation by preventing macrophage egress from inflamed sites.” I like the word egress; I guess Ira Tabas used it for the first time describing macrophage function. What do the studies tell us?

Aranzazu Mediero and colleagues presented: “Netrin-1 and Its Receptor Unc5b Are Novel Targets for the Treatment of Inflammatory Arthritis.” Conclusion: “Blockade of Netrin-1 and its receptor Unc5b by treatment, in vivo, with murine monoclonal antibodies prevents bone destruction and K/BxN serum transfer-induced arthritis. Netrin-1 may be a novel therapeutic target for inflammatory bone destruction and other forms of osteoclast-mediated bone resorption.” Which means, we could expect from this principle a drug against erosive rheumatoid arthritis and would have to look closely if inflammation per se would be reduced.

The second study was also presented by Aranzazu Mediero: “Stimulation of the Adenosine A2A Receptor (A2AR) Regulates the Expression of Netrin-1 (Ntn1) and Its Receptors (Unc5b, DCC) and Inhibits Wear Particle-Induced Inflammatory Osteolysis in a Model of Joint Prosthesis Loosening.” Conclusion: “Ntn1 expression on macrophages and OC plays a central role in wear particle-induced osteolysis and adenosine A2AR stimulation downregulates Ntn1expression and inhibits bony destruction at sites of wear particle-induced osteolysis. Moreover, Ntn1-unc5b and A2AR stimulation reciprocally diminish signaling by each other. These results suggest that targeting Ntn1 directly or via stimulation of adenosine A2AR may be a novel approach to prevent osteolysis and joint prosthesis loosening.”

Also the third study was presented by Aranzazu Mediero: “Netrin-1 and Its Receptors Unc5b and DCC May be Useful Targets for Preventing Multiple Myeloma Bone Lesions”. Conclusion: “Anti-netrin-1 and -Unc5b treatment decreases osteoclast formation in a murine model of myeloma and decreases myeloma bone lesions. Targeting Netrin-1 or its receptor Unc5b may be a novel therapeutic approach for multiple myeloma.”

The researchers around Aranzazu Mediero presented data on Netrin-1, which showed to influence inflammatory bone destruction and resorption. Netrin-1 might  be a target to treat rheumatoid arthritis as well as other diseases.

References:

Mediero A, Wilder T, Cronstein B. Netrin-1 and Its Receptor Unc5b Are Novel Targets for the Treatment of Inflammatory Arthritis [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). http://acrabstracts.org/abstract/netrin-1-and-its-receptor-unc5b-are-novel-targets-for-the-treatment-of-inflammatory-arthritis/. Accessed December 11, 2015.

Mediero A, Ramkhelawon B, Perez-Aso M, Moore K, Cronstein B. Stimulation of the Adenosine A2A Receptor (A2AR) Regulates the Expression of Netrin-1 (Ntn1) and Its Receptors (Unc5b, DCC) and Inhibits Wear Particle-Induced Inflammatory Osteolysis in a Model of Joint Prosthesis Loosening [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). http://acrabstracts.org/abstract/stimulation-of-the-adenosine-a2a-receptor-a2ar-regulates-the-expression-of-netrin-1-ntn1-and-its-receptors-unc5b-dcc-and-inhibits-wear-particle-induced-inflammatory-osteolysis-in-a-model-o/. Accessed December 11, 2015.

Mediero A, Wilder T, Cronstein B. Netrin-1 and Its Receptors Unc5b and DCC May be Useful Targets for Preventing Multiple Myeloma Bone Lesions [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). http://acrabstracts.org/abstract/netrin-1-and-its-receptors-unc5b-and-dcc-may-be-useful-targets-for-preventing-multiple-myeloma-bone-lesions/. Accessed December 11, 2015.

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Bay 11-7085 at the ACR 2015 Meeting in San Francisco

There has been one publication on Bay 11-7085 at the ACR 2015 Annual Meeting in San Francisco. NF-κB and other transcription factors seem to play major roles in the regulation of inflammatory genes. NF-κB is a pivotal regulator of inflammation etc. in rheumatoid arthritis. “BAY 11-7085 is an inhibitor of IκBα phosphorylation that leads to NF-κB inactivation and downregulation of inflammation in mouse model of asthma, in articular chondrocytes as well as in synovial fibroblasts.” BAY 11-7085 has also shown to block TLR4 (Toll-like receptor 4) and ERK expression. So NF-κB is a feasible target in rheumatoid arthritis. If you want to get deeper into this topic, please read the article by Paul Tak and Gary S. Firestein (see link below)

Biserka Relic and colleagues presented: „ Bay 11-7085 Induces Glucocorticoid Receptor Activation and Autophagy to Initiate Human Synovial Fibroblast Cell Death”. Conclusion: “BAY 11-7085 induced human synovial fibroblast autophagy that acts as an agonist to promote BAY 11-7085-induced apoptosis. Furthermore, our results suggest that BAY 11-7085-induced autophagy in synovial fibroblasts is mediated through GR activation and PPAR-γ inactivation.”

Do we get something out of this research right away? Yes, knowledge. But if you wanted a new drug, that’s another story. I think I’ve heard enough talks that mentioned NF-κB, so I think, we eventually will see NF-κB targeted in a therapeutical approach. I don’t think that this will be Bay 11-7085.

References:

Paul P. Tak and Gary S. Firestein: NF-κB: a key role in inflammatory diseases. J Clin Invest. 2001 Jan 1; 107(1): 7–11. doi: 10.1172/JCI11830 PMC198552. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC198552/.

Relic B, Charlier E, Deroyer C, Malaise O, Neuville S, Desoroux A, Gillet P, Malaise MG, de Seny D. Bay 11-7085 Induces Glucocorticoid Receptor Activation and Autophagy to Initiate Human Synovial Fibroblast Cell Death [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). http://acrabstracts.org/abstract/bay-11-7085-induces-glucocorticoid-receptor-activation-and-autophagy-to-initiate-human-synovial-fibroblast-cell-death/. Accessed December 8, 2015.

Tanezumab in Osteoarthritis at the ACR 2015 Meeting in San Francisco

There has been one publication on tanezumab in osteoarthritis at the ACR 2015 Annual Meeting in San Francisco. After 2013 we didn’t hear much about tanezumab, because the US FDA had imposed a partial clinical hold on studies due to unexpected adverse events. Pfizer announced earlier this year to resume phase 3 studies on chronic pain for tanezumab (see link below). “Tanezumab is a humanized monoclonal antibody that selectively targets nerve growth factor (NGF), a regulator of pain processing and sensitivity.”

P.G. Conaghan talked on: “What is new: osteoarthritis” at the 2013 EULAR Annual Meeting in Madrid. “New evidence supporting the analgesic efficacy of anti-nerve growth factor monoclonal antibodies has been provided with another RCT employing tanezumab; managing potential side effects of this class remains problematic.”

Leslie Tive and colleagues, who worked in the original studies, presented: “Pooled Efficacy and Safety from Phase 3 Controlled Studies of Tanezumab in Patients with Osteoarthritis”. Methods: “Four, phase 3 placebo (PBO)-controlled clinical trials of TNZ in patients with moderate-to-severe OA of the knee or hip completed before the clinical hold were pooled to evaluate efficacy and 9 phase 3 controlled OA studies were pooled to evaluate safety. […]”. Pooled data from older studies … “Patients received 1 to 3 injections of intravenous TNZ 2.5, 5, or 10 mg every 8 weeks, naproxen 500 mg twice daily (BID), celecoxib 100 mg BID, oxycodone controlled release 10-40 mg BID, or PBO.” In Results we read: “TNZ 10 mg but not 2.5 or 5 mg was associated with a higher rate of rapidly progressive OA than active comparator.” Conclusion: “TNZ provides significant improvement of pain, physical function, and PGA of OA. Non-joint-related safety was similar in patients treated with TNZ 2.5-10 mg versus active comparator but increased versus PBO-treated patients.”

I have my problems with the reappearance of tanezumab in osteoarthritis. A monoclonal autoantibody in osteoarthritis pain (not to treat structural deterioration)! The studies didn’t last long enough to evaluate long term safety. This evaluation doesn’t tell us, if tanezumab is better than naproxen, celecoxib, or oxycodone. It tells us that it’s better than placebo. Hooray! But let’s see if the phase 3 program comes up with stressable data.

References:

Pfizer And Lilly Preparing To Resume Phase 3 Chronic Pain Program For Tanezumab http://www.pfizer.com/news/press-release/press-release-detail/pfizer_and_lilly_preparing_to_resume_phase_3_chronic_pain_program_for_tanezumab

P.G. Conaghan: “WHAT IS NEW: OSTEOARTHRITIS”. Abstract No. SP0098. DOI: 10.1136/annrheumdis-2015-eular.6817 / http://ard.bmj.com/cgi/content/long/74/Suppl_2/25-c

Tive L, Radin D, Bello A, Nguyen H, Brown MT, West CR, Verburg KM. Pooled Efficacy and Safety from Phase 3 Controlled Studies of Tanezumab in Patients with Osteoarthritis [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). http://acrabstracts.org/abstract/pooled-efficacy-and-safety-from-phase-3-controlled-studies-of-tanezumab-in-patients-with-osteoarthritis/. Accessed December 7, 2015.

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Adipokines at the ACR 2015 Meeting in San Francisco

There have been some publications on adipokines at the ACR 2015 Annual Meeting in San Francisco, but I’ll restrict myself to the two studies related to rheumatoid arthritis.

Adipokines are cytokines and hormones, which are primarily synthesized in white adipose tissue. Some adipokines have already been identified to be associated with bad outcomes in rheumatoid arthritis. Lean people with a normal metabolic function produce anti-inflammatory adipokines, whereas obese people with mild metabolic dysfunction produce anti- and pro-inflammatory adipokines. Obese people with marked metabolic dysfunction produce pro-inflammatory cytokines etc. like TNF-alpha, IL-6, CCL2, CXCL5, leptin, resistin, to name a few.

Adrian Levitsky and colleagues presented: “Adipokines and Insulin-like Growth Factor 1 As Predictors of Clinical and Radiographic Outcomes in Early Rheumatoid Arthritis”. The authors looked at serum levels of adiponectin, leptin, IGF-1, and resistin of patients enrolled in the SWEFOT trial. Conclusion: “Differences in certain adipokines and IGF-1 were associated with clinical and radiographic outcomes within specific treatment groups. Thus, they may be useful predictors and may give insight into pathogenic mechanisms influencing RA outcomes such as high BMI and disease activity.” Please have a look at the charts yourself and you might agree that the first sentence of conclusion is correct, but the rest is speculation. Right now we can’t identify radiographic progressors by adipokines at baseline. But “may be in the future” is strong enough to wish the authors and other teams good luck and persistence.

Rebecca Hasseli and colleagues looked at: “The Influence of Adipokines on the Interaction of Rheumatoid Arthritis Synovial Fibroblasts with Endothelial Cells”. Methods: “Primary RASF [rheumatoid arthritis synovial fibroblasts] and EC [endothelial cells] were stimulated with adiponectin (10 µg/ml), visfatin (100 ng/ml) and resistin (20 ng/ml) as well as with MTX (1.5 µM) and the glucocorticoids prednisolone (1 µM) and dexamethasone (1 µM). […]”Conclusion: „Adipokines have an influence on the cellular expression of adhesion molecules on RASF and EC as well as their interaction. Adipokines increase adhesion of RASF to EC and therefore influence RASF migration. Therapeutics such as glucocorticoids and MTX antagonized these effects, which may represent a mechanism of the protective effects of these drugs observed in patients. […]”

What can we take out of these studies? Knowledge on adipokines will certainly influence our approach to rheumatoid arthritis in the future. I’d like to suggest more effort in psoriatic arthritis and adipokines as in this group of patients the level of metabolic dysfunction is especially high.

References:

Levitsky A, Brismar K, Saevarsdottir S, Hambardzumyan K, Andersson A, van Vollenhoven RF. Adipokines and Insulin-like Growth Factor 1 As Predictors of Clinical and Radiographic Outcomes in Early Rheumatoid Arthritis [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). http://acrabstracts.org/abstract/adipokines-and-insulin-like-growth-factor-1-as-predictors-of-clinical-and-radiographic-outcomes-in-early-rheumatoid-arthritis/. Accessed December 5, 2015.

Hasseli R, Frommer KW, Umscheid T, Schönburg M, Rehart S, Müller-Ladner U, Neumann E. The Influence of Adipokines on the Interaction of Rheumatoid Arthritis Synovial Fibroblasts with Endothelial Cells [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). http://acrabstracts.org/abstract/the-influence-of-adipokines-on-the-interaction-of-rheumatoid-arthritis-synovial-fibroblasts-with-endothelial-cells/. Accessed December 5, 2015.

Chialà A, Rotondo C, Anelli MG, Praino E, Cantarini L, Scioscia C, Giannini M, Lapadula G, Iannone F. Evaluation of Serum Levels of Adipokines and Interleukines in Pericardial Effusion Related to Systemic Sclerosis [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). http://acrabstracts.org/abstract/evaluation-of-serum-levels-of-adipokines-and-interleukines-in-pericardial-effusion-related-to-systemic-sclerosis/. Accessed December 5, 2015.

Korman B, Goncalves Marangoni R, Hinchcliff ME, Shah S, Carns MA, Ramsey-Goldman R, Varga J. Association of Serum Adipokines Adipsin, Adiponectin, and Leptin/Adiponectin Ratio with Systemic Sclerosis [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). http://acrabstracts.org/abstract/association-of-serum-adipokines-adipsin-adiponectin-and-leptinadiponectin-ratio-with-systemic-sclerosis/. Accessed December 5, 2015.

Ferreira da Silva T, Levy Neto M, Caparbo V, Takayama L, Pereira RMR. Abnormal Body Composition in Takayasu Arteritis Patients: Role of Inflammatory Cytokines and Adipokines [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). http://acrabstracts.org/abstract/abnormal-body-composition-in-takayasu-arteritis-patients-role-of-inflammatory-cytokines-and-adipokines/. Accessed December 5, 2015.

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Certolizumab (Part 1) at the ACR 2015 Meeting in San Francisco

There have been 14 publications on certolizumab at the ACR 2015 Annual Meeting in San Francisco. For this blogpost (Part 1) I’ve picked only two studies for a specific reason as you will see later

Michael Weinblatt and colleages presented: “Certolizumab Pegol in Combination with Methotrexate in DMARD-Naïve Patients with Active, Severe, Progressive Rheumatoid Arthritis: Results from a Randomized, Double-Blind, Controlled Phase 3 Study”. The study is called C-EARLY and is a phase 3 study in DMARD-naïve patients with severe, active, progressive rheumatoid arthritis. The primary endpoint has been sustained DAS28(ESR) remission (sREM), defined as DAS28[ESR] ≤ 2.6 at both week 40 and week 52. Certolizumab reached this endpoint at a p value of < 0.001 (OR 2.3). Radiographic progression was assessed by the van der Heijde modified total Sharp score (mTSS). Conclusion: “CZP+MTX treatment of DMARD-naïve pts with active, severe, progressive RA resulted in a greater proportion of pts in sREM and sLDA; greater improvements in RA signs and symptoms; and inhibition of structural damage vs PBO+MTX. Safety profile of CZP+MTX was similar to PBO+MTX.”

Tatsuya Atsumi and colleagues looked at: “Clinical Benefit of 1-Year Certolizumab Pegol Treatment in MTX-Naïve, Early Rheumatoid Arthritis Patients Is Maintained after Discontinuation up to 1 Year”. Conclusion: “The clinical benefit of initial 1-year CZP treatment in MTX-naïve early RA patients was still observed after discontinuing CZP for an additional 1 year while continuing optimized MTX monotherapy.”

At the 20th of November UCB received a positive opinion by CHMP (Committee for Medicinal Products for Human Use ) of EMA (European Medicines Agency) for CIMZIA® (certolizumab pegol) to treat severe, active and progressive rheumatoid arthritis in DMARD-naïve patients. “ The positive opinion was based on period 1 of UCB’s Phase 3 C-EARLY™ study, which found that adding CIMZIA® to optimized methotrexate achieved statistically significant sustained remission and inhibition of radiographic progression (change from baseline in van der Heijde modified total Sharp score) at week 52 in DMARD-naïve patients with early, active RA.” So, I don’t think it will take long until this indication will be approved. We could argue on the differences between DMARD-naïve and MTX-naïve, but all in all, it would make it easier to use a biologic as early as needed.

References:

Weinblatt M, Bingham C, Burmester G, Bykerk V, Furst DE, Mariette X, van der Heijde D, Tatla D, Arendt C, Mountian I, VanLunen B, Emery P. Certolizumab Pegol in Combination with Methotrexate in DMARD-Naïve Patients with Active, Severe, Progressive Rheumatoid Arthritis: Results from a Randomized, Double-Blind, Controlled Phase 3 Study [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). http://acrabstracts.org/abstract/certolizumab-pegol-in-combination-with-methotrexate-in-dmard-naive-patients-with-active-severe-progressive-rheumatoid-arthritis-results-from-a-randomized-double-blind-controlled-phase-3-study/. Accessed December 4, 2015.

Atsumi T, Yamamoto K, Takeuchi T, Yamanaka H, Ishiguro N, Tanaka Y, Eguchi K, Watanabe A, Origasa H, Shoji T, Togo O, Okada T, van der Heijde D, Miyasaka N, Koike T. Clinical Benefit of 1-Year Certolizumab Pegol Treatment in MTX-Naïve, Early Rheumatoid Arthritis Patients Is Maintained after Discontinuation up to 1 Year [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). http://acrabstracts.org/abstract/clinical-benefit-of-1-year-certolizumab-pegol-treatment-in-mtx-naive-early-rheumatoid-arthritis-patients-is-maintained-after-discontinuation-up-to-1-year/. Accessed December 4, 2015.

UCB receives positive EU CHMP opinion for CIMZIA® (certolizumab pegol) http://www.ucb.com/presscenter/News/article/UCB-receives-positive-EU-nbsp-CHMP-opinion-for-CIMZIA-certolizumab-pegol-to-treat-severe-active-and-progressive-rheumatoid-arthritis-in-DMARD-na-ve-patients

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Modified-Release Prednisone at the ACR 2015 Meeting in San Francisco

There has been one study on Modified-Release Prednisone at the ACR 2015 Annual Meeting in San Francisco. I have voiced my concerns about Modified-Release Prednisone before and this study makes me even more confident in my views.

Maurizio Cutolo and colleagues presented: “Efficacy and Safety of Modified-Release Prednisone in Patients with Polymyalgia Rheumatica: Results of a Multicenter, Randomized, Active-Controlled Phase 3 Study”. Methods: “Patients meeting the 2012 EULAR/ACR classification criteria for PMR (excluding US) were randomized to double-blind MR prednisone or IR prednisone 15 mg/day for 4 weeks. MR prednisone/placebo was taken at approx. 10pm and IR prednisone/placebo was taken between 5am and 9am. […]” The duration of the study is too short to say anything about adverse events in long term therapy using glucocorticoids. Comparing “ approx. 10pm” with “between 5am and 9am” looks suspicious as one compares an optimized time slot with one that wasn’t optimized. Why compare approx. 10pm and approx. 5am? Results: “The study randomized 62 patients; 66% female, mean age 69 years. […].” I’d say the study is very low powered. Conclusion: “Although the primary analysis of non-inferiority was not met, the consistently positive and clinically meaningful results for MR prednisone compared with IR prednisone observed in this study provide an indication of a beneficial clinical effect of MR over IR prednisone in patients with PMR, with improvements observed as early as Week 1.”

My own conclusion is different: “Although Modified-Release Prednisone has been given an advantage, the primary analysis of non-inferiority was not met.” Especially morning stiffness, global pain, and CRP didn’t show significant differences (please look at the chart in the abstract). If you really want to test, if the modified-release mechanism has any advantage over prednisone, you would have to give both at the same time in the evening. 

References:

Cutolo M, Hopp M, Liebscher S, Dasgupta B, Buttgereit F. Efficacy and Safety of Modified-Release Prednisone in Patients with Polymyalgia Rheumatica: Results of a Multicenter, Randomized, Active-Controlled Phase 3 Study [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). http://acrabstracts.org/abstract/efficacy-and-safety-of-modified-release-prednisone-in-patients-with-polymyalgia-rheumatica-results-of-a-multicenter-randomized-active-controlled-phase-3-study/. Accessed December 3, 2015.

http://rheumatologe.blogspot.de/2012/11/lodotra-auf-dem-kongress-der.html(Text in German)

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

http://rheumatologe.blogspot.de/2010/06/lodotra-my-problems-with-new-miracle.html

Modified Release Prednisone at the EULAR 2013 http://rheumatologe.blogspot.de/2013/06/modified-release-prednisone-at-eular.html

Lodotra (modified or delayed release prednisone) at the ACR 2013 Meeting in San Diego http://rheumatologe.blogspot.de/2013/11/lodotra-modified-or-delayed-release.html

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Gout (Part 2) at the ACR 2015 Meeting in San Francisco

There has been a multitude of publications on Gout at the ACR 2015 Annual Meeting in San Francisco. I’ve select my personal highlights and updates. The second part in on studies concerning drugs to reduce inflammation or to lower uric acid.

Let’s first look at what’s new on febuxostat.

Nicola Dalbeth and colleagues presented: “Imaging and Safety Assessments Following Treatment with Febuxostat and Placebo for 2 Years in Subjects with Early Gout”. Conclusion: “This first clinical trial in early gout subjects demonstrated that treatment with febuxostat can achieve a significant reduction in synovitis compared to placebo.” They didn’t see any difference in the RAMRIS erosion and bone edema scores, which might be due to the fact of having restricted the study to patients with early gout.

Pierre-Antoine Juge and colleagues looked at: “Efficacy and Safety of Febuxostat in 55 Gouty Patients with Stage 4/5 Chronic Kidney Disease: Results from a Retrospective Multicenter Study”. Conclusion: “Febuxostat appears efficient in gouty patients with stage 4/5 CKD or renal transplants. However, safety data is not yet validated with respect to renal function. Further studies with larger samples are warranted for assessing this issue.” That leaves us much at the point, where we’ve been before.

The next study is on arhalofenate, a novel urate lowering anti flare therapy in gout. “It lowers serum uric acid (sUA) by blocking URAT1, a tubular UA transporter, and reduces gout flares by blocking the local release of IL-1β.”

Alexandra Steinberg and colleagues presented: “A Study to Evaluate the Efficacy and Safety of Arhalofenate for Preventing Flares and Reducing Serum Uric Acid in Gout Patients”. “Subjects [N=239] were randomized 1:2:2:2:2 to placebo, arhalofenate 600 mg or 800 mg, allopurinol 300 mg or allopurinol 300 mg combined with colchicine 0.6 mg.“ Conclusion: “Arhalofenate at 800 mg significantly decreases gout flares when compared to allopurinol 300 mg. There was no statistical difference in flares between arhalofenate 800 mg and allopurinol 300 mg combined with colchicine. Arhalofenate 800 mg also significantly decreased flares when compared to placebo. These results indicate that Arhalofenate has intrinsic anti-inflammatory activities clinically associated with improvement in gout flares. Arhalofenate sUA lowering activity, while significant compared to placebo, was lower than in the allopurinol 300 mg groups. Arhalofenate was well tolerated and appeared safe. Arhalofenate is currently in development for the treatment of gout as a combination therapy with ULT, both to lower serum uric acid and prevent flares.” The idea might be to suggest a single therapy for flares and lowering uric acid, and achieving this with a single drug. It looks more like a marketing stunt, no matter how much effect there is on IL-1β. Maybe arhalofenate is aiming at too much at the same time. Just a thought. It’s much too early to evaluate this. Arhalofenate might be useful in the time after the first / a flare.

There were two studies on adding lesinurad either to febuxostat or the allopurinol. I guess, you’re not too surprised that these combinations work.

Let’s close this 2nd part with a study on canakinumab.

Naomi Schlesinger and colleagues presented: “A 3-Year Follow-up Study of Canakinumab in Frequently Flaring Gouty Arthritis Patients, Contraindicated, Intolerant, or Unresponsive to Nonsteroidal Anti-Inflammatory Drugs and/or Colchicine”. The authors looked at patients, who were radomized in the two phase 3 studies (N=456), of these 272 patients were followed up in extension studies, where re-treatment was initiated after a flare. Conclusion: “Over 3 years, a mean “on demand” dosing of CAN was 2.68 per pt. Efficacy of CAN was demonstrated […]”.

I think both flares and urate lowering therapies were addressed in the studies. Gout still is a challenge. I hope that studies will also look at the problem of adherence to drugs.

References:

Dalbeth N, Saag KG, Palmer W, Choi H, Hunt B, MacDonald P, Thienel U, Gunawardhana L. Imaging and Safety Assessments Following Treatment with Febuxostat and Placebo for 2 Years in Subjects with Early Gout [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). http://acrabstracts.org/abstract/imaging-and-safety-assessments-following-treatment-with-febuxostat-and-placebo-for-2-years-in-subjects-with-early-gout/. Accessed November 16, 2015.

Steinberg A, Chera H, Choi YJ, Martin R, McWherter C, Zhang Y, Boudes P. A Study to Evaluate the Efficacy and Safety of Arhalofenate for Preventing Flares and Reducing Serum Uric Acid in Gout Patients [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). http://acrabstracts.org/abstract/a-study-to-evaluate-the-efficacy-and-safety-of-arhalofenate-for-preventing-flares-and-reducing-serum-uric-acid-in-gout-patients/. Accessed November 16, 2015.

Juge PA, Truchetet ME, Ottaviani S, Vigneau C, Loustau C, Cornec D, Pascart T, Cornec-Legall E, Florien M, Bailly F, Schaeverbeke T, Saraux A, Dieude P, Flipo RM, Jean-Baptiste G, Richette P, Lioté F, Bardin T, Chales GH, Ea HK. Efficacy and Safety of Febuxostat in 55 Gouty Patients with Stage 4/5 Chronic Kidney Disease: Results from a Retrospective Multicenter Study [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). http://acrabstracts.org/abstract/efficacy-and-safety-of-febuxostat-in-55-gouty-patients-with-stage-45-chronic-kidney-disease-results-from-a-retrospective-multicenter-study/. Accessed November 16, 2015.

Saag KG, Bardin T, So A, Khanna P, Storgard C, Baumgartner S, Fung M, Bhakta N, Adler S, Kopicko J, Becker MA. Analysis of Gout Subjects Receiving Lesinurad and Allopurinol Combination Therapy By Baseline Renal Function [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). http://acrabstracts.org/abstract/analysis-of-gout-subjects-receiving-lesinurad-and-allopurinol-combination-therapy-by-baseline-renal-function/. Accessed November 16, 2015.

Dalbeth N, Jones G, Terkeltaub R, Khanna D, Kopicko J, Adler S, Bhakta N, Fung M, Storgard C, Baumgartner S, Perez-Ruiz F. Efficacy and Safety in Patients with Tophaceous Gout Receiving Lesinurad and Febuxostat Combination Therapy: Interim Analysis of an Extension Study [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). http://acrabstracts.org/abstract/efficacy-and-safety-in-patients-with-tophaceous-gout-receiving-lesinurad-and-febuxostat-combination-therapy-interim-analysis-of-an-extension-study/. Accessed November 16, 2015.

Schlesinger N, Bardin T, Bloch M, Lheritier K, Machein U, Junge G, So A, Alten R. A 3-Year Follow-up Study of Canakinumab in Frequently Flaring Gouty Arthritis Patients, Contraindicated, Intolerant, or Unresponsive to Nonsteroidal Anti-Inflammatory Drugs and/or Colchicine [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). http://acrabstracts.org/abstract/a-3-year-follow-up-study-of-canakinumab-in-frequently-flaring-gouty-arthritis-patients-contraindicated-intolerant-or-unresponsive-to-nonsteroidal-anti-inflammatory-drugs-andor-colchicine/. Accessed November 16, 2015.

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