North wind without snow
Brown leaves brushing
against legs
The tavern’s dim lights
Up in the high North
Fallen soldiers, fallen
trees
Weeping at the fire
Snow is arriving
Covering beauty and fail
Birds keep silent now
Sunday, December 6, 2015
Saturday, December 5, 2015
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.
.
Infusionen mit Biologika in Arztpraxen
Die Zeit berichtete über
eine Praxis für Kinder- und Jugendrheumatologie, in der um 3000 Infusionen pro
Jahr durchgeführt werden. Der Artikel beschäftigt sich mit der Frage, ob es in
seinem Einzugsgebiet überhaupt so viele Kinder mit entsprechend schweren
Verläufen gibt, also ob es nicht zu Fehldiagnosen gekommen ist.
Mich
interessiert ein anderer Aspekt. Wenn die Praxis 3000 Infusionen pro Jahr
durchführt, müssen für jeden Arbeitstag 12-14 Infusionen angesetzt werden. Ich
meine, dass dies nicht zu verantworten ist.
Biologika oder Biopharmazeutika sind Arzneistoffe, die mit
Mitteln der Biotechnologie in gentechnisch veränderten Organismen (also
Zellkulturen) hergestellt werden. Es handelt sich bei den Wirkstoffen, die in
der Rheumatologie eingesetzt werden, meistens um monoklonale Antikörper oder
Fusionsproteine. Das sind Stoffe, die im Körper allergische Reaktionen und auch
Zytokin vermittelte Reaktionen auslösen können. Und solche Reaktionen können
von leichtgradig bis lebensbedrohlich ausfallen. Die muss man behandeln können.
Das Negativbeispiel ist immer noch TGN1412; da kam es bei sechs Probanden im
Rahmen einer Phase 1 Studie zu einem Multiorgan-versagen.
Die meisten Praxen scheuen
deshalb gleichzeitig mehrere Infusionen durchzuführen. Die Logistik einer
Praxis gestattet das in der Regel nicht. Anders ist das an einem Rheuma
Zentrum / Krankenhaus. Da arbeite ich nämlich. Ich könnte im Notfall auf 10
Rheumatologen (also Internisten, die für Notfälle ausgebildet sind) sowie 2-3
Anästhesisten (die das ebenso können) zurückgreifen. Dazu kommt natürlich ausgebildetes Fachpersonal –
und für diese Notfälle hat das Krankenpflegepersonal die sinnvollere Ausbildung
als die Medizinschen Fachangestellten. Wir haben in der letzten Woche 40
Infusionen durchgeführt. Das entspricht in etwa 2/3 der Anzahl, die in der
Arztpraxis in Schleswig-Holstein durchgeführt werden.
Wenn alles gut geht, ist
die Infusionstherapie eine einfache Angelegenheit. Da aber Notfälle möglich sind,
muss man diese Situationen auch für jeden anvertrauten Patienten beherrschen
können. Wir können das an unserem Zentrum. Und ich bin mir sicher, dass dies für
1-2 Patienten gleichzeitig von rheumatologischen Praxen geleistet werden kann. Genauso
sicher bin ich mir, dass 3000 Infusionen in einer Praxis (auch mit vier Ärzten)
zu viel sind.
Links:
Friday, December 4, 2015
Carpe Diem Haiku Special No. 185 Georgia's first "Autumn Reflections" (Troiku)
Some warm sunshine still
The geese aren’t ready to
leave
Night colours the leaves
Some warm sunshine still
The squirrel happy with
nuts
But golden leaves fall
The geese aren’t ready to
leave
Paddling on the pond
Unaware of frost
Night colours the leaves
This brilliant foliage
Soon covers the ground
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
.
Carpe Diem Haiku No. 872 across the field; one patch of a rice field; roots of elegance
The fresh rice seedlings
Waiting for the rain to
come
Paddy still mirrors
Lonesome willow tree
I shall return to see thee
When harvest begins
Thursday, December 3, 2015
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.
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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