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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Next Round of Tanezumab in Osteoarthritis

About a year ago I’ve written about tanezumab in osteoarthritis [1]. Two years earlier I’ve already voiced my concerns about the substance [2]. My conclusion in 2018 had been: “Until further notice I’ll stay skeptical about tanezumab in osteoarthritis.”

And now there’s a study by Th.J. Schnitzer and colleagues [3]: “Effect of Tanezumab on Joint Pain, Physical Function, and Patient Global Assessment [PGA] of Osteoarthritis Among Patients With Osteoarthritis of the Hip or Knee: A Randomized Clinical Trial”. The authors described the significant improvement in pain and PGA as “moderate”. Under results we find: “Rapidly progressive OA occurred only in tanezumab-treated patients (2.5 mg: n = 5, 2.2%; 2.5/5 mg: n = 1, 0.4%). The incidence of total joint replacements was 8 (3.5%), 16 (6.9%), and 4 (1.7%) in the tanezumab, 2.5 mg; tanezumab, 2.5/5 mg; and placebo groups, respectively.”

In conclusion the study shows an analgesic effect of tanezumab, but only against placebo. What about naproxen, celecoxib, or oxycodone? Or even paracetamol? “Rapidly progressive OA occurred only in tanezumab-treated patients”, and therefore the incidence of total joint replacements was higher in the tanezumab groups.

To sum it up, I’m even more skeptical about seeing tanezumab as a drug in osteoarthritis than I had been before.

Links:

[1] https://rheumatologe.blogspot.com/2018/03/tanezumab-in-patients-with-knee-or-hip.html

[2] https://rheumatologe.blogspot.com/2015/12/tanezumab-in-osteoarthritis-at-acr-2015.html

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Lutikizumab in Osteoarthritis

Lutikizumab (ABT-981) is an anti-interleukin-1α/β (anti-IL-1α/β) dual variable domain immunoglobulin. I’ve once discussed bispecific antibodies with Prof. Burmester as I have concerns about the fact that each part is as strong as the other and this might not reflect the need of each compound. Prof. Burmester had a more practical approach as you don’t have to apply for two different drugs in studies and later in looking for approval by agencies such as the FDA or EMA. I remain skeptic.

There has been a study by R.M. Fleischman and colleagues [1]: “A Phase II Trial of Lutikizumab, an Anti-Interleukin-1α/β Dual Variable Domain Immunoglobulin, in Knee Osteoarthritis Patients With Synovitis.” The authors found only a limited improvement in the WOMAC pain score and a lack of synovitis improvement with lutikizumab. The concluded further that “together with published results from trials of other IL-1 inhibitors, suggest that IL-1 inhibition is not an effective analgesic/antiinflammatory therapy in most patients with knee OA and associated synovitis.”

M. Kloppenburg and colleagues published a study [2]: “Phase IIa, placebo-controlled, randomised study of lutikizumab, an anti-interleukin-1α and anti-interleukin-1β dual variable domain immunoglobulin, in patients with erosive hand osteoarthritis.” The had chosen as primary endpoint a “change in Australian/Canadian Osteoarthritis Hand Index (AUSCAN) pain subdomain score from baseline to 16 weeks. At baseline and week 26, subjects had bilateral hand radiographs and MRI of the hand with the greatest number of baseline tender and/or swollen joints.” The authors concluded: “Despite adequate blockade of IL-1, lutikizumab did not improve pain or imaging outcomes in erosive HOA [erosive hand osteoarthritis] compared with placebo.”

I said: I remain skeptic. I don’t see a niche for lutikizumab in the treatment of osteoarthritis. Bye bye!

Links:

[1] https://www.ncbi.nlm.nih.gov/pubmed/30653843

[2] https://ard.bmj.com/content/78/3/413.long

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Tanezumab in Patients with Knee or Hip Osteoarthritis at the 2017 ACR Annual Meeting in San Diego

You might recall that I had been very critical about tanezumab in osteoarthritis [1]. There has been one abstract/poster on tanezumab at the 2017 ACR Annual Meeting in San Diego. Let’s have a closer look!

C.A. Birbara and colleagues presented [2]: “Efficacy and Safety of Subcutaneous Tanezumab in Patients with Knee or Hip Osteoarthritis (NCT01089725)”. The authors concluded: “SC TNZ [subcutaneous tanezumab] provided improvements in Pain, Physical Function, and PGAOA [Patient’s Global Assessment of Osteoarthritis] at all doses. Efficacy and safety of SC TNZ were generally similar to IV [intravenous] in patients with OA [osteoarthritis] pain.”

If you look up NCT01089725 [3], you’ll find a study with this title: “Phase 3, Randomized, Double-Blind, Placebo-Controlled, Multicenter Study Of The Analgesic Efficacy And Safety Of Subcutaneous Administration Of Tanezumab In Patients With Osteoarthritis Of The Knee”. Moreover you find this: “This study was terminated on 08 Nov 2010 following a US FDA clinical hold for tanezumab osteoarthritis clinical studies which halted dosing and enrollment of patients on 23 June 2010 for potential safety issues.” Last update on this study had been on July 3, 2013. Am I missing something?

In the study that C.A. Birbara presented we find under methods: “Patients (N=379) with knee or hip OA were randomized and treated with placebo (n=72), TNZ 2.5 mg SC (n=74), 5 mg SC (n=63), 10 mg SC (n=86) or 10 mg IV (n=84) every 8 weeks.” In Clinical Trials we find: “Actual Enrollment: 385 participants”. Do we look at hitherto unpublished data of an older study? I’m growing even more skeptical about tanezumab.

So, we’ve got some patient-reported outcome measures. Where are structural outcome measures? Why aren’t we told if tanezumab is better than naproxen, celecoxib, or oxycodone?

Until further notice I’ll stay skeptical about tanezumab in osteoarthritis.

Links: 

[1] http://rheumatologe.blogspot.de/2015/12/tanezumab-in-osteoarthritis-at-acr-2015.html

[2] Birbara CA, Dabezies EJ, Burr AM, Fountaine RJ, Smith MD, Brown MT, West CR, Arends RH, Verburg KM. Efficacy and Safety of Subcutaneous Tanezumab in Patients with Knee or Hip Osteoarthritis (NCT01089725) [abstract]. Arthritis Rheumatol. 2017; 69 (suppl 10). http://acrabstracts.org/abstract/efficacy-and-safety-of-subcutaneous-tanezumab-in-patients-with-knee-or-hip-osteoarthritis-nct01089725/. Accessed March 16, 2018.

[3] https://clinicaltrials.gov/ct2/show/NCT01089725

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Psoriasis in Salzburg

Vielleicht kenne Sie Salzburg von den Salzburger Festspielen und erwarten hier etwas zu Mozart. Nein, dieses Salzburg ist nicht gemeint. Ich meine das Salzburg in Siebenbürgen/Rumänien in der Nähe von Sibiu/Hermannstadt. Einer meiner Patienten besuchte dort Verwandtschaft und ist wg. der Psoriasis/Psoriasisarthritis in das Städtchen Ocna Sibiului/Salzburg gefahren, da dort Salzseen sind; daher auch der Name Salzburg. Salzburg hat etwas 3500 Einwohner. [1] Es handelt sich um einen traditionellen Kurort, der von Wiesen und Eichenwäldern umgeben ist. Erste Kurgäste wurden dort 1845 begrüßt. „Anfang der 1990er Jahre wird der Kurort nur halbjährlich; erst 2002 wieder ganzjährig mit verminderter Kapazität betrieben. 2006 wird der Badekomplex offiziell eröffnet.“ [1,2] Die Seen haben unterschiedliche Größen und der Salzgehalt variiert stark. Die höchste Salzkonzentration wurde im Wasser des Brâncoveanu-Sees mit 300 g pro Liter gemessen. Teilweise werden auch Schlammbäder durchgeführt.

Ich habe einen deutschsprachigen Artikel von Hannelore Baier aus dem Jahr 2011 (Das kleine Meer bei Hermannstadt / Das siebenbürgische Salzburg – ein in Vergessenheit geratener Kurort) gefunden, in dem beschrieben wird, wie verschiedene der Seen sind, z.B. welchen Salzgehalt, welche Anlagen vorhanden sind und wie man dorthin gelangen kann [3]. Auch Preise sind erwähnt, allerdings sind die jetzt schon ein paar Jahre alt.

Auf einer rumänischen Seite fand ich folgenden Text: „Aici tratăm cu succes afecţiuni ale aparatului locomotor, patologia degenerativă, artrotică, coxartroza, reumatismele inflamatorii, articulare, poliartrita reumatoidă, patologia post-traumatică a aparatului locomotor.“ [2] Übersetzung: „Hier beschäftigen wir uns erfolgreich mit Erkrankungen des Bewegungsapparates, degenerativer Pathologie, Arthrosen, Coxarthrose, entzündlicher Rheumatismus von Gelenken, rheumatoider Arthritis, posttraumatischer Pathologie des Bewegungsapparates.“ Aber auch gynäkologische Störungen, neurologische Erkrankungen und Hautkrankheiten wie die Psoriasis werden neben weiteren erwähnt. Ob das wissenschaftlich belastbar ist, weiß ich natürlich nicht. Aber eine medizinisch begründete Balneotherapie darf man dahinter vermuten.

Das Salz dieser Seen um Salzburg und dem Toten Meer unterscheidet sich. Hier ist das vorherrschende Salz Kochsalz (Natriumchlorid) und im Toten Meer macht Magnesiumchlorid den höchsten Anteil aus.

Ich weiß, dass bei Psoriasiserkrankten das Tote Meer einen guten Ruf für Kuraufenthalte hat. Unter Umständen ist aber das näher gelegene Salzburg/Ocna Sibiului eine weitere Option. Hier müssten sich einmal die Entdecker aus diesem Personenkreis aus das Wagnis einlassen, um auszuprobieren, ob der gewünschte Erholungs- und Kureffekt auch dort eintritt. Das könnte man dann z.B. im Psoriasis-Netz [4] diskutieren.

Links:

[1] https://de.wikipedia.org/wiki/Ocna_Sibiului

[2] www.mesageruldesibiu.ro/complexul-balnear-ocna-sibiului-paradis-exotic-pentru-sibieni-si-turisti/

[3] http://www.adz.ro/artikel/artikel/das-kleine-meer-bei-hermannstadt/

[4] https://www.psoriasis-netz.de/community/

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