Saturday, July 4, 2020

Hydroxychloroquine and Colchicine in Hand Osteoarthritis at the 2020 EULAR Online Meeting


Hydroxychloroquine and colchicine in hand osteoarthritis isn't so far from the main stream of medicine. Hydroxychloroquine is important in the treatment of systemic lupus erythematodes. The current president of the U.S.A. has been advocating hydroxchloquine to fight covid-19 disease, though lacking scientific support. For colchicine there have been studies concerning osteoarthritis of weight bearing joints, mostly knee osteoarthritis.
For hydroxychloroquine and colchicine in hand osteoarthritis there have been two studies at the 2020 EULAR Online Meeting.

But let me start with a study by L.R Bryant and colleagues in 1995 [1]: „Hydroxychloroquine in the Treatment of Erosive Osteoarthritis“. The study had been underpowered (N=8). The authors concluded: „The use of hydroxychloroquine in patients with erosive OA unresponsive to NSAID appears promising. Prospective studies are needed to confirm our observations.“

C. Kedor and colleagues presented [2] at the 2020 EULAR Online Meeting: „OP0186 HYDROXYCHLOROQUINE IN PATIENTS WITH INFLAMMATORY AND EROSIVE OSTEOARTHRITIS OF THE HANDS: RESULTS OF A RANDOMIZED, DOUBLEBLIND, PLACEBO CONTROLLED, MULTI-CENTRE, INVESTIGATOR-INITIATED TRIAL (OA TREAT)“. The study originated in 2014. „The primary endpoint was AUSCAN for pain and hand disability at week 52 (W52). A secondary endpoint was radiographic progression from baseline (BL) to W52.“ „Of 156 patients 3 were excluded and 75 were randomized to HCQ and 78 to PBO.“ With only morning stiffness having been significantly reduced in the HCQ group, the authors had to conclude: „HCQ was no more effective than PBO for changes in pain, function and radiographic scores in the 52-week period.“
The study is congruent with a study that originated in 2013 and had been published earlier [3]: „Hydroxychloroquine Effectiveness in Reducing Symptoms of Hand Osteoarthritis: A Randomized Trial“. „The primary end point was average hand pain during the previous 2 weeks (on a 0- to 10-point numerical rating scale [NRS]) at 6 months.“ The authors concluded: „Hydroxychloroquine was no more effective than placebo for pain relief in patients with moderate to severe hand pain and radiographic osteoarthritis.“
So we now have two large randomized studies showing that hydroxychloroquine is ineffective in hand osteoarthritis.

C. Davis and colleagues presented [4]: „FRI0399 COLCHICINE IS NOT EFFECTIVE FOR REDUCING OSTEOARTHRITIC HAND PAIN COMPARED TO PLACEBO: A RANDOMISED, PLACEBO-CONTROLLED TRIAL (COLAH)“. Colchicine is effective as an anti-inflammatory agent in gouty arthritis, but has not been investigated before in hand osteoarthritis. The authors could evaluate 58 participants, who completed the study (N=27 colchicine, N=31 placebo). The authors concluded: „Colchicine 1mg daily for 12 weeks was not effective in improving pain, tender and swollen joint count or grip strength in symptomatic hand osteoarthritis patients. This study does not support colchicine for treatment of symptoms of hand osteoarthritis.“

It would have been nice to have drugs to prevent progression and treat symptoms of hand osteoarhritis, but hydroxychloroquine and colchicine are ineffective and should not be prescribed in patients with (erosive) hand osteoarthritis.


Links and References:
[1] Bryant LR, des Rosier KF, Carpenter MT. Hydroxychloroquine in the treatment of erosive osteoarthritis. J Rheumatol. 1995;22(8):1527-1531.
[2] C. Kedor1, J. Detert2, R. Rau3, S. Wassenberg3, J. Listing4, P. Klaus5, T. Braun1, W. Hermann6, S. Weiner7, M. Bohl-Buhler8, F. Buttgereit1, G. R. Burmester1. OP0186 HYDROXYCHLOROQUINE IN PATIENTS WITH INFLAMMATORY AND EROSIVE OSTEOARTHRITIS OF THE HANDS: RESULTS OF A RANDOMIZED, DOUBLEBLIND,
PLACEBO CONTROLLED, MULTI-CENTRE, INVESTIGATOR-INITIATED TRIAL (OA TREAT). DOI: 10.1136/annrheumdis-2020-eular.819
[3] Kingsbury SR, Tharmanathan P, Keding A, et al. Hydroxychloroquine Effectiveness in Reducing Symptoms of Hand Osteoarthritis: A Randomized Trial. Ann Intern Med. 2018;168(6):385-395. doi:10.7326/M17-1430
[4] C. Davis1,2, C. Ruediger1,2, K. Dyer2, S. Lester1,2, S. Graf3, F. P. B. Kroon4, S. Whittle2, C. Hill1,2. FRI0399 COLCHICINE IS NOT EFFECTIVE FOR REDUCING OSTEOARTHRITIC HAND PAIN COMPARED TO PLACEBO: A RANDOMISED, PLACEBO-CONTROLLED TRIAL (COLAH). DOI: 10.1136/annrheumdis-2020-eular.4040

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Friday, July 3, 2020

D-0120, a Novel Oral Selective Uric Acid Transporter Inhibitor, at the 2020 EULAR Online Meeting


It seems that we never have enough different drugs to lower hyperuricemia for the individual patient. Lesinurad is an oral selective uric acid transporter (URAT1) inhibitor, which has both FDA (2015) and EMA (2016) approval and is on the market under the brand name of Zurampic, but isn't sold in Germany for instance [1]. Now comes D-0120, a novel oral selective uric acid transporter (URAT1) inhibitor with one study at the 2020 EULAR Online Meeting. Will there be a market for such a drug?

L. Zhang presented the following study [2]: „OP0205 PHASE I STUDY OF D-0120, A NOVEL URAT1 INHIBITOR IN CLINICAL DEVELOPMENT FOR HYPERURICEMIA AND GOUT“. Daily oral D-0120, at dose levels from 2.5 mg/day to 20 mg/day in 32 healthy volunteers for 7 days was well tolerated. The pharmacokinetics profile demonstrated a dose proportional increase. There had been a significant reduction of serum uric acid levels.

Will there be a market for D-0120? D-0120 showed in a cell model a 150-fold more potent inhibitory activity than lesinurad, which might result in less side effects (hope and speculation!). This might be the pivotal point to go on studying D-0120. There will be patients needing an oral selective uric acid transporter (URAT1) inhibitor, but will there be enough patients to support the another drug of the kind that we already have?

Nevertheless I hope that studies go on and that D-0120 will come to market. That will take some years. In the mean time lesinurad should be available on the German market.


Links and References:
[2] L. Zhang1, D. Wyatt2, K. Stazzone1, Z. Shi1, Y. Wang1. OP0205 PHASE I STUDY OF D-0120, A NOVEL URAT1 INHIBITOR IN CLINICAL DEVELOPMENT FOR HYPERURICEMIA AND GOUT. DOI: 10.1136/annrheumdis-2020-eular.5107

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FreitagsGedichte / #KurzLyrik 03.07.2020

Sarg
wir
Nehmen
Etwas
Stoff
Mit
VerRotten
In ihm
Immer
Feucht
Dunkel
Nass & kalt
     Was
Wird bleiben?

Kern
     in Schatten
Tragen
Die
Nächte
Die
Katastrophen
Vorbei
Was
Du sehen
     Willst
Ist vorbei

RückKehr
     alles
Kehrt
Zurück
Zum
Ursprung
Nur
Nicht
Die Zeit
     Oder
Der Regen

NachHer
     Zeitungen
Briefe
Bücher
Bilder
Musik
Und Filme
Alles
BeWahren
Für
NachHer
Wann ist
     Dieses
NachHer?

Im Nu
     das weinende
Gesicht
Im Nu
Wandelt
Es sich
Die
Last
Ist
Fort-
GeFallen
     Der Stein
Vom Herzen

Bilder
     die ÖlBilder
In
Der
Guten Stube
Die
Kredenz
Die
StandUhr
Die
Stunden
Schlägt
Und
Der
Geruch
Von frisch
     GeBrühtem
Kaffee

IrrFahrten
     welche
IrrFahrten
Werden
Noch
VerLangt
Bis
Das Auto
In
Der Garage
Bis
Das Schiff
Im
Hafen ist
Ruhe sanft
     Auf
HerzensWellen

Tal
     im Tal
Öffnet
Man
Die Fenster
Der
Winter
Ist
GeGangen
 SonnenSchein
Warum
Zieht
Nicht
Das Gewölk
Aus
Dem Hirn

EichenTisch
     der schwere
EichenTisch
Auf
Den
Man
Sich
AufStützen
Darf
Und
Unter
Dem
Platz
Ist für
     Die
Nackten Füße




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CR6086 at the 2020 EULAR Online Meeting


When I've checked for novel drug candidates, I've stumpled on CR6086. Somehow the number reminded me of Intel's 8086-series and others might associate Nokia's 6086-series. But CR6086 is an EP4 [a prostanoid receptor] receptor antagonist, which “may improve the response of tumours to immuno-oncology therapies, e.g. immune checkpoint inhibitors such as anti-PD-1 and anti-CTLA-4 drugs” [1]. CR6086 wouldn't be the first drug that proves useful not only in oncology but also in rheumatology.

There had been a study at the 2016 ACR/ARHP Annual Meeting [2], in which the authors concluded: "CR6086 was safe up to the maximum tested dose of 300 mg."

Adis Insight [3] has data up to March 28th 2020 (“No recent reports of development identified for phase-I development in Rheumatoid-arthritis(In volunteers) in Italy (PO)”), and mentions two dates for study NCT03163966 in the Czech Republic (3rd November 2017) and the preliminary data presented at the 2018 ACR/ARHP Annual Meeting as CREATIVE trial data [4]. Now there is data on study NCT03163966.

K. Pavelka and colleagues presented the following study [5] at the 2020 EULAR Online Meetin: „AB0360 EFFICACY AND SAFETY OF THE PROSTAGLANDIN EP4 RECEPTOR ANTAGONIST CR6086 ADDED TO METHOTREXATE IN DMARD-NAIVE EARLY RA PATIENTS: A PHASE 2 RANDOMIZED CONTROLLED TRIAL“. The authors concluded: „There was no benefit demonstrated for CR6086 added to MTX in the study cohort as a whole. However, in a post-hoc analysis, enhanced responses were observed with CR6086 90mg bid added to MTX in patients >6 months disease duration. This generated the hypothesis that addition of CR6086 90mg bid may benefit in RA patients initiating MTX after the window of opportunity, to be tested in further studies.“ There aren't any irregularities in methods and results. Even without post-hoc analysis there's a difference for MTX with or without CR6086. But 'll show you, why I habor doubts.

I've looked at a study by G. Caselli and colleagues [6]: „Pharmacological Characterisation of CR6086, a Potent Prostaglandin E2 Receptor 4 Antagonist, as a New Potential Disease-Modifying Anti-Rheumatic Drug“. In results the authors tell us: „ In models of human immune cells in culture, CR6086 reduced key cytokine players of RA (IL-6 and VEGF expression in macrophages, IL-23 release from dendritic cells, IL-17 release from Th17 cells). In the CIA model of RA in rats and mice, CR6086 significantly improved all features of arthritis: severity, histology, inflammation and pain. In rats, CR6086 was better than the selective cyclooxygenase-2 inhibitor rofecoxib and at least as effective as the Janus kinase inhibitor tofacitinib.“ But there's no hint to what happens to MTX if combined with CR6086.
J.M. Kremer and R.A. Hamilton published in 1995 [7]: „The effects of nonsteroidal antiinflammatory drugs on methotrexate (MTX) pharmacokinetics: impairment of renal clearance of MTX at weekly maintenance doses but not at 7.5 mg“. So NSAIDs alter renal clearance of MTX at normal weekly maintenance doses. In a more recent study (2011) Yuichi Uwai and colleagues [8] showed in their meta-analysis „that NSAIDs increase blood levels of methotrexate by influencing renal excretion of the antifolate“.
Now, CR6086 isn't an NSAID, but it may (ot may not) effect the renal clearance of MTX.

K. Pavelka and colleagues stated the „hypothesis that addition of CR6086 90mg bid may benefit in RA patients initiating MTX after the window of opportunity“. I have my doubts, but I agree that this has to be tested in further studies. Hopefully, K. Pavelka and colleagues are right.



Links and References:
[2] Persiani S, Manzotti C, Vitalini C, Giacovelli G, Girolami F, D'Amato M, Caselli G, Rovati LC. a First-in-Human Study of CR6086, a New Potent EP4 Prostanoid Receptor Antagonist, Demonstrates Good Safety and Tolerability at Therapeutically Relevant Exposures [abstract]. Arthritis Rheumatol. 2016; 68 (suppl 10). https://acrabstracts.org/abstract/a-first-in-human-study-of-cr6086-a-new-potent-ep4-prostanoid-receptor-antagonist-demonstrates-good-safety-and-tolerability-at-therapeutically-relevant-exposures/. Accessed July 2, 2020.
[4] Vitalini C, Barbetta B, Giacovelli G, Brambilla N, D'Amato M, Girolami F, Rovati LC. Acr Hybrid Analysis: Blinded Data from the Ongoing Phase IIb Trial with the EP4 Receptor Antagonist CR6086 in DMARD-Naïve Patients with Early Rheumatoid Arthritis [abstract]. Arthritis Rheumatol. 2018; 70 (suppl 10). https://acrabstracts.org/abstract/acr-hybrid-analysis-blinded-data-from-the-ongoing-phase-iib-trial-with-the-ep4-receptor-antagonist-cr6086-in-dmard-naive-patients-with-early-rheumatoid-arthritis/. Accessed July 3, 2020.
[5] K. Pavelka1, I. D. Delina2, M. Mazur3, M. D’amato4, G. Giacovelli4, F. Girolami4, M. Krogulec5, R. Ostgard6, A. R. Bihlet7, O. Kubassova8, L. Rovati4,9, P. C. Taylor10. AB0360 EFFICACY AND SAFETY OF THE PROSTAGLANDIN EP4 RECEPTOR ANTAGONIST CR6086 ADDED TO METHOTREXATE IN DMARD-NAIVE EARLY RA PATIENTS: A PHASE 2 RANDOMIZED CONTROLLED TRIAL. DOI: 10.1136/annrheumdis-2020-eular.5636
[6] Caselli G, Bonazzi A, Lanza M, et al. Pharmacological characterisation of CR6086, a potent prostaglandin E2 receptor 4 antagonist, as a new potential disease-modifying anti-rheumatic drug. Arthritis Res Ther. 2018;20(1):39. Published 2018 Mar 1. doi:10.1186/s13075-018-1537-8
[7] Kremer JM, Hamilton RA. The effects of nonsteroidal antiinflammatory drugs on methotrexate (MTX) pharmacokinetics: impairment of renal clearance of MTX at weekly maintenance doses but not at 7.5 mg. J Rheumatol. 1995;22(11):2072-2077. https://pubmed.ncbi.nlm.nih.gov/8596147/
[8] Uwai Y, Suzuki R, Iwamoto K. Yakugaku Zasshi. 2011;131(5):853-861. doi:10.1248/yakushi.131.853 https://pubmed.ncbi.nlm.nih.gov/21532282/

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Otti Romm, Karl Fuck und weitere Künstler stellen aus



Über eine Ausstellung von Otti Romm hatte ich bereits berichtet [1]. Jetzt werden erneut Bilder von ihr, Karl Fuck und weiteren Künstlern ausgestellt. Man kann verschiedene Werke schon auf der Waldecker Straße in Köln-Buchforst ansehen, aber die Austellungsräume befinden sich in der Galerie Kunstmeile (Kalk-Mülheimer-Straße 320 in Köln-Buchforst) [2]. Das Bestattungshaus Josef Schmitz auf der Waldecker Straße in Köln-Buchforst existiert bereits seit 1932. In einem der Schaufenster stellen Künstler ihre Werke aus. Hier sind aktuell Werke von Otti Romm und Karl Fuck zu sehen.

Die Ausstellung zeigt Aquarelle von Otti Romm unter dem Titel Momente der Glückseligkeit und läuft bereits; sie geht aber noch bis zum 26.07.2020 (die Galerie ist sonntags von 15:00-18:00 Uhr geöffnet). Es sind auch noch Werke von Heinz Diekmann, Karl Fuck, Dr. Abdelhaf El Dodo, Sabine Losacker und Jutta Goldbach zu sehen.

Otti Romm wurde 1925 in Leverkusen geboren und war im bürgerlichen Beruf Oberstudienrätin. Malerei hatte sie in München bei Prof. Xaver Fahr studiert (1948-1954). 1954 absolvierte sie ein Werklehrerexamen an der Kunstakademie Düsseldorf.1955 bestand sie an der Kunstakademie München bei Prof. Marxmüller das Staatsexamen. Otti Romm hat sich der Darstellung von Landschaft und Natur verschrieben [3,4]. Ihre Bilder sind von Farbenpracht geprägt.

Karl Fuck wurde 1941 geboren und war als Designer, Typograph und Formulargestalter tätig [5]. Er ist Mitglied im Berufsverband Bildender Künstler, der Malakademie WDR-Aktiv, der Künstlergruppe Mit-Art und der Galerie Kunstmeile Buchforst. In die letzten 20 Jahre fallen ca. 40 Ausstellungen. Hier sind zwei seiner Werke.





Links:

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Wednesday, July 1, 2020

Olokizumab at the 2020 EULAR Annual Online Meeting and a look at IL-6-Inhibitors


I've been interested in olokizumab for about decade now. In 2016 I've written: „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.” [1] And now, at the EULAR Meeting there are two studies. These studies concern rheumatology and not Covid-19.

Let's stay for a moment at the Covid-19 issue and the possible use of IL-6-inhibitors. In patients with dramatic infectious diseases, especially septic shock, IL-6 levels might increase 1000-fold creating cytokine storm or cytokine release syndrome. This is life threatening.

C. Zhang and colleagues published a paper [2] in which they discussed blocking IL-6 signal transduction pathway with tocilizumab, which could become an effective drug for patients with severe COVID-19.

D. McGonagle and colleagues published on the role of cytokines in Covid-19 induced pneumonia and macrophage activation syndrome-like disease [3]. They “discuss the potential impact of timing of anti-cytokine therapy on viral clearance and the impact of such therapy on intra-pulmonary macrophage activation and emergent pulmonary vascular disease.”

But back to rheumatology and the EULAR Annual Meeting. We already have tocilizumab (Actemra) and sarilumab (Kevzara), which were approved both by EMA (2009 and 2017) and FDA (2010 and 2017). So where is the niche for olokizumab? Maybe that's the reason why the development of the drug has been so slow. But maybe Covid-19 will also speed things up.

There has been a study by E. Nasonov and colleagues [4]: “OP0021 OLOKIZUMAB, MONOCLONAL ANTIBODY AGAINST IL6, IN PATIENTS WITH MODERATELY TO SEVERELY ACTIVE RHEUMATOID ARTHRITIS INADEQUATELY CONTROLLED BY METHOTREXATE: EFFICACY AND SAFETY RESULTS OF PHASE III CREDO-1 STUDY”. If you are surprised by he Russian names, don be as in July 2013 there had been an announcement by UCB: “UCB out-licenses RA drug olokizumab to Russia's R-Pharm”.Back to the study. “428 patients were randomized to OKZ 64mg q2w (n=143), OKZ 64mg q4w (n=142), and PBO (n=143).” The authors found: “Treatment with OKZ over a 24-week period was associated with significant improvements in the signs, symptoms and physical function of RA, ...” There has be a numerically higher rate of adverse events and one death due to septic shock. There were no differences between the two dosages of olokizumab in efficacy or safety outcomes.

The second study is on patient related outcomes. [5] Conclusion sny E. Nasonov and olleagues: „1. Treatment with OKZ over a 24-week period was associated with significant improvements in PRO in patients with moderate to severe RA. 2. There were no discernible differences between the two regimens of OKZ from patient’s perspective.”

Do we need another IL-6-Inhibitor? If we compare olokizumab to tocilizumab and sarilumab on the qualitativ level, there would not be need for it. If it comes to altered demand (quantitativ level), there might be need for it. But let's wait for the coming studies in rheumatology and how the world copes with Covid-19.


Links and References:
[2] Zhang C, Wu Z, Li JW, Zhao H, Wang GQ. Cytokine release syndrome in severe COVID-19: interleukin-6 receptor antagonist tocilizumab may be the key to reduce mortality. Int J Antimicrob Agents. 2020;55(5):105954. doi:10.1016/j.ijantimicag.2020.105954
[3] McGonagle D, Sharif K, O'Regan A, Bridgewood C. The Role of Cytokines including Interleukin-6 in COVID-19 induced Pneumonia and Macrophage Activation Syndrome-Like Disease. Autoimmun Rev. 2020;19(6):102537. doi:10.1016/j.autrev.2020.102537
[4] E. Nasonov1, R. Stoilov2, T. Tyabut3, M. C. Genovese4 on behalf of Saeed Fatenejad (United States of America), Diana Krechikova, Elena Korneva,
Alexey Maslyansky, Tatiana Plaksina, Marina Stanislav, Sergey Yakushin, Elena Zonova (Russian Federation). OP0021 OLOKIZUMAB, MONOCLONAL ANTIBODY AGAINST IL6, IN PATIENTS WITH MODERATELY TO SEVERELY ACTIVE RHEUMATOID ARTHRITIS INADEQUATELY CONTROLLED BY METHOTREXATE: EFFICACY AND SAFETY RESULTS OF PHASE III CREDO-1 STUDY. DOI: 10.1136/annrheumdis-2020-eular.1688
[5] E. Nasonov1, M. Ivanova2, M. Samsonov3, T. Tyabut4, M. C. Genovese5 on behalf of Saeed Fatenejad (United States of America), Diana Krechikova, Sofia Kuzkina, Alexey Maslyansky, Tatiana Plaksina, Marina Stanislav, Sergey Yakushin, Elena Zonova (Russian Federation). THU0176 OLOKIZUMAB IMPROVES PATIENT REPORTED OUTCOMES IN PATIENTS WITH MODERATELY TO SEVERELY ACTIVE RHEUMATOID ARTHRITIS INADEQUATELY CONTROLLED BY METHOTREXATE: RESULTS FROM THE DOUBLE-BLIND, RANDOMIZED CONTROLLED PHASE III STUDY (CREDO-1). DOI: 10.1136/annrheumdis-2020-eular.2102

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