Saturday, March 31, 2012

Haiku - written in Indonesia and Atlanta


Indonesia

Bamboo swaying
Behind the rice field
      Birds calling the evening

After the muezzin´s call
The rooster crows
      Until the morning brightens

Clouds gather
People dispers
      Oh, what a rain!

Yellow bamboo leaves
Twirling down
      As evening arrives 


Coconut fronds bowing
Ripe fruits
      Will they fall down?


Lonely road
A motorcycle passes
      Chickens scattering

After the wind
Heavy rain falling
      Running down banana leaves

Dying embers
No fire anymore
      Peasant still working the paddy

Night has fallen
Shadow of the bamboo
      Frogs challenging crickets

Floaded paddy field
Growing rice
      Dragonflies lingering above


Unmoved pond
Single Lotus blossom
      Smiling buddha

Night has fallen
Shadow of the bamboo
      Frogs challenging crickets

Breaking waves
Smell of Frangipani
      Bats silent in the cave

Sound of the surf
Pandanus under the sun
      A cricket sitting on a blue blossom

Hurrying clouds above the sea
Shade under a lonely roof
     A gecko crying out

Rolling surf
Amongst the blue blossoms
      A yellow butterfly

Stones clattering down the cliff
Between two bushes
      The dragonfly lingers

Waves whitening
Hot wind on the cliff
      While the swallows hunt

A moment of silence
Sun covered by clouds
      Then roars the surf

Black veil
Sent sun to sleep
      Morning unveils 



Atlanta

Was ist der Tod mir
Blätter sterben lichterloh
      Und freu’ mich dran


At last there it is
The word to disguise a world 
      That has lost its grace

“Paddy’s Day Parade”
Green waters of Chicago
      Life means marching on
 

Merapi firing
All Yogya covered in dust
      Yet not Pompeii

Renouncing the world
With apple pie in the mouth
      We are still so young 


Stars peek from above
Airplane curves to runway
      Where will we arrive?

Wir standen wartend
AbendGesellschaft bricht auf
      Licht fließt in die Nacht

Winter’s still to come
Awful stretch of wasted time
      Waiting for next spring

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




This is basically the translation of a talk into English, I have held on 22 March 2012 in the Rheumatoid Academy. I cannot display all the slides because of copyright reasons. For the talk I had collected data from posters, session, and abstracts,
Here I have collected some information and other materials, which are been presented on the two major conferences in the world. The first Congress was the eular in London 2011 (June). The second Congress was the ACR 2011 in Chicago (November).





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






Synovialitic swelling of finger joints in rheumatoid arthritis






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


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


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

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


Overview of the mechanisms of action of DMARDs/anti-rheumatic:
Gold salts (unclear mechanism) - aurothiomalat
Folic acid inhibition - methotrexate
Antimalarials - chloroquine and hydroxychloroquine
Aminosalicylate - sulfasalazine
Purine synthesis inhibition - azathioprine
Pyrimidine synthesis inhibition - leflunomide
T Cell immune suppression - cyclosprin A, (tacrolimus)

Biologics
Shortly afterwards we moved in the treatment of rheumatoid arthritis to new era: the era of biologics.
But stop - Biologics also have their problems:



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


Now, we already have a range of biologics being available for treatment, more and more we appreciate the effectiveness of these drugs and also the problems. Even a drug being sparingly used in rheumatoid arthritis, anakinra, is further tested.
Since 2008 rituximab, abatacept, tocilizumab, golimumab, and certulizumab heave been approved for the treatment of rheumatoid arthritis as effective drugs. There is only few data on direct comparison of different treatments. Jasvinder A. Singh presented a meta-analysis in 2009, which addresses this question (Jasvinder A. Singh MD: CMAJ 2009. DOI:10.1503/cmaj.091391). The data of this meta-analysis confirmed of our own approach in the choice of an appropriate drug.


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

[eular 2011 / SAT0283] CLINICAL REMISSION IN RHEUMATOID ARTHRITIS ADULT PATIENTS TREATED WITH ANAKINRA AS FIRST-LINE BIOLOGIC THERAPY. RESULTS FROM THE GISEA REGISTRYP.
Sfriso et al.
Conclusions: The study shows that anakinra in clinical practice could lead to remission in some patients even if the frequency of remission is lower when compared to other biologic therapies (adalimumab/etanercept).


Abatacept

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

[eular 2011 / SAT0292] SAFETY OF SUBCUTANEOUS ABATACEPT IN PATIENTS WITH RHEUMATOID ARTHRITIS (RA): INTEGRATED ANALYSIS OF FIVE CLINICAL TRIALS UP TO 4.5 YEARS
R. Alten et al.
Conclusions: These pooled safety data, from 1879 patients with up to 4.5 years and 3086 p-y of exposure, demonstrate that SC abatacept has acceptable safety and medicine. The safety profile which generally consistent with that of IV abatacept. 1 few SC injection site reactions were observed, which were mostly mild in intensity.

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


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


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


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


More were presented: BMS-945429 (ALD518), CDP6038, and Sarilumab. These will be competitive to tocilizumab. But the question remains whether there is a benefit in these developments for patients or whether only another company wants to make money as well.
[eular 2011 / SAT0304] BMS-945429 (ALD518), A HIGH-AFFINITY ANTI-INTERLEUKIN-6 MONOCLONAL ANTIBODY, IS ASSOCIATED WITH IMPROVEMENTS IN HEALTH-RELATED QUALITY OF LIFE IN PATIENTS WITH RHEUMATOID ARTHRITIS AND AN INADEQUATE RESPONSE TO METHOTREXATE
V. Strand et al.
Objectives: Here, we report health-related quality of life (HRQoL) outcomes from a Phase II randomized controlled trial of intravenous BMS945429 in patients ...
Conclusions: Treatment with the IL-6 inhibitor BMS945429 resulted in statistically significant and clinically meaningful improvements in physical and mental aspects of HRQoL.
[eular 2011 / FRI0378] SAFETY AND PHARMACOKINETICS OF CDP6038, AN ANTI-IL-6 MONOCLONAL ANTIBODY, ADMINISTERED BY SUBCUTANEOUS INJECTION AND INTRAVENOUS INFUSION TO HEALTHY MALE VOLUNTEERS: A PHASE 1 STUDYM.
Hickling et al.
Conclusions: CDP6038 was tolerated at single doses of up to 3 mg/kg s.c. and 10 mg/kg i.v. exhibiting a median half-life of 31.1 days, absolute bioavailability of 84–92% and no apparent target-mediated clearance. These findings support the ongoing clinical evaluation of CDP6038 for the treatment of RA.
[eular 2011 / TUE L2]
Sarilumab for the Treatment of Moderate-to-Severe Rheumatoid Arthritis: Results of a Phase 2, Randomized, Double-Blind, Placebo-Controlled, International Study
Mark C. Genovese, Stanford University Medical Center, Palo Alto, CA, Alan J. Kivitz, Altoona Center for Clinical Research, Duncansville, PA, J. Abraham Simon Campos, Centro De Especialidades Médicas, Merida, Mexico, Maria Rell-Bakalarska, Rheumatology and Osteoporosis Outpatient Clinic, Warsaw, Poland, Roy M. Fleischmann, Metroplex Clinical Research Center, Dallas, TX, Martine Jasson, Sanofi, Paris, France, Allen R. Radin, Regeneron Pharmaceuticals Inc, Tarrytown, NY, Xiaohong Huang, Sanofi, Bridgewater, NJ and Tom W. J. Huizinga, Leiden University Medical Centre, Leiden, Netherlands
Conclusions: In this phase 2 study, sarilumab in combination with methotrexate demonstrated efficacy in patients with active, moderate-to-severe rheumatoid arthritis. The types and incidence of adverse events were consistent with those previously reported with IL-6 inhibition. Part B, the phase 3 portion of the MOBILITY seamless study, will assess long-term efficacy of sarilumab in rheumatoid arthritis.



More, biologics with novel mode of action
About LY2127399 (an anti-BAFF monoclonal antibody), MLTA3698A (a lymphotoxin-alpha monoclonal antibody), and AIN457 / Secukinumab (an anti-IL17A monoclonal antibody) there isn’t yet much to say.
[eular 2011 / OP0017] A PHASE 2 STUDY OF MONTHLY SUBCUTANEOUS LY2127399 (AN ANTI-BAFF MONOCLONAL ANTIBODY) IN PATIENTS WITH ACTIVE RHEUMATOID ARTHRITISM.
Genovese et al.
Conclusions: The LY safety profile in this study was similar to available RA therapies and no unexpected safety signals were seen. The 120mg dose group demonstrated significant reductions in the signs and symptoms of RA, and this was not contingent on complete B cell depletion. These results support further exploration of LY to treat RA
[eular 2011 / OP0018] ANTI-LYMPHOTOXIN-ALPHA MONOCLONAL ANTIBODY: RESULTS FROM A PHASE I RANDOMIZED, PLACEBO-CONTROLLED CLINICAL TRIAL IN PATIENTS WITH ACTIVE RHEUMATOID ARTHRITISB.
Emu et al.
Conclusions: MLTA3698A was generally well tolerated across SD and MD phases in patients with RA. Preliminary evidence of clinical activity was seen in patients with active RA.
Interestingly, etanercept has also activity against lymphotoxin-alpha.


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


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






Biosimilars
Biosimilars are biologics that a second manufacturer produces after the initial company patent rights have expired. It has been discussed that the subsequent product might not be totally identical, at least these concerns have arisen with biologics.
[eular 2011 / SP0062] ADVANTAGES AND DISADVANTAGES OF BIOSIMILARS – ARE THEY GENERIC BIOLOGIC AGENTS?
V. Strand
Targets for ''biosimilars'' include etanercept (ETN), infliximab and rituximab.
Disadvantages include that relatively small changes in manufacturing,
characterization and/or formulation can significantly alter the efficacy, safety and/or immunogenicity of the biosimilar product.

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



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

Small molecules



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


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


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


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


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


GLPG0259, a so-called MAPKAP kinase 5 inhibitor looked very well in the first trials. According to the studies of Vanhoutte and Andrews onecould hope for a new drug.
[eular 2011 / SAT0249] SAFETY AND PHARMACOKINETIC PROFILE IN HEALTHY VOLUNTEERS OF GLPG0259, A SMALL MOLECULE MAPKAPK5 INHIBITOR CURRENTLY IN A PHASE II RA STUDY
F. Vanhoutte
Conclusions: GLPG0259 showed good safety and a PK profile supporting once daily dosing. Based on these promising results, a randomized, placebo-controlled multi-center Phase II dose-finding study was initiated in October 2010, where three dose levels of GLPG0259 will be evaluated in 180 active RA patients with an inadequate response to MTX.
[eular 2011 / OP0292] IDENTIFICATION OF GLPG0259, AN ORALLY BIOAVAILABLE INHIBITOR OF MAPKAPK5, AS A CLINICAL CANDIDATE FOR THE TREATMENT OF RHEUMATOID ARTHRITIS
M. Andrews et al.
Conclusions: Compound screening and rational drug design were applied to generate a series of potent inhibitors of the novel RA target MAPKAPK5. Of these promising molecules, ... GLPG0259 is currently being evaluated in a Phase II trial in RA patients.

At his second lecture Andrews himself had to admit that the phase 2 study, after submission of the abstract, had to be canceled due to lack of efficacy.
[eular 2011 / OP0292] IDENTIFICATION OF GLPG0259, AN ORALLY BIOAVAILABLE INHIBITOR OF MAPKAPK5, AS A CLINICAL CANDIDATE FOR THE TREATMENT OF RHEUMATOID ARTHRITIS
M. Andrews et al.
Conclusions: Compound screening and rational drug design were applied to generate a series of potent inhibitors of the novel RA target MAPKAPK5. Of these promising molecules, ... GLPG0259 is currently being evaluated in a Phase II trial in RA patients.

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


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

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

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


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




Friday, March 30, 2012

FreitagsGedichte


VollKommenheit

Treiben, dahinTreiben
Nicht zum Zentrum angezogen
Und nicht in die Peripherie

Schauen, umherSchauen
In das Licht des Zentrums hinein
Und in die Schatten der Peripherie

Dieses Leben im Halben -:
Die VollKommenheit


Zentral

ZimbelKlänge und der Geruch vom SchlachtHof
ZimtGeruch und der Klang von Schmerzen

Am Beton bleibt SchulterBlut
Auf Asphalt trocknet SchreckHarn

SargFarbene Halluzinationen, glänzend
AsphodelenDuft und Verwesung

Der Tod verEndet in der Peripherie
Aber manchmal schreckt er das Zentrum


Sikkim

Nebel vom Wind geteilt
Dann von ihm ablassend
Um an weißen GebetsFahnen zu rütteln
Gebete in die Welt tragend

Schwarz stehen die Bäume auf der Kuppe
Und am Fuß des Berges
Doch schon smaragdenes Grün

Nur ein Moment des Lichts
In der Schwärze der Ewigkeit

GesundheitsTipps (9)



Bei Stress wird Interleukin-6, ein die Entzündungsreaktion förderndes Zytokin (Botenstoff) ausgeschüttet.


Magnesium kann Stress entgegenwirken. Eine Banane enthält viel Magnesium und kann eine großartige Stresspause darstellen.


Gelassener werden durch tiefe Bauchatmung. Die meisten Menschen atmen zu flach. Tief und langsam in den Bauch atmen.


Weniger Egoismus hilft der geistigen Gesundheit.


Mit Geduld und Toleranz hilft man seinem Gegenüber, und sich selbst.


Lachen ist gesund. Und jedes Lächeln verändert die Welt.


Mehr Kohlenhydrate und weniger Proteine in der Ernährung verbessert die Stresstoleranz.


Sport wie Walking, Radfahren, Schwimmen kann helfen, Stresshormone besser abzubauen.

Sammelsurium (48)



Männlein
Das rotBäckige Männlein im bleuen Kittel lief zum LastWagen. So ähnlich muß Hans Duschke im ANO-TeppichLaden agiert haben.


Karikatur
Ich habe ihn gesehen, den alten AutoFahrer mit Hut und starrem Blick nach vorne. Die BeiFahrerin trug einen KompottHut. Ich meinte, eine Karikatur zu sehen.


Milch
„Dat die keinen Kakao mache künne. Immer nur Wasser und Pulver. Dabei ist die Milch, dieste nimmst, das wichtigste.“ Düsseldorfer FlugHafen. Ich sehe das anders, ich nehme SojaMilch.


Mode
Was veranlaßt die Menschen, Moden zu folgen? Aktuell trägt man den Schal als Schlaufe, die beiden Enden werden durch sie gezogen. Wer hat das in die Welt gesetzt. Ich muss endlich „Manufacturing consent“ von Noam Chomsky lesen; steht schon lange genug bei mir herum.


Hildrun
Da treffe ich auf eine Frau mit dem Vornamen Hildrun. Heidrun oder Hiltrud hätte ich noch verstanden. Gut, dass meine Eltern keine Zusammenziehung wie Manthar oder Manta versucht haben.


Abend
Die Wolken hatten sich bereits mit der Nacht abgefunden, aber der Himmel darüber spielte noch ein wenig mit Tönen von Orange, Rot und Blau.



Thursday, March 29, 2012

Sammelsurium (47)



Henry Allingham
To commemorate „Henry Allingham, 109, Britain’s oldest serving World War I veteran, lighting a candle in a church …” Da lebt der Mensch so lange, um den Krieg mit sich herumzuschleppen. Aber alles Gestrige liegt für den Menschen wirklich gestern und nicht 90 Jahre zurück. Vielleicht hat Henry Allingham auch ein ganz anderes Leben gelebt, eines, das nur zu einem JahresTag die Erinnerungen hervorholt, nicht so wie in „Jahrestage“.

Jodie Foster
Die Jugend ist aus dem Gesicht von Jodie Foster verschwunden, Fältchen sind zu sehen und wahrscheinlich hat sie (früher) die Nase korrigieren lassen. Aber sie versteckt ihre Falten nicht und die Faszination des Lächelns bleibt.

Coronado  
Ich setzte von San Diego nach Coronado über und ging zum Strand. Dort steht auch das Hotel von „Manche mögen’s heiß“. Und so klärte sich für mich das Problem mit dem Schatten. Der fällt im Film nämlich falsch, denn das Hotel sollte ja in Miami Beach sein.

RückKehr
Ich kehre zurück und sehe zwei junge Türkinnnen, fröhlich miteinander redend, einen KinderWagen dabei, und ich merke, dass ich wieder zu Hause bin.

Blitzer vor den Köln Arcaden
Die Polizei blitzt vor den Köln Arcaden. Ich frage einen Polizisten, ob die Leute denn auch so dicht am PolizeiPräsidium zu schnell fahren. Er sagt, dass sie es gerade dort tun, da sie nicht daran denken.

GesundheitsTipps (8)



Während der Arbeit innehalten, sich entspannen. Mit mehr Gelassenheit durch den Alltag.


Zink zur Unterstützung des Immunsystems, enthalten in: Mohnsamen, Kürbiskernen, Linsen


Gegen Schnupfen: Nasenspülungen mit lauwarmer isotonischer Kochsalz-Lösung (0,9 %), also 0,9 g Kochsalz auf 100 ml Wasser.


Gegen Schnupfen: eine Nasenspülkanne bietet die Barmer/GEK. http://bit.ly/m1UYa1 Messbecher für Salzmenge ist vorhanden.


Rastlosigkeit, Stress, Hetze lassen sich vermeiden, wenn wir aus dem vielfältigen Angebot bewusst eine Wahl treffen.


Verrückt! Stress verkürzt das Leben, ohne geht es aber auch nicht, geringer Stress verlängert wieder das Leben.


Bisweilen ein Dinner cancelling – also der Verzicht aufs Abendessen kann ebenfalls ein langes Leben fördern.