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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ERAP1 at the EULAR 2014 Meeting in Paris

After I've seen a tweet by Jean-francois Carre (@jfcarre69) about ERAP1 on twitter, I researched what's behind ERAP1. ERAP1 (endoplasmic reticulum aminopeptidase 1) has a strong genetic association of with ankylosing spondylitis, which is restricted to HLA-B27 positive cases. More is told in a study by S. Keidel and colleagues (link: http://www.ncbi.nlm.nih.gov/pubmed/23452840). The authors hypothesize that that ERAP1 inhibition could represent a future treatment strategy (in HLA B27 positive patients). Right now there should be ending a research project by the University of Queensland Diamantina Institute. Title of the project: "Development of ERAP1 inhibitors as a novel class of therapeutics for the treatment of Ankylosing Spondylitis (AS) and other immune-mediated diseases"; link: http://www.di.uq.edu.au/winter-research.

And concerning ERAP1 there have been two studies at the EULAR 2014 Meeting in Paris.

N. Haroon and colleagues presented [FRI0166]: “ANKYLOSING SPONDYLITIS ASSOCIATED ERAP1 VARIANTS ALTER THE UNFOLDED PROTEIN RESPONSE”. Conclusions: “ERAP1 suppression leads to increased UPR (unfolded protein response). AS-associated ERAP1-variants, which are known to have reduced function, leads to more UPR compared to the common variant of ERAP1.” That leaves you asking for relevance, doesn’t it? Me too!  We should have read, what the authors told in background: “Unfolding of HLA-B27 and the formation of FHC can cause the release of inflammatory cytokines by triggering the unfolded protein response (UPR).” And this means that there might be a novel class of therapeutics for the treatment of Ankylosing Spondylitis (AS)

E.H. Kang and colleagues presented [AB0004]: “ERAP1 POLYMORPHISMS IN KOREAN PATIENTS WITH BEHCET’S DISEASE”. A genetic study, but of no concern with ERAP1 and ankylosing spondylitis.

My guess is that it isn’t the last we hear about ERAP1 in ankylosing spondylitis.

Tabalumab at the EULAR 2014 Meeting in Paris

I've already said bye bye to tabalumab a year ago as I had been very disappointed with the data shown during the past two years, but here we still are. Tabalumab (LY2127399) is a human IgG4 monoclonal antibody against B-cell activating factor (BAFF). And there have been two abstracts/posters.

J.S. Smolen and colleagues presented [FRI0326]: "EFFICACY AND SAFETY OF TABALUMAB, AN ANTI-B CELL ACTIVATING FACTOR MONOCLONAL ANTIBODY, IN PATIENTS WITH RHEUMATOID ARTHRITIS WHO HAD AN INADEQUATE RESPONSE TO METHOTREXATE THERAPY: RESULTS FROM A PHASE 3 MULTICENTER, RANDOMIZED, DOUBLE-BLIND STUDY". Conclusions: "In this phase 3 study, tabalumab demonstrated no clinical efficacy despite evidence of biologic activity. There were no differences in reports of AEs of interest and no new or unexpected safety findings for RA pts receiving tabalumab."

M. Schiff and colleagues presented [AB0438]: "EFFICACY AND SAFETY OF TABALUMAB, AN ANTI-B CELL ACTIVATING FACTOR MONOCLONAL ANTIBODY, IN PATIENTS WITH RHEUMATOID ARTHRITIS WHO HAD AN INADEQUATE RESPONSE TO TNF-ALPHA INHIBITORS: RESULTS FROM A PHASE 3 MULTICENTER, RANDOMIZED, DOUBLE-BLIND STUDY". Conclusions: "In this phase 3 study, tabalumab demonstrated no clinical efficacy despite evidence of biologic activity, suggesting that targeting BAFF may not be a viable therapeutic approach to treating pts with RA. There were no differences in reports of infection or allergic/hypersensitivity events and no new or unexpected safety findings for RA pts receiving tabalumab."

In the case of tabalumab I hate to be proven right: it's bye bye tabalumab!

Link:

http://rheumatologe.blogspot.de/2013/06/tabalumab-at-eular-2013-meeting.html 

Secukinumab at the EULAR 2014 Meeting in Paris

Secukinumab is an anti-IL-17a MAB. I'm pretty sure, it won't work in rheumatoid arthritis patients, but we need more drugs in the field of treating patients with psoriatic arthritis. 

A. Gottlieb and colleagues presented the following study [AB0738]: "SECUKINUMAB REDUCES HSCRP LEVELS IN SUBJECTS WITH MODERATE-TO-SEVERE PLAQUE PSORIASIS AND CONCOMITANT PSORIATIC ARTHRITIS: A SUB-ANALYSIS FROM THE PHASE 3 ERASURE STUDY". Conclusions: "In subjects with psoriasis and concomitant PsA, secukinumab was associated with pronounced and sustained reductions in serum hsCRP levels indicating a reduction in inflammatory burden during secukinumab therapy."

I won't call it a major breakthrough, but it's enough to keep me interested. Hope to hear more about secukinumab in the future.

Link:

http://rheumatologe.blogspot.de/2013/06/secukinumab-at-eular-2013-meeting.html

GLPG0634 at the EULAR 2014 in Paris

GLPG0634 is selective inhibitor of Janus kinase 1 (JAK-1) and I have been quite thrilled by this new drug since the ACR 2012 in Washington. The big news is, GLPG0634 has a name now: filgotinib.

F. Namour and colleagues presented [THU0123]: "DOSE SELECTION OF GLPG0634, A SELECTIVE JAK1 INHIBITOR, FOR RHEUMATOID ARTHRITIS PHASE 2B STUDIES: PK/PD AND EXPOSURE-DAS28 MODELING APPROACH". Conclusions: "Current modelling and simulation on the basis of early clinical data suggests that the pharmacokinetics of GLPG0634 is dose proportional at doses up to 200 mg QD, in agreement with observed data, and shows that both GLPG0634 and its main metabolite contribute to biomarker response. Simulations of the pSTAT1 and DAS28 dose-response relation suggest that the efficacy is favorable up to a daily dose of 200 mg GLPG0634, with clinical response in the range of that observed with registered compounds. A daily dose range from 50 to 200 mg is currently being tested in the DARWIN Phase 2B program."

C. Belleville-Da-Costa and colleagues presented [THU0138]: "GLPG0634M1, A MAJOR METABOLITE OF THE JAK1-SELECTIVE INHIBITOR GLPG0634, IS ALSO JAK1-SELECTIVE AND EFFICIENT IN THE RAT CIA MODEL". I skip this one.

F. Namour and colleagues presented [AB0460]: "GLPG0634, A SELECTIVE JAK1 INHIBITOR, CONFIRMS ITS LOW LIABILITY FOR DRUG-DRUG INTERACTIONS". Let's skip this one, too.

Darwin returned from his voyage with the beagle in 1836 and published his abstract "On the Origin of Species by Means of Natural Selection, or The Preservation of Favoured Races in the Struggle for Life" in 1859. Let's hope that the DARWIN study will publish results more quickly.

Links:

http://rheumatologe.blogspot.de/2013/06/glpg0634-at-eular-2013.html

http://rheumatologe.blogspot.de/2012/12/glpg0634-at-acr-2012-in-washington.html

Brodalumab at the EULAR 2014 in Paris

Brodalumab is an anti-IL 17 receptor MAB, which I think is a dead end in rheumatoid arthritis but a promising new drug on the horizon against psoriatic arthritis as it targets IL-17, which plays a role "in the pathogenesis and ongoing inflammation of psoriatic disease". Out of the three abstracts/posters on brodalumab, two are of interest for us.

P.J. Mease and colleagues presented the following study [SAT0404]: "FIFTY-TWO WEEK CLINICAL RESPONSE TO BRODALUMAB, AN ANTI-IL-17R ANTIBODY, IN SUBJECTS WITH PSORIATIC ARTHRITIS". Conclusions: "Brodalumab treatment was associated with improvements in musculoskeletal and skin symptoms in subjects with PsA. Clinical responses were sustained through week 52. These results support continued evaluation of brodalumab for treatment of PsA." I know, it's a phase 2 study and more shouldn't be expected.

M.C. Genovese and colleagues presented [AB0752]: "EFFICACY AND SAFETY OF BRODALUMAB OVER ONE YEAR IN PATIENTS WITH PSORIATIC ARTHRITIS WITH AND WITHOUT PRIOR EXPOSURE TO A BIOLOGIC". Conclusions: "Prior exposure to a biologic does not seem to affect the efficacy or tolerability of brodalumab over one year in the treatment of PsA." Good to hear as we might try after approval to treat patients with failures to TNF-inhibitors and/or failure to ustekinumab.

Brodalumab is promising in psoriatic arthritis, but still has a long way to go, which means for us: we have to wait. I won't expect approval within the next two years.

Link:

http://rheumatologe.blogspot.de/2013/06/brodalumab-at-eular-2013.html

http://rheumatologe.blogspot.de/2012/12/brodalumab-at-acr-2012-in-washington.html

Baricitinib at the EULAR 2014 Meeting in Paris

Baricitinib, the artist formerly known as LY3009104 / INCB028050 (a novel oral inhibitor of JAK1/2), made me very enthusiastic at the ACR 2012 Meeting. A year ago there had only been a study telling me not to worry about cholesterol in patients receiving baricitinib. What do we have now? A phase 2b study from Japan. And that's all, folks!

Y. Tanaka and colleagues [THU0149] presented the following study: "EFFICACY AND SAFETY OF BARICITINIB IN JAPANESE RHEUMATOID ARTHRITIS PATIENTS AT 12 WEEKS". Conclusions: "Clinical efficacy was demonstrated in this Phase 2b study of baricitinib in combination with background MTX in Japanese RA pts through 12 weeks. Safety signals observed through 12 weeks were consistent with a previous study of baricitinib in non-Japanese pts with RA." Nothing to say against this study. Everything is fine, but it only tells us little more than what we already know.

We are desperately waiting for a phase 3 study! I've talked to the Lilly people and they told me that phase 3 studies haven't completed recruiting. So we still have to wait for these important studies.

I had already thought that FDA and EMEA are getting stricter in applying drug efficiency and safety requirements as seen after last year's ruling of EMEA concerning tofacitinib; the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) had adopted a negative opinion for Xeljanz® (tofacitinib). Maybe the current phase 3 studies need more time than expected to make them watertight. Despite my new worries and disappointments I hope that baricitinib will make it to the market.

Link:

http://rheumatologe.blogspot.de/2013/06/baricitinib-at-eular-2013-meeting.html

Clazakizumab at the EULAR 2014 Meeting in Paris

Clazakizumab is an anti-IL-6 MAB. I haven't written much on clazakizumab so far. Last year at the ACR 2013 Meeting in San Diego there had been a poster/abstract on clazakizumab, on which clazakizumab showed a higher potency than tocilizumab [#2385]. But will this be an advantage? Tocilizumab SC is already available and is still might take a while until clazakizumab comes to the market.

S. Du and colleagues presented the following study [SAT0210]: "X-RAY AND MRI RESULTS FROM A PHASE IIB STUDY OF

SUBCUTANEOUS ANTI-INTERLEUKIN-6 MONOCLONAL ANTIBODY CLAZAKIZUMAB WITH OR WITHOUT MTX IN ADULTS WITH MODERATE-TO-SEVERE ACTIVE RA AND INADEQUATE RESPONSE TO CONVENTIONAL DMARDS INCLUDING METHOTREXATE". Conclusions: Clazakizumab in combination with MTX demonstrated reduced progression of joint damage by MRI as early as 12 weeks and by X-ray after 24 weeks. Larger trials with clazakizumab in RA are warranted to confirm these findings." But good as preliminary data!

M. Weinblatt and colleagues presented [SAT0244]: "A PHASE IIB STUDY OF THE EFFICACY AND SAFETY OF SUBCUTANEOUS CLAZAKIZUMAB (ANTI-IL-6 MONOCLONAL ANTIBODY) WITH OR WITHOUT METHOTREXATE IN ADULTS WITH MODERATE-TO-SEVERE ACTIVE RHEUMATOID ARTHRITIS AND AN INADEQUATE RESPONSE TO METHOTREXATE". N=418 patients were randomized! In results we find: " The rates of serious adverse events ranged from 8.3 to 13.3% in CLZ arms versus 3.3% for pbo ...". Conclusions: "Clazakizumab as monotherapy or in combination with MTX demonstrated efficacy in controlling the signs and symptoms of RA. At Week 24, remission rates with clazakizumab + MTX trended higher than with ADA + MTX. Its safety profile was consistent with the known pharmacology of IL-6 blockade. Clazakizumab is a promising future treatment for RA that warrants further investigation." Still too early to call us off safety concerns!

E. Alemao and colleagues presented [AB0423] "IMPACT OF ANTI-IL-6 MONOCLONAL ANTIBODY, CLAZAKIZUMAB, ON PATIENT-REPORTED OUTCOMES IN PATIENTS WITH RHEUMATOID ARTHRITIS AND AN INADEQUATE RESPONSE TO METHOTREXATE IN A PHASE IIB STUDY".

Conclusions: Treatment with clazakizumab with or without MTX resulted in improvements in multiple PROs and a greater proportion of patients achieved MCID (minimal clinically important differences) on these PROs (patient-reported outcomes) compared with MTX alone in patients with RA with an inadequate response to MTX."

Promising drug candidate, but still has to present phase 3 studies. I hope there won't be new safety concerns as I'm already alerted by the 8.3% to 13.3% serious adverse events in the clazakizumab arms versus 3.3% for placebo [SAT0244]; the authors of the study call the safety profile consistent with the known pharmacology of IL-6 blockade, however. Maybe, we'll get a new drug, but as there already exists an approved anti-IL-6 MAB, where's the niche for this one? Hopefully the company answers this question before coming to the market.

MOR103 at the EULAR 2014 in Paris

MOR10 is an anti-GM-CSF MAB like mavrilimumab, but didn’t show up at the EULAR 2014 Meeting in Paris. I wonder why! Earlier this year there had been a phase 1b/2a study; link: http://www.ncbi.nlm.nih.gov/pubmed/24534756. At the ACR 2012 Meeting in Washington MOR103 showed up with a late breaking poster (Trial Registration Number NCT01023256). Frank Behrens and colleagues presented a poster with the title (Abstract No. L11): “First in Patient Study of Anti-GM-CSF Monoclonal Antibody (MOR103) in Active Rheumatoid Arthritis: Results of a Phase 1b/2a Randomized, Double-Blind, Placebo-Controlled Trial”.

Nothing at the EULAR 2013 Meeting in Madrid and nothing at the ACR 2013 Meeting in San Diego. Now nothing again.

So how fits this study in?

F. Behrens and colleagues published in Ann Rheum Dis. 2014, Feb. 17 (doi: 10.1136/annrheumdis-2013-204816) this study: "MOR103, a human monoclonal antibody to granulocyte-macrophage colony-stimulating factor, in the treatment of patients with moderate rheumatoid arthritis: results of a phase Ib/IIa randomised, double-blind, placebo-controlled, dose-escalation trial." Out of the 96 randomised and treated subjects, 85 completed the trial. The objectives were to determine the safety, tolerability and signs of efficacy of MOR103. Conclusions:

"MOR103 was well tolerated and showed preliminary evidence of efficacy in patients with active RA. The data support further investigation of this monoclonal antibody to GM-CSF in RA patients and potentially in those with other immune-mediated inflammatory diseases." It has of course been the study that has been presented almost two years ago (Trial Registration Number NCT01023256).

Maybe I hear the grass grow and maybe it's just that recruiting proves to be difficult, but not showing up at any of the important meetings makes me think. So we have to wait, until "further investigation" has been done.

Good luck for a new mode of action drug, but keep us informed. See you at the next meeting!

Methotrexate at the EULAR 2014 Meeting in Paris

Methotrexate (MTX) is an old drug, but at the same time it remains a most interesting drug, which still retains quite a lot of secrets. If you search the abstracts for MTX you find a plethora of studies mentioning the drug. It turned out to be difficult not to discard too many studies and yet keep the following text focussed on issues specific for the EULAR 2014 Meeting. # indicates the Number in the abstract book.

Adherence / patient compliance

    Not only for MTX adherence is presently a hot topic.

Most frequently reported reasons for noncompliance with MTX were forgetting or not remembering to take it. #OP0004

    Abstract #THU0130 also ponted out: unintentional omission of MTX doses was the main reason for non-adherence.

    Nearly half of patients with MTX reported less than perfect compliance with MTX. #OP0004 [Less is more! I wouldn't make a fuss if MTX is omitted every now and then. Less is more means: physicians aren't gaining anything in making their patients feel guilty.]

    Reducing treatment burden, may improve patient compliance. #OP0004

    Patients on etanercept and MTX had greater adherence and persistence than those on triple therapy. #THU0441 [Easy to agree with, but one has to make such a study to prove the hypothesis. And it doesn't men the end of triple therapy as there are enough patients with contraindications to biologics.]

    Treatment at hospital or in private practice did not influence the adherence to MTX. #FRI0183

Oral versus subcutaneous MTX

    Use of injectable MTX was associated with a significantly longer duration of MTX monotherapy compared with oral MTX. #THU0115

    Rheumatoid arthritis patients with an inadequate response to oral MTX maintained satisfactory disease control when switched to subcutaneous MTX. #THU0111

    Efficacy of SC MTX therapy is associated with reduced proinflammatory cytokines, chemokines and growth factor. #THU0110

    SC MTX is effective and well-tolerated in rheumatois arthritis patients. 50% didn’t need addition of biologics. St. Gallen Cohort Early RA. #THU0140

    [I come from a center, where oral MTX is used less than subcutaneous MTX. We start MTX SC and might switch to oral MTX later. We encourage our patients to switch to oral MTX in the same dosage during holidays and switch back to SC after their return.]

    GEMS (The Guildford Evaulation of Methotrexate Subcutaneous) audit suggests that there is added benefit of switching patients to SC MTX at the same dose. # AB0457

Efficacy

    Patients with early rheumatoid arthritis under MTX require much less biologics than patients with long-standing rheumatoid arthritis. #THU0160

    Early therapeutic intervention with MTX in patients with undifferentiated arthritis prevents development rheumatoid arthritis. #THU0249

    Response more often in patients with early arthritis in whom start of MTX is driven by the 2010 ACR/EULAR criteria than by the 1987 ACR criteria. #FRI0041

SC MTX monotherapy allowed to achieve LDA or remission in the vast majority of rheumatoid arthritis patients with good response to treatment. #THU0160

    Parenteral MTX is associated with improved survival over oral MTX for initial treatment in patients with rheumatoid arthritis. #THU0255

    SC MTX has better efficacy and tolerability than in oral MTX, if there is inefficacy or intolerability due to GIS side effects. #AB0473

    Higher cumulative use of MTX / trad. DMARDs within the 1st year after RA diagnosis is associated with less joint replacements. #THU0120

    Compared to oral MTX repeated intra-articular MTX injections show a quicker suppression of knee synovitis. #SAT0364

    The combination of leflunomide plus MTX was effective in the majority of rheumatoid arthritis patients and is a cost-effective. #AB0456

    Patients with polymyositis and dermatomyositis do not significantly benefit from upfront MTX addition to glucocorticoids. #OP0289

    Methotrexate should be consideres in GCA patients with severe corticosteroid-related side effects / prolonged corticosteroid therapy. #SP0004

Adverse events

    There hasn't been much on adverse events; maybe because we think we know these side effects well enough.

Only 14% of rheumatois arthritis patients developed macrocytosis after conversion from oral to SC MTX. #AB0458

    None of the patients (any Autoimmune Inflammatory Rheumatic Disease - AIIRD) developed MTX pneumonitis and only one had ILD related to RA. N=43 (!) #AB0459

Hope you stayed through these condensed results on methotrexate.

Fibromyalgia at the EULAR 2014 Meeting in Paris

There always is an abundance of posters and abstracts on fibromyalgia at the international meetings. One has to select a few and leave the rest for more specific discussions.

[SP0061]

W. Häuser talked about: “FIBROMYALGIA – WHAT REALLY WORKS? FROM ANCIENT TO RECENT MANAGEMENTS“. He stated: “Multiple systematic reviews of randomised controlled trials (RCTs) demonstrated that no therapy (complementary/alternative, drug, physical, psychological) in FM “really works” in the sense of substantial symptom relief in the majority of patients.“ “…“old drugs” such as amitryptiline or fluoxetine did not differ from “new” drugs such as duloxetine, milnacipran and pregabalin in terms of symptom reduction and tolerability.“ Effects of were comparable to aerobic exercise and cognitive behavioral therapies, only the latter show evidence of sustained positive effects after the end of treatment. As there are no predictors, treatment responders should be treated. “Patients with mild FM do not need a specific treatment.” Häuser refers to the recent guidelines (Canada, Germany, Israel) and comments on drug therapy. "A recent study which combined aerobic exercise with tailored psychological therapies showed promising long-term results.“

Aerobic exercise plus cognitive behavioral therapy has a positive effect in patients, who allow such treatment. We have been treating patients successfully in this way at our centre since the late 1990ies and therefore it’s depressing for me to see one drug study following the next (duloxetine, milnacipran, and pregabalin) and a lack of studies addressing the issue of cognitive behavioral therapy plus aerobic exercise. I’m optimistic that this will change.

A little aside: recently German physicians have been warned about the risk of addiction to pregabalin.

[SP0125]

F. Mckenna on: “MANAGEMENT OF FIBROMYALGIA”. Very interesting talk. “Current data [therefore] supports the hypothesis that both fatigue and chronic widespread pain in FM result from abnormalities in sleep architecture in patients with psychological vulnerability, leading to dysfunction in the descending pain regulating system. These data suggest that management of FM should be multifaceted. In addition to physical, behavioural and other psychological therapies, treatment programmes must include active management of sleep pathology.”

Fatigue and sleep have been issues since the beginning of fibromyalgia research, but pain has been addressed more often than fatigue and sleep. I have used tips and recommendation as well as discussions with patients.

Please refer to “Recommendations for a sound sleep 2.0” http://rheumatologe.blogspot.de/2013/06/recommendations-for-sound-sleep-20.html

[OP0122]

M.J. Beasley and colleagues presented: “ASSOCIATION BETWEEN ALCOHOL CONSUMPTION AND CHRONIC WIDESPREAD PAIN: RESULTS FROM A POPULATION-BASED CROSS-SECTIONAL STUDY“. Conclusions: “Moderate alcohol consumption was associated with lower CWP (chronic widespread pain) prevalence, and strongly associated with lower levels of disability in those with CWP. A potential biological mechanism is alcohol’s agonist effects on the neurotransmitter γ-aminobutyric acid (GABA), and disruptions to GABA pain inhibitory pathways have been suggested in persons with FM. Further investigation of the mechanism for these associations is required, specifically whether the excess of highly disabling pain in lifetime non-drinkers with CWP can be explained by other lifestyle or psychosocial factors.

The topic fibromyalgia and alcohol has already been discussed. I’ve written a blogpost on “Fibromyalgia and Alcohol as a Treatment?” as there had been a study by C.H. Kim and colleagues with the title: “Association between alcohol consumption and symptom severity and quality of life in patients with fibromyalgia“; link: http://rheumatologe.blogspot.de/2014/04/fibromyalgia-and-alcohol-as-treatment.html.

[OP0288-PARE]

R. Greiff presented: „PAIN SCHOOL “KNOWLEDGE FOR LIFE” MAKES LIFE EASIER FOR PEOPLE WITH CHRONIC PAIN“. Conclusions: “… “Knowledge for Life” becomes for many of the participants with chronic pain/fibromyalgia a turning point in life. Where there was no hope only despair, there is new belief in their own abilities.“

[THU0329]

X. Chen and coleagues presented: “PLACEBO EFFECT IN FIBROMYALGIA – A SYSTEMATIC REVIEW OF RANDOMISED CONTROLLED TRIALS”

Methods: We searched Medline, PubMed, Web of Science, EMBASE, and

Results: „3375 studies were found from the literature search. After scrutiny, 204 trials met the inclusion criteria. In total 13,968 participants were included from all trials, (mean age 49.2 years; 95.4% women).“ …  Conclusions: „Although considered a hard-to-treat condition, people with FM treated with placebo can show significant improvement in pain and other outcomes. Several variables influence the magnitude of this effect. Optimisation of such contextual response could have relevance to clinical care.“

I’ve looked at this problem, too. Here are my ideas: http://rheumatologe.blogspot.de/2012/06/fibromyalgia-and-pregabalin-some-ideas.html

[THU0318]

M.-A. Fitzcharles and colleagues presented: “REAL-LIFE ASSESSMENT OF THE VALIDITY OF PATIENT GLOBAL IMPRESSION OF CHANGE IN FIBROMYALGIA“. Conclusions: “The results of this analysis suggest that overall, a weak correlation exists between PGIC (Patient Global Impression of Change) and improvement in standard FM outcome measures. Furthermore, FUP (follow-up) duration was identified as a significant confounder of patient perception of disease improvement which could be due to recall bias or survival bias. Altogether, these results have important implications for FM management and designing new instruments assessing outcomes in FM.”

OK, I’ve made a subjective selection of studies / abstracts, and others might stress other studies. But I think the EULAR 2014 Meeting showed, that fibromyalgia still needs research and subsequent consensus. The disparities between researchers/experts and non-rheumatologists/GPs on what fibromyalgia is need to be bridged. I am optimistic for the future as scientific proofs on fibromyalgia accumulate with every meeting.

Sarilumab at the EULAR 2014 Meeting in Paris

I hadn’t heard much in a while about sarilumab, fully human monoclonal antibody (MAB) against IL-6R alpha. So I have been very interested in presentations at the EULAR 2014 Meeting in Paris.

[OP0028]

M. Genovese and colleagues presented: “EFFECTS OF SARILUMAB PLUS MTX ON CLINICAL, RADIOGRAPHIC, AND FUNCTIONAL ENDPOINTS IN PATIENTS WITH MODERATE-TO-SEVERE RHEUMATOID ARTHRITIS: RESULTS OF A PHASE 3, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, INTERNATIONAL STUDY”. N=1197!!! Conclusions: “In this phase 3 study, both sarilumab doses (150 mg and 200 mg q2w), in combination with MTX, demonstrated efficacy in pts with active RA who had inadequate response to MTX. Both sarilumab doses met clinical, radiographic, and functional endpoints. Clinical response was maintained throughout the 52-wk study period. Infection SAEs and laboratory abnormalities with sarilumab are consistent with IL-6 signaling blockade.” This looks much better than the studies presented a year ago.

[THU0275]

S. Fiore and collegaegues looled at: “IL-6 RECEPTOR (IL-6R) BLOCKADE WITH SARILUMAB REDUCED CIRCULATING MARKERS RELATED TO

SYNOVIAL INFLAMMATION AND STRUCTURAL DAMAGE IN PATIENTS WITH RHEUMATOID ARTHRITIS (RA) IN A PHASE 2 “.STUDY” Conclusions: “Sarilumab treatment in patients with RA resulted in significant dose-dependent reduction in MMP-generated neo-epitope biomarkers related to joint and tissue turnover.”

I’m a bit more confident in the future of sarilumab. At least it looks much better than a year ago. This year I’d like to say: sarilumab get to the market! Hope it won’t take too long.

Links:

ACR 2012: http://rheumatologe.blogspot.de/2012/12/sarilumab-at-acr-2012-in-washington.html
EULAR 2012: http://rheumatologe.blogspot.de/2012/06/sarilumab-news-from-eular-2012.html  

EULAR 2013 http://rheumatologe.blogspot.de/2013/07/sarilumab-at-eular-2013-meeting.html

ABT-122 at the EULAR 2014 Meeting in Paris

ABT-122 is an anti-TNF/IL-17 Dual Variable Domain immunoglobulin (DVD-Ig™). It had been "demonstrated that dual neutralization of TNF and IL-17 provides greater efficacy than blocking either cytokine alone in mouse collagen induced arthritis".

Allow me to voice my skepticism already at this point. M. Genovese and colleagues have presented a study two years ago, in which secukinumab (an anti-IL-17a MAB) has been studied in patients with rheumatoid arthritis still active despite methotrexate therapy. “Primary endpoint was the proportion of patients achieving American College of Rheumatology (ACR) 20 at wk16.” This endpoint hadn’t been achieved. I'm not convinced that IL-17-inhibition is working in rheumatoid arthritis, but let's come to the study, which has been presented in  Paris.

[THU0521]

C. Cuff and colleagues presented this study: "DUAL NEUTRALIZATION OF TNF AND IL-17 WITH A DVD-IG PROTEIN IS EFFICACIOUS IN COLLAGEN INDUCED ARTHRITIS". A mouse study! Conclusions: "These data demonstrate that dual blockade of TNF and IL-17 with a DVD-Ig™ molecule is efficacious in a pre-clinical model of arthritis and support the rationale to clinically evaluate the anti-human TNF/IL-17 DVD-Ig protein, ABT-122, in rheumatoid arthritis and other inflammatory disorders."

I would expect a benefit in " other inflammatory disorders" like psoriatic arthritis or anylosing spondylitis. But ... I have my reservations. Blocking two cytokines at the same time has been avoided so far. All combinations look at a biologic DMARD (boDMARD) and a conventional/chemical DMARD (csDMARD) and not two biologics. The fear is high that one induces more side effects. Even if further studies prove, that ABT-122 isn't working in rheumatoid arthritis, it might open Pandora's box to study combinations of two biologic DMARDs.

Links:

Secukinumab at the EULAR 2012 Meeting: http://rheumatologe.blogspot.de/2012/06/secukinumab-anti-il17a-monoclonal.html

Sirukumab at the EULAR 2014 in Paris

Two years ago, I’ve already posted about sirukumab (formerly known as CNTO 136), which is a human anti-IL-6 MAB. B. Hsu and colleagues presented a phase 2 study. I asked myself, if there is a market for sirukumab in rheumatoid arthritis, as tocilizumab is already there (and now with an SC option) sirukumab needs methotrexate as co-medication.

At the EULAR 2014 Meeting in Paris there hasn’t been a study on sirukumab on rheumatoid arthritis. But there has been a study on lupus nephritis.

[OP0047]

R. van Vollenhoven and colleagues presented a study: “A PHASE 2, MULTICENTER, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, PROOF-OF-CONCEPT STUDY TO EVALUATE THE EFFICACY AND SAFETY OF SIRUKUMAB IN PATIENTS WITH ACTIVE LUPUS NEPHRITIS”. Conclusions: IL-6 inhibition with sirukumab in pts with active lupus nephritis did not result in a median improvement in proteinuria, however approximately 15-20% of treated patients did show a notable reduction in proteinuria. A high frequency of serious adverse events was observed in this population of immunosuppressed patients with refractory lupus nephritis.” Read between the lines. Sirukumab doesn’t seem to be doing good job.

Does this dim the outlook for sirukumab? Maybe not. The SIRROUND-LTE study on long-term safety and efficacy of sirukumab in rheumatoid arthritis (a phase 3 study) is still recruiting. Therefore we still have to wait, even if there wasn’t new data at the EULAR 2014 Meeting.

Link:

http://rheumatologe.blogspot.de/2012/07/sirukumab-at-eular-2012.html

http://clinicaltrials.gov/ct2/show/NCT01856309

IL-33 / ST2 in Rheumatoid Arthritis at the EULAR 2014 Meeting in Paris

A year ago I had written about the potential role of IL-33, a member of the IL-1 family, in rheumatoid arthritis and experimental inflammatory arthritis. Last year it had been shown, that serum IL33 levels are increased especially in anti-CCP positive RA patients. W.D. Xu and colleagues concluded, that “the role of the IL-33/ST2 axis in B-cell immunopathology in RA needs to be further addressed.”

This year J.-J. Kim and colleagues presented the following study [AB0066]: “Clinical usefulness of serum soluble ST2 in rheumatoid arthritis with anti-TNF-α therapy”. Conclusions: “The serum sST2 level was increased in RA patients, and correlated with other inflammatory markers of disease activity. Monitoring of serum sST2 levels may be a possible marker of effectiveness to anti-TNF-α therapy for RA patients, when this is supported by an extended study with more patients.”

So we see further use of IL-33/ST2 as a marker, but we don’t know more about “the role of the IL-33/ST2 axis in B-cell immunopathology in RA”. There were two more studies, one on Sjogren’s syndrome and one on Adult Onset Still’s Disease.

Link:

EULAR 2013 - http://rheumatologe.blogspot.de/2013/07/il-33-at-eular-2013.html

Studies at EULAR 2014:

[THU0054] INTERLEUKIN-33/ST2 AXIS IN PRIMARY SJOGREN’S SYNDROME: EXPRESSION IN SERUM AND SALIVARY GLAND, AND CLINICAL ASSOCIATION

S.M. Jung 1, J.Y. Kang1, H.K. Min 1, J.H. Koh 1, Y.S. Suh1, J.H. Lee 1, J. Lee 1, J.Y. Lee 1, J.-M. Kim2, J.H. Ju 1, K.-S. Park 1, S.-H. Park 1, H.-Y. Kim3

[THU0531] SERUM SOLUBLE ST2 LEVEL IN PATIENTS WITH ADULT-ONSET STILL’S DISEASE: A POTENTIAL BIOMARKER OF DISEASE ACTIVITY

J.H. Park 1, J.-J. Kim 2, D.-H. Yoo 2

[AB0066] CLINICAL USEFULNESS OF SERUM SOLUBLE ST2 IN RHEUMATOID ARTHRITIS WITH ANTI-TNF-α THERAPY

J.-J. Kim, J.-I. Choi, Y.-B. Joo, D.-H. Yoo

Itolizumab at the EULAR 2014 Meeting in Paris

Itolizumab (Alzumab by Biocon) is a humanized IgG1 MAB that selectively targets CD-6, which is involved in co-stimulation, adhesion, and maturation of T cells. Itolizumab down regulates T cell activation and so reduces synthesis of pro-inflammatory cytokines. It has already been approved by the Drugs Controller General of India (DCGI) for the treatment of chronic plaque psoriasis.

Now, itolizumab has been introduced to the rheumatogy public with one study. But this study is worth mentioning.

[OP0027]

A. Chopra and colleagues presented: “ITOLIZUMAB, A HUMAN ANTI-CD6 MONOCLONAL ANTIBODY, FOR TREATMENT OF RHEUMATOID ARTHRITIS: RESULTS OF A RANDOMIZED, PLACEBO CONTROLLED, PHASE 2 STUDY”. For a dose of 0.2 mg/kg itolizumab ACR20 has been 60%, ACR50 35%, and ACR70 15%. “Overall, at 12 weeks, 58.3% of the itolizumab patients achieved moderate or good response by DAS28-EULAR criteria vs. 20% in MTX-only group; 51.6% of the itolizumab patients maintained moderate or good response at week 24.” Conclusions: “These results provide strong preliminary evidence for the safety and efficacy of itolizumab in combination with MTX in active RA patients with inadequate response to MTX.” N=70

I guess, we’ll hear more of itolizumab. As there is an unmet need of new and effective drugs in psoriatic arthritis; this might be one of these.

Links:

D.S. Krupashankar et al.: Efficacy and safety of itolizumab, a novel anti-CD6 monoclonal antibody, in patients with moderate to severe chronic plaque psoriasis: Results of a double-blind, randomized, placebo-controlled, phase-III study. http://www.ncbi.nlm.nih.gov/pubmed/24703722

Iguratimod at the EULAR 2014 Meeting in Paris

Iguratimod (T-614) is a novel disease modifying anti-rheumatic drug (DMARD). Iguratimod is characterized by inhibitory effects on immunoglobulin production in B cells as well as inhibiting cytokine production. Its' mode of action comes by suppression of nuclear factor kappa B (NF-kB) activation. As I have already written this before, please look for the links below. 2012 there had been three studies, 2013 one study at the EULAR Meeting in Madrid (a study by a Chinese group) and also only one study at the ACR 2013 Meeting.

This time there have been three posters/abstracts on iguratimod. But alas, all with a very limited number of patients.

[AB0464]

K. Kume and colleagues presented: "THE EFFICACY AND SAFETY OF IGURATIMOD IN RHEUMATOID ARTHRITIS PATIENTS WITH CHRONIC RENAL FAILURE". Conclusions: "Iguratimod was effective and safety in RA patients with chronic renal failure. Iguratimod could be used for RA patients with chronic renal failure." But: N=21, of whom 18 completed the study!

[AB0465]

K. Okamura and colleagues presented: "CLINICAL EFFICACY OF THE SYNTHETIC ANTI-RHEUMATIC DRUG, IGURATIMOD". Conclusions: "Our results suggest that IGU is clinically one of the useful synthetic DMARDs to RA patient." N=41 over 24 weeks. No placebo controlled study.

[AB0478]

Y. Hirano looked at: "INFLUENCES OF DISEASE ACTIVITY AT INITIATION OF IGURATIMOD, A SMALL-MOLECULE ANTIRHEUMATIC DRUG, ON EFFICACY OF IGURATIMOD IN PATIENTS WITH RHEUMATOID ARTHRITIS: A MULTICENTER STUDY". Conclusions: "More treatment options other than sufficient MTX and BIO are needed in RA patients with concomitant disease such as lung disease or renal dysfunction. High cost of BIO is another issue to inhibit improvement of signs and symptoms in RA patients. This study suggests that IGU is one of the options not only in RA patients treated with sufficient MTX but also in RA patients with high disease activity treated with insufficient MTX." N=34 over 24 weeks.

I think iguratimod has shown to be a promising candidate for treatment of active rheumatoid arthritis and might become a needed alternative in the conventional (traditional) DMARD class, but the sponsor of studies must show more commitment. Now, we don't need more of the above studies. What we need are double-blind placebo controlled studies with enough patients over a longer period of time. And we need data, if radiographic progression is inhibited or not.

Iguratimod - go for it!

Links:

Iguratimod at the EULAR Meeting 2012

http://rheumatologe.blogspot.de/2012/06/iguratimod-at-eular-2012.html

Iguratimod at the EULAR Meeting 2013

http://rheumatologe.blogspot.de/2013/06/iguratimod-at-eular-2013.html

Iguratimod at the ACR 2013 Meeting

http://rheumatologe.blogspot.de/2014/01/iguratimod-at-acr-2013-meeting-in-san.html

Tofacitinib at the EULAR 2014 Meeting in Paris

Tofacitinib (Xeljanz®) had a negative opinion for marketing authorization in Europe by the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) about a year ago. The issueas had been: an insufficient demonstration of a consistent reduction in disease activity and structural damage to joints; moreover the CHMP had also been concerned about serious infections, gastrointestinal perforations, and malignancies as observed in studies.

At the EULAR 2014 Meeting in Paris tofacitinib has been present in quite a lot of studies. These studies show the commitment of the company to get tofacitinib approved in Europe. I'll show the studies at the end of this blogpost.

[THU0131]

K. Katayama and colleagues presented: "LONG TERM RESULTS OF INHIBITION OF RADIOGRAPHIC JOINT DAMAGE PROGRESSION IN SMALL AND MEDIUM AND LARGE JOINTS IN PATIENTS WITH RHEUMATOID ARTHRITIS TREATED WITH TOFACITINIB MONOTHERAPY". Conclusions: "Progression of small and M-L sized joints were effectively inhibited by tofacitinive mono-therapy." The study shows 4 year data, but only for N=8.

[THU0143]

M. Lamba and colleagues looked at: "PHARMACOKINETICS, BIOAVAILABILITY AND SAFETY OF A MODIFIED RELEASE ONCE DAILY FORMULATION OF TOFACITINIB IN HEALTHY VOLUNTEERS". Conclusions: "This study demonstrates the single dose equivalence of AUCinf

and Cmax of the MR and IR formulations of tofacitinib. Single doses of both formulations were well tolerated. This novel MR formulation of tofacitinib facilitates an opportunity to enable QD dosing, while maintaining systemic drug concentrations similar to the IR formulation (administered BID)." As N=26 isn't adequately powered: "Multiple-dose studies will be conducted to confirm the predictions of the SS PK profile and demonstrate equivalence between formulations following SS dosing."

We don't know if the studies to demonstrate a consistent reduction in disease activity and structural damage to joints have come so dar to be published soon. But we know, that we have at least another year to wait for tofacitinib (Xeljanz®).

Links:
Xeljanz® (tofacitinib) and the Negative Opinion for Marketing Authorization in Europe http://rheumatologe.blogspot.de/2013/04/xeljanz-tofacitinib-and-negative.html
My statement on tofacitinib after EULAR 2012: http://rheumatologe.blogspot.de/2012/07/tofacitinib-oral-jak-inhibitor-at-eular.html

Here are the titles an Abstract numbers of the other studies on for tofacitinib (Xeljanz®):

[OP0152] EFFECTS OF TOFACITINIB MONOTHERAPY VERSUS METHOTREXATE ON PATIENT-REPORTED OUTCOMES IN THE 2-YEAR PHASE 3 ORAL START TRIAL IN METHOTREXATE-NAIVE PATIENTS WITH RHEUMATOID ARTHRITIS

[OP0154] INTEGRATED SAFETY ANALYSIS OF TOFACITINIB IN RA CLINICAL TRIALS WITH A CUMULATIVE EXPOSURE OF 12,664 PATIENT-YEARS

[THU0126] EVALUATION OF THE EFFECT OF TOFACITINIB ON MEASURED GLOMERULAR FILTRATION RATE IN PATIENTS WITH ACTIVE RHEUMATOID ARTHRITIS

[THU0145] ASSOCIATION OF MEAN CHANGES IN LABORATORY SAFETY PARAMETERS WITH C-REACTIVE PROTEIN AT BASELINE AND WEEK 12 IN RHEUMATOID ARTHRITIS PATIENTS TREATED WITH TOFACITINIB

[THU0147] TOFACITINIB, AN ORAL JANUS KINASE INHIBITOR: ANALYSIS OF MALIGNANCIES ACROSS THE RHEUMATOID ARTHRITIS CLINICAL PROGRAMME

[THU0148] TOFACITINIB, AN ORAL JANUS KINASE INHIBITOR: ANALYSIS OF MALIGNANCIES IN JAPANESE PATIENTS ACROSS THE RHEUMATOID ARTHRITIS CLINICAL PROGRAMME

[FRI0178] ESTIMATED MEDICAL EXPENDITURES AMONG PATIENTS WITH RHEUMATOID ARTHRITIS UNDERGOING TREATMENT WITH TOFACITINIB, AN ORAL JANUS KINASE INHIBITOR

[FRI0333] EFFECTS OF TOFACITINIB TREATMENT ON LEPTIN AND OTHER COMPONENTS OF THE MULTI-BIOMARKER DISEASE ACTIVITY SCORE IN PATIENTS WITH RHEUMATOID ARTHRITIS

[AB0089] TOFACITINIB MEDIATES SYNOVIAL ANGIOGENESIS IN PSORIATIC ARTHRITIS

[AB0463] TOFACITINIB IMPROVES ARTERIAL STIFFNESS WITH METHOTREXATE-RESISTANT ACTIVE RHEUMATOID ARTHRITIS. A COHORT STUDY

[AB0474] CHANGES IN T AND B LYMPHOCYTE SUBSETS WITH TOFACITINIB DO NOT TRANSLATE FROM NONCLINICAL SPECIES TO HUMANS

[AB1057] CONTEXTUALISATION OF SAFETY ENDPOINTS IN THE TOFACITINIB RHEUMATOID ARTHRITIS (RA) DEVELOPMENT PROGRAMME: COLLABORATION WITH THE CONSORTIUM OF RHEUMATOLOGY RESEARCHERS OF NORTH AMERICA (CORRONA) REGISTRY

Newer Biologics at the EULAR 2014 Meeting in Paris

I've listed the newer biologics. Already I've marked some red as there haven't been new studies for a long time or an old study had been presented. This traffic light rating is subjective, but I think it may be helpful. None could be marked green as none is near approval as a drug.

Anti-IL-17 MAB

Brodalumab is doing fine, but the phase 3 study needs further recruiting. Ixekizumab seems to be abandoned as nothing has been published at the EULAR 2014 Meeting and usually the companies see that they publish a minor study. Secukinumab (anti-IL-17a MAB) showed data of a phase 3 study.

Anti-IL-6 MAB

Clazakizumab showed a phase 2b study including radiographic data; I think that's promising. Olokizumab seems to be abandoned as nothing has been published at the EULAR 2014 Meeting. Sarilumab (anti-IL-6 Receptor Alpha MAB met clinical, radiographic, and functional endpoints in a phase 3 study.

Anti-CD-6 MAB

Itolizumab showed results, that "provide strong preliminary evidence for the safety and efficacy".

Fibronectin-A-chain connected to IL-10

There's only one MAB and it's called dekavil. The study group presented 7 patients at the EULAR 2013 Meeting, 14 patients at the ACR 2013 Meeting, and now 20 patients. The patients were recruited in four different centers. I don't see the future of this approach as favourable as the authors.

Anti-GM-CSFR-Alpha MAB

Mavrilimumab has been presented in two studies, but no phase 3 study, but I guess that recruiting is a problem.

Anti-complement-factor-5a-receptor MAB

NNC0151-0000 has been stopped because of side effects. NNC0215-0384 is in phase 1.

Anti-B Cell Activating Factor MAB

Tabalumab has been presented with a phase 3 study (N=456) in two abstracts, but "demonstrated no clinical efficacy despite evidence of biologic activity, suggesting that targeting BAFF may not be a viable therapeutic approach to treating pts with RA."

Quite a lot of dead ends! But some interesting developments to get drugs with new modes of action as some of the existing options might not work due to class effects.

Links:

http://rheumatologe.blogspot.de/2014/01/newer-biologics-at-acr-2013-meeting-in.html

Mavrilimumab http://rheumatologe.blogspot.de/2014/06/mavrilimumab-at-eular-2014-meeting-in.html

SAN-300 http://rheumatologe.blogspot.de/2014/01/san-300-at-2013-acr-meeting-in-san-diego.html

Tregalizumab http://rheumatologe.blogspot.de/2014/01/tregalizumab-at-acr-2013-meeting-in-san.html