High Hopes and Aspirations or how ASP015K / Peficitinib brings back the Small Molecule Hype

ASP015K, now called peficitinib is an oral Janus kinase (JAK) inhibitor with selectivity for JAK1/3, developed by Astellas Pharma for treatment of rheumatoid arthritis (RA) and other autoimmune diseases [1]. A year later, as the hype about JAK and small molecules were cooling down, I’ve written: “Could ASP015K keep up with its’ aspirations at the EULAR 2013 meeting?” And: “My positive impression dwindles considerably! I hope we’ll see results from a phase 2b study later this year.” [2] So we already had a Phase 2b study presented at the EULAR 2013 Meeting.

As tofacitinib and baricitinib are approved in the EU right now, hype and hopes in protein kinase inhibitors return. Last year I’ve speculated: “I guess that the pharmaceutical industry isn’t prudent enough not to overprice small molecules, so that our patient's needs are addressed.” [3] And I’ve proven right. [4]

Recently Gregory M. Weiss, M.D. has published an article [5]: “JAK Inhibitor Peficitinib Reduces RA Symptoms”. He refers to a phase 2b study. So, it seemed to me nothing new under the sun. I stumbled over the sentence: “The authors suggest that rheumatoid arthritis patients with elevated C-reactive protein levels may respond better to higher doses of peficitinib than those with elevated sedimentation rates.” Most of my patients, who have elevated sedimentation rates also have elevated C-reactive protein levels, and vice versa.

There is already a phase 3 study on Peficitinib under way [6]. I’ve checked the abstracts for the 2017 EULAR Meeting (still under embargo), but there isn’t any study mentioned, so that I expect news on this study could be published at the ACR 2017 Meeting later this year.

There will be an open extension phase 2b study on filgotinib being presented at the EULAR 2017 Meeting. No study on decernotinib expected at the EULAR 2017 Meeting.

The race for the high end price level small molecules is open again. Let’s hope that besides the hype there’ll be some benefit for our patients.

Links:

[1] http://rheumatologe.blogspot.de/2012/12/asp015k-at-acr-2012-in-washington.html

[2] http://rheumatologe.blogspot.de/2013/06/asp015k-at-eular-2013-meeting.html

[3] http://rheumatologe.blogspot.de/2016/08/protein-kinase-inhibitors-small.html

[4] http://rheumatologe.blogspot.de/2017/05/tofacitinib-xeljanz-kommt-gerade-an.html Text in German.

[5] http://www.rheumatologynetwork.com/rheumatoid-arthritis/jak-inhibitor-peficitinib-reduces-ra-symptoms?GUID=71CAAEF6-94A2-4616-B379-17C18CF13750&rememberme=1&ts=30052017

[6] http://adisinsight.springer.com/drugs/800028907

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FDA Approval for Apremilast (Otezla) in Patients with Psoriatic Arthritis (PsA)

The FDA has approved apremilast (Otezla) to treat adult patients with active psoriatic arthritis (PsA). The currently approved DMARDs include biologics like THN-alpha-inhibitors and an IL-12/IL-23 inhibitor (ustekinumab).

The safety and effectiveness of apremilast (Otezla), a phosphodieasterase-4-inhibitor (PDE-4), were evaluated in three clinical trials involving 1,493 patients with active PsA. Patients treated with apremilast (Otezla) showed improvement in signs and symptoms of PsA compared to placebo. Link: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm390091.htm

There has been a study by Arthur Kavanaugh and colleagues (Abstract No. L13) at the 2012 ACR Meeting in Washington: “Apremilast, an Oral Phosphodiesterase 4 Inhibitor, in Patients with Psoriatic Arthritis: Results of a Phase 3, Randomized, Controlled Trial”. Conclusion: “Apremilast significantly improved signs and symptoms of PsA and resulted in statistically and clinically meaningful improvements in physical function. Apremilast was generally well tolerated and no new safety or laboratory signals were detected.” Lets look at some side effects: diarrhea (placebo: 2.4%; apremilast 20 mg BID: 11.3%; and apremilast 30 mg BID, 19.0%), nausea (high dose: 18.5%), headache (10.1%, and 10.7%), and more.

At the 2013 ACR Meeting in San Diego we saw even more studies.

C.J. Edwards and colleagues presented the following study [Abstract No. 311]: “Long-Term (52-Week) Results Of a Phase 3, Randomized, Controlled Trial Of Apremilast, An Oral Phosphodiesterase 4 Inhibitor, In Patients With Psoriatic Arthritis and Current Skin Involvement (PALACE 3).” Conclusion: “Over 52 wks, APR continued to demonstrate efficacy in the treatment of PsA and associated psoriasis, including clinically meaningful improvements in signs and symptoms and physical function. APR demonstrated an acceptable safety profile with up to 52 wks of treatment and was generally well tolerated.”

M. Cutolo and colleagues presented the following study [Abstract No. 317]: “Apremilast, An Oral Phosphodiesterase 4 Inhibitor, Is Associated With Long-Term (52-Week) Improvement In Tender and Swollen Joint Counts In Patients With Psoriatic Arthritis: Results From Three Phase 3, Randomized, Controlled Trials.” Conclusion: “Over 52 wks, APR continued to demonstrate efficacy in the treatment of PsA, including clinically meaningful improvements in SJC and TJC. APR demonstrated an acceptable safety profile and was generally well tolerated for up to 52 wks.”

G. Schett and colleagues presented the following study [Abstract No. 331]: “Apremilast, An Oral Phosphodiesterase 4 Inhibitor, Is Associated With Long-Term (52-Week) Improvement In Physical Function In Patients With Psoriatic Arthritis: Results From Three Phase 3, Randomized, Controlled Trials.” Conclusion: “Over 52 wks, APR continued to demonstrate meaningful clinical response in PsA pts, including measures of physical function. APR demonstrated an acceptable safety profile and was generally well tolerated for up to 52 wks.”

There were some more studies shown at the  ACR 2013 Meeting in San Diego, for long-term safety look at the following study.

A. Kavanaugh and colleagues presented the following study [Abstract No. 310]: “ Long-Term Safety and Tolerability Of Apremilast, An Oral Phosphodiesterase 4 Inhibitor, In Patients With Psoriatic Arthritis: Pooled Safety Analysis Of Three Phase 3, Randomized, Controlled Trials.” Conclusion: “APR demonstrated an acceptable safety profile and was generally well tolerated for up to 52 wks with no new safety concerns identified with long-term exposure. These data do not indicate a need for laboratory monitoring.”

We now must look, which group of patients really benefits from the new drug. We must compare efficacy and costs in everyday life. And we still need some head to head evaluation against established biologics. How about radiographic changes erosions as well as proliferations? Still some work to be done and still a long way to go, but

Welcome Otezla!

There sure are patients waiting for you! And hopefully Otezla will get EMEA approval soon.

Fatigue and Rheumatoid Arthritis


During the past months it seend that nearly every patient complained about fatigue and flare or remission weren't good predictors. I've already written a blogpost on fatigue, link: http://rheumatologe.blogspot.de/2012/08/fatigue.html. And fatigue is different from morning stiffness, another common symptom.

Recently I've read the following tweet on Twitter:
AmerCollRheumatology @ACRheum The Puzzle of Fatigue in #Rheumatoid Arthritis ow.ly/jjC32 #rheumatology
http://www.the-rheumatologist.org/details/article/4460461/ACRARHP_Annual_Meeting_2012_Fatigue_for_People_With_Rheumatoid_Arthritis_Rooted_.html#src=social

Fatigue has been indexed for about 25 abstracts presented at the ACR 2012 in Washington. Quite a lot of studies can't be applied to patients with rheumatoid arthritis, but a lot of these studies are relevant. So the tweet and the article by Mary Beth Nierengarten prompted me to look again into the abstracts and fatigue in general.

R. Alten and colleagues presented: "Improved Fatigue-Related Quality of Life in CAPRA-2, a 12 Week Study of 5-Mg Modified (Delayed) Release Prednisone in Rheumatoid" (Abstract No. 367). If fatigue is associated with inflammation it isn't farfetched to expect fatigue getting better under prednisone.

J. P. Hampson and colleagues presented: "Frontal Brain Connectivity to the Default Mode Network Is Associated with Subjective Fatigue Irrespective of Pain and Depression" Abstract No. 803). They tested fibromyalgia patients, but maybe some of the results might also apply to patients with rheumatoid arthritis. They concluded: "This study suggests that connectivity of multiple brain regions to the DMN is associated with subjective reports of fatigue."

S. van Dartel and colleagues presented: "Association of Actometer Assessed Physical Activity and Fatigue in Patients with Rheumatoid Arthritis: Patients with a Lower Daily Activity Have More Fatigue" (Abstract No. 1232). They concluded: "In RA, a higher level of physical activity was associated with less fatigue."

H. Lööf and colleagues presented: "Pain and Fatigue in Adult Patients with Rheumatoid Arthritis - Associations with Demographic Factors, Disease Related Factors, Body Awareness, Emotional and Psychosocial Factors" (Abstract No. 1571). They concluded: "This study identifies that in patients with Rheumatoid arthritis fatigue and pain appears to be associated with disease related factors. Furthermore, fatigue was related to body awareness and emotional factors."

I've already quoted the study of B. I. Bremander and colleagues: "Smoking Is Associated with Worse and More Widespread Pain, Worse Fatigue, General Health and Quality of Life in a Swedish Population Based Cohort of Patients with Psoriatic Arthritis" (Abstract No. 1828). If smoking worsens fatigue in patients with psoriatic arthritis it's only a matter of time to show that smoking also worsens fatigue in patients with rheumatoid arthritis.

N. Lukkahatai and colleagues looked at: "Genomic Categories of Fatigue in Women with Fibromyalgia" (Abstract 1874). They concluded: "Within FM women with high fatigue, there appears to be two distinct patterns of gene expression. These genomic patterns correspond with differences in behavioral characteristics." Though this study is on patients with fibromyalgie, I doubt that one won't find corresponding genomic patterns in patients with rheumatoid arthritis.

P. P. Katz and colleagues presented: "Obesity Is Associated with Higher Levels of Fatigue in RA" (Abstract No. 2411). They concluded: " Obesity appears to play a role in RA fatigue, even after controlling for important covariates such as disease activity, sleep, and depression."

K. Loeppenthin and collegues presented: "Quality of Sleep, Physical Activity and Fatigue in Patients with Rheumatoid Arthritis. A Cross-Sectional Study" (Abstract No. 2689). They concluded: "A high prevalence of sleep disturbances was observed. This study indicates that PA and fatigue play a significant role in self-reported sleep quality." Very intersting, as these findings show parallels to fibromyalgia.

In her article Mary Beth Nierengarten cited R. Geenen from Utrecht University in the Netherlands: “Fatigue is much more strongly correlated with cognitive variables, such as helplessness and catastrophizing thoughts, and behavioral variables, such as pacing of activities, physical fitness, and patterns of sleep and awakening”. So it might well be that we'll reach a better understanding of what has often been called fibromyalgianess in rheumatoid arthritis patients, "the precise physiological substrate of fatigue remains largely unknown". Inflammatory parameters only show a low correlation to fatigue.

We still lack established instruments for monitoring fatigue. There are some being used in research, but they aren't in current every day practice use. So using a VAS or NRS scale concerning fatigue at every visit would already give an overview until better tools are developed. Ch. Bode from the University of Twente in the Netherlands, "reviewed a number of novel measurements of fatigue that can be useful in helping to tailor intervention strategies". There's a table of possible tools, which are interesting for research, but aren't useful in daily practice as rheumatologist won't have the time to read and evaluate diaries. For research however these tools are relevant.

S. Hewlett of the University of the West of England, looked at nonpharmacological interventions of fatigue in rheumatoid arthritis patients. Cognitive behavioral therapy, low-impact aerobic exercise, pool therapy and others showed efficacy. At our center, we use low-impact aerobic exercise and pool therapy as a routine measure. We have a clinical psychologist, who is called, when the patient agrees, though we don't initiate cognitive behavioral therapy during the short stay at our hospital, but would recommend CBT, when indicated. I found quite a lots of interventions on Saraf Hewlett's list that we use successfully in treatment of fibromyalgia patients.

I'm a bit surprised, because it's more than I had expecetd before. R. Geenen presented a chart, but I think we have to make adjustments, because we already have more information. Have a look at my chart.

To fight fatigue in rheumatoid arthritis we have to reduce inflammation and may do so with DMARDs, biologics, corticosteroids (influence on pain, morning stiffness). We can influence stuctural and functional brain changes by early and consequent therapy ("hit hard and early"), which reduce pain, morning stiffness, and stress. With graded exercise we influence the level of fitness and obesity. Reducing corticosteroids as early as possible reduces obesity. Lifestyle changes should also reduce obesity. Sleep hygine, lifestyle changes, pain controll restore sleep.

To sum it up: Fatigue needs more attention by the scientific part of rheumatology. Fatigue is complex and challenging, but it's worth the time to work on the different factors to reduce the burden of fatigue on on rheumatoid arthritis patients.

Two more Studies on Osteoarthritis at the ACR 2012 Meeting in Washington

I’m still reading studies presented at the last ACR meeting. I’d like to talk about two studies on osteoarthritis.

Bing Lu and colleagues looked into “Soft Drink Intake and Progression of Radiographic Knee Osteoarthritis: Data From the Osteoarthritis Initiative” (Abstract No. 745). Their Conclusion: “Our results suggest that frequent consumption of soft drinks may be associated with increased OA progression in men.”
There is a positive association between uric acid level and knee osteoarthritis, but Lu’s study didn’t look into uric acid. Soft drinks might contain fructose and this increases uric acid levels. So uric acid or fructose might be the missing link. According to the study, lifestyle is an issue.

The second study has been presented by Xavier Chevalier and colleagues: “A Randomized, Multicentre, Double Blind, Placebo-Controlled Trial of Anti TNF Alpha (adalimumab) in Refractory Hand Osteoarthritis: The Dora Study” (Abstract No. 2472). Conclusion: “In a group of patients with refractory hand OA, TNFa blockers (adalimumab, 2 sc injections) failed to demonstrate any clinical improvement.” Even if “TNF a is involved in the osteoarthritic process” and osteoarthritis might present flares, TNF alpha doesn’t play the prominent role in osteoarthritis that it does in rheumatoid arthritis. So for me the results of this study are as I would have predicted. I guess the force behind was greed, looking for another field, where to get a FDA or EMA approval. Good, that this study has been published!

ARRY-797 at the ACR2012 in Washington

There has been a late breaking abstract on ARRY-797 about ... osteoarthritis. ARRY-371797 is a p38 inhibitor. There have been some studies on the way:
• A Study of ARRY-371797 in Patients With Rheumatoid Arthritis
• A Study of ARRY-371797 in Patients With Active Ankylosing Spondylitis
These studies had been completed by July 2012, but nothing has been published at the EULAR 2012 meeting in Berlin or at the ACR 2012 meeting in Washington. And then a late breaking poster on osteoarthritis. What does it mean? My guess is that p38 inhibition isn’t working in RA and AS, but the producer (Array BioPharma) is looking desperately for an indication to put the drug on the market. OK, let’s have a closer look, if ARRS-797 is a candidate to treat osteoarthritis.

Alan J. Kivitz and colleagues presented the following study [Abstract No. L1]: “A Randomized, Placebo-Controlled Phase 2 Study of ARRY-797 in Patients with Osteoarthritis Pain Refractory to NSAID Treatment Showed Statistically Significant Improvements in WOMAC Pain and in Biomarkers of Bone and Cartilage Degradation.” Conclusion: “ARRY-797 treatment resulted in durable, statistically significant improvement in OA pain and in reduction of circulating biomarkers of both cartilage and bone degradation in this 4-week study. Further evaluation of the efficacy of this non-opioid analgesic and the potential for disease modifying activity are warranted.”

Wait a Minute! Let’s have a closer look at the results of the WOMAC Pain Score!

Change from Baseline in WOMAC Pain (0-10 NRS)
Study Visit    ARRY-797    Placebo    Oxy ER
Week 1            1.6*             0.9           2.0*
Week 2            1.7              1.3           2.0*
Week 3            2.1              1.7           2.0
Week 4            2.4*             1.6           1.9
BOCF/LOCF. * p _0.05 (2-sided) versus Placebo

“Durable improvement” – ARRY-797 is significantly better than placebo only at week 1 and week 4. The pain reduction of ARRY-797 at week one is equal to placebo at week 4. At best ARRY-797 reduces the pain better than placebo by 0.8 on the NRS. Let’s put the initial pain score at 8.5, placebo would reduce this to 6.9 and ARRY-797 to 6.1. Big deal! Even the much criticized study of L.A. Crofford on pregabalin in fibromyalgia worked with a pain reduction of at least 50% against baseline. ARRY-797 is very far from this goal.

The authors also listed some adverse events in patients treated with ARRY-797: “mild to moderate skin-related disorders, dizziness, diarrhea and stomatitis. Transient increases in CK and mild prolongations in the QTc interval were also noted.”

Well, I don’t think ARRY-797 is a good candidate for a drug on treating osteoarthritis. ARRY-797 hasn’t yet shown so much efficacy to warrant already noticed risks and expected costs.

19.06.2013
Nothing new on ARRY-797 at the EULAR Meeting 2013 in Madrid. But according to the homepage of Array Biophama the project isn't abandoned. Not working in RA and AS, and only mild effects in OA. It seems strange that the company ran for a late breaking poster and doesn't publish more now. I don't see ARRY-797 on the market.

Fibromyalgia at the ACR 2012 in Washington

Fibromyalgia has been an important issue for me at the ACR 2012 in Washington. As there have been 65 abstracts on fibromyalgia, I have to select a few.

Robert S. Katz and colleagues looked at: "Events That Trigger the Onset of the Fibromyalgia Syndrome (FMS)" [Abstract No. 867]. Robert S. Katz is well know in the world of fibromyalgia. Conclusion: "Surgery, severe illness, and accidents precipitated the onset of fibromyalgia in some patients. ... Fibromyalgia symptoms usually began with neck or back pain. Some of the FMS patients experienced symptoms consistent with hypervigilance and post-traumatic stress disorder." The findings aren't so new, but the abstracts illustrates that all kinds of trauma may trigger fibromyalgia.

Dennis C. Ang and collegues were interested in: "Cognitive Behavioral Therapy and Milnacipran in Combination Appears to Be More Efficacious Than Either Therapy Alone" [Abstract No. 952]. Conclusion: "Based on the observed effect sizes, our preliminary data justifies pursuing a larger definitive trial to test the superiority of combination therapy vs. monotherapy.Additionally, a direct comparison of CBT vs. drug monotherapy is warranted to inform future health care decisions." This is due to the fact, that in result the following appeared: "Compared to drug alone, CBT alone was marginally efficacious in improving SF-36 physical function." The problem of this study may be found in the decription of methods: "Subjects also received 8 sessions of telephone-delivered CBT or educational instructions, but only from baseline to week 9." This isn't enough to lead to behavioral changes. But it shows that educational efforts are positive and should be pursued.

Robert S. Katz and colleagues presented another interesting study: "How FMS Patients Become Workaholics" [Abstract No. 1565]. Conclusion: "Pain, fatigue and cognitive dysfunction seriously limited the ability of fibromyalgia patients to work. Patients who were able to continue working utilized tactics including not giving up, staying busy, maintaining a positive attitude, exercise, eating well, getting enough sleep and other strategies. Those who are disabled generally felt they were incapable of successfully using those strategies." I see lots of patients with fibromyalgia who go after the all or nothing principle. This point of view leads to looking at incapabilities rather than looking at chances how to reduce self overload and strain.

Oh, I just happen to notice, I've chosen another study of Robert S. Katz and colleagues. They looked at hypervigilance: "Hypervigiliance in Fibromyalgia" [Abstract No. 1858]. Conclusion: "Results suggest that FMS patients are more aware of social and environmental stressors and more likely to be hypervigilant. They have trouble sleeping and are more easily startled. They are less likely to trust their surroundings. Hypervigilance might confer a survival advantage in threatening circumstances, but the hyper-reactivity associated with the condition could also be associated with the central sensitization of pain and dysesthesias, insomnia and other symptoms associated with FMS." Yes! It's easy to observe this hypervigilance in patients with fibromyalgia starting to learn progressive muscle relaxation after Jacobson. But one can train patients to become less hypervigilant. OK, that's hard work, but very rewarding.

Neda Faregha and colleagues presented an abstracts on: "Emotional Pain and Catastrophizing Influence Quality of Life in Fibromyalgia" [Abstract No. 1865]. Conclusion: "Higher scores on emotional pain and catastrophizing were predictors of poor quality of life, whereas sensory scores better predicted function. Emotional pain, especially when associated with high levels of catastrophization has important negative effects on well-being for FM patients. Psychological interventions targeting these aspects may offer additional benefits to the standard pharmacological management of pain." Another study that directs us to use cognitive behavioral therapy in treating fibromyalgia adequately.

Terry H. Oh and colleagues looked at: "Association of Opioid Use with Symptom Severity and Quality of Life in Patients with Fibromyalgia" [Abstract No. 1866]. Conclusion: "The frequency of opioid use was 24 % in patients with fibromyalgia seen in the FTP at a tertiary medical center. Our results demonstrate that opioid use is associated with adverse social factors and worse symptom severity and physical health in patients with fibromyalgia. To better deal with this problem in clinical practice, factors that predispose to opiod use in patients with fibromyalgia need to be further investigated." Then do this reseaqrch, but lets already start not treating fibromyalgia with opioids. There's no evidence showing a benefit, but strong evidence for opioids leading to central pain sensitization.

Winnie K. Pang and colleagues presented a spirited study: "Financial Conflicts of Interest and Industry Sponsorship Are Associated with Positive Outcomes in Fibromyalgia Randomized Controlled Trials" [Abstract No. 1870]. Conclusion: "Industry sponsorship and FCOIs [financial conflicts of interest] are common in published fibromyalgia drug therapy RCTs and are more likely to be associated with positive outcomes. The small number of eligible trials precluded adjustment for potential confounders to assess whether these represent independent association with study outcome." Positive results are published, to only a lesser effect negative results are published. And marketing does the rest. I won't say that drugs have no place in treating fibromyalgia, but the importance of drugs is much lower than the current practice of prescriptions.

Emma K. Guymer and colleagues (includes Geoffrey O. Littlejohn, whom I konow from my research time in Victoria) looked at: "Increased Psychosocial Stress Is a Major Component of Fibromyalgia Triggers" [Abstract No. 1881]. Conclusion: "Most patients report a specific trigger for their fibromyalgia. The majority of these involved increased levels of psychosocial stress, including those with injury or illness. Patients with an increased psychosocial stress component to their trigger had less severe clinical features if they regularly exercised." Another study, which stresses the combination of exercise and cognitive behavioral therapy (coping with psychosocial stress).

Frederick Wolfe and colleagues presented a study on a cohort of 2,322 fibromyalgia patients: "Rate and Predictors of Work Disability in Fibromyalgia" [Abstract No. 2642]. Conclusion: "The receipt of a SSD [Social Security disability] award is common in fibromyalgia, with an annual incidence of 3.4% (3.0, 3.9%). Although many variables were predictive of SSD in univariate models, only self-report of functional status and current unemployment and/or self-reported disability predicted future SSD. One explanation for the few predictors is that BMI, smoking, education and symptoms contribute to functional status, which then dominates all other predictors." Ann B. I. Bremander and collegues showed [Abstract No. 95], that smoking is associated with worse and more widespread pain, worse disease activity, function, fatigue and health related quality of life in patients with axial spondyloarthritis. Same applies to psoriatic arthritis [Abstract No. 1828]. There's still much to be found in smoking and rheumatology, but also fibromyalgia patients might benefit from stopping to smoke, though this still needs a study for effect size.

There have been lots of new studies on fibromyalgia at the ACR 2012, let's see, what the next meetings around the world will bring to us!

Weather and Rheumatoid Arthritis at the ACR 2012 in Washington

Annika Cutinha and colleagues looked at the effect of weather on symptoms in RA (Abstract No. 88, full title: ). Conclusion: “Although widely believed, no consistent association in the literature between weather and RA symptoms was seen.”

I’d like to tell another story as lots of my patients also tell me about their weather sensitivity.

You might also like to check on the abstract of E. Bossema’s presentation on the influence of weather in patients with fibromyalgia at the EULAR 2012: http://rheumatologe.blogspot.de/2012/06/fibromyalgia-and-influence-of-weather.html  

Neue Therapien bei Rheumatoider Arthritis

Rheumatoide Arthritis

Alte und neue DMARDs - EULAR und ACR 2012

Vortrag in der RheumaAkademie

17. Januar 2012

Die Rheumatoide Arthritis (chronische Polyarthritis) ist die häufigste Erkrankung in der Rheumatologie. Dabei sind besonders Gelenke betroffen, die sich entzünden. Es handelt sich um eine Autoimmunerkrankung, bei der unbehandelt die betroffenen Gelenke zerstört werden. Aber die Krankheit kann außer den Gelenken auch innere Organe angreifen. Die aktuelle Forschung beschäftigt sich auch mit der Frage, ob es sich überhaupt um eine Erkrankung handelt und nicht um mehrere eines Spektrums. In diesem Vortrag soll besonders der Frage von therapeutischen Möglichkeiten, alten und neuen, aber auch zukünftigen, nachgegangen werden.

Synovialitische Schwellungen der Fingergrundgelenke bei Rheumatoider Arthritis

Röntgenbild der Hände mit Ausbildung eines Os carpale (Verschmelzung einzelner Handwurzelknochen zu einem Knochen)
Mehr Informationen zur Rheumatoiden Arthritis auch über Wikipedia: http://de.wikipedia.org/wiki/Rheumatoide_Arthritis

Zu den frühen Therapien gehört das parenterales Gold oder Goldspritzen. Weitere Medikamente kamen hinzu und haben nach wie vor ihren Stellenwert. Die meisten Patienten werden mit Methotrexat behandelt, da es ein gutes Verhältnis von Wirksamkeit zu unerwünschten Arzneimittelwirkungen hat.
Mehr Informationen zu Basistherapien auch über Wikipedia:
http://de.wikipedia.org/wiki/Basistherapie
Mehr Informationen zu Basistherapien auch über die Rheumaliga:
http://www.rheuma-liga.de/home/layout2/page_sta_204.html

Ende der 90iger Jahre kam ein neues Präparat auf den Markt, das für die Therapie der Rheumatoiden Arthritis entwickelt worden war. An der internationalen Multizenterstudie RELIEF haben auch wir uns beteiligt. Es handelt sich um das Medikament Arava (Wirkstoff Leflunomid).

Übersicht über die Wirkmechanismen der DMARDs/Basistherapeutika
    Goldsalze (unklarer Wirkmechanismus) – Aurothiomalat
    Folsäure Inhibition – Methotrexat
    Antimalariamittel – Chloroquin und Hydroxychloroquin
    Aminosalicylate – Sulfasalazin
    Purin Synthese Inhibition – Azathioprin
    Pyrimidin Synthese Inhibition – Leflunomid
    T-Zell Immunsuppression – Cyclosprin A, (Tacrolimus)

Iguratimod
• Iguratimod ist ein neues langwirksames Antirheumatikum (DMARD)
• Effekte auf die Produktion von Immunoglobulinen in B-Zellen
• Die Produktion von Zytokinen wird herabgesetzt
• Die Aktivierung des nuclear factor kappa B (NF-kB) wird herabgesetzt
Mehr unter: http://rheumatologe.blogspot.de/2012/06/iguratimod-at-eular-2012.html
• Es wurden einige Studien vorgestellt
• Kein neuen Studien auf dem ACR
• Medikament ist noch nicht zugelassen
• Wird wahrscheinlich noch dauern

Biologika
Biologika, der Ausdruck klingt harmlos, aber TGN1412 (CD28-SuperMAB) führte zu einem cytokine release syndrome auch cytokine storm genannt. Vier Probanden erlitten heftigstes Multiorgan-Versagen.
Ein  Proband scheint Krebs zu entwickeln. Mehr dazu steht unter Wikipedia, nämlich hier: http://en.wikipedia.org/wiki/TGN1412 und hier: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2964774/ (beide Texte auf Englisch).

Tuberkulose
Die Zahl der Erkrankten an Tuberkoulose ist nach Screening deutlich zurückgegangen. Die unentdeckte Tuberkulose kann unter Biologika lebensgefährlich werden. Wir testen jeden Patienten, dem ein solches Medikament verschrieben werden soll.
Wir haben jetzt eine ganze Reihe von Biologika zur Verfügung, deren Wirksamkeit wir immer besser einschätzen lernen. Selbst das bei der Rheumatoiden Arthritis wenig verwendete Präparat Anakinra wird weiter getestet.

Seit 2008 sind Rituximab, Abatacept, Tocilizumab, Golimumab und Certulizumab als wirksame Medikamente zur Therapie der Rheumatoiden Arthritis zugelassen worden. Es gibt insgesamt nur wenige Daten zum direkten Vergleich der einzelnen Therapeutika. Jasvinder A. Singh hat 2009 eine Metaanalyse vorgelegt, die diese Frage zu beantworten sucht (Jasvinder A. Singh MD: CMAJ 2009. DOI:10.1503/cmaj.091391). Die Daten dieser Metaanalyse waren eine Bestätigung für unser eignes Vorgehen in der Wahl des geeigneten Medikaments.

Übersicht über die Wirkmechanismen der aktuell zugelassenen Biologika
    TNF-alpha Inhibition – Etanercept, Infliximab, 
             Adalimumab, Golimumab, Certolizumab
    Interleukin-1 Blockade – Anakinra
    T-Zell Modulation / Kostimulationshemmung – Abatacept
    B-Zell Depletion – Rituximab
    Interleukin-6 Rezeptor Blockade – Tocilizumab

Ozoralizumab
“Ozoralizumab (ATN-103), a novel TNF-alpha inhibitor, is a trivalent, bispecific NanobodyR that potently neutralises TNF and binds to human serum albumin to increase its in vivo half-life.” Wir werden erst in den nächsten Jahren sehen, ob sich daraus ein zugelassenes Medikament entwickelt.

Abatacept
Das Medikament ist unter dem Namen Orencia zugelassen. Die subkutane Anwendung von Abatacept ist nun zugelassen, so dass man auf die Infusionen verzichten kann.

Ocaratuzumab
Ocaratuzumab is a Fc- and Fab engineered anti-CD20 antibody.
Adrienne O'Reilly and colleagues presented a study (Abstract No. 835): "Low Doses of Ocaratuzumab, a Fc- and Fab-Engineered Anti-CD20 Antibody, Result in Rapid and Sustained Depletion of Circulating B-Cells in Rheumatoid Arthritis Patients".
Wenn Ocaratuzumab es schafft, als B-Zell gerichtete Therapie subkutan zur Verfügung zu stehen, könnte es ein großer Erfolg werden, denn die Infusionen mit Rituximab dauern lange.

Tocilizumab
Für Tocilizumab stehe Studien für die Spritze unter die Haut zur Verfügung, aber die Zulassung für die subkutane Gabe wird noch dauern. Das Marketing der Firma verfolgt aktuell einen anderen Vorteil in der Werbung.

Anti-IL-6 Receptor Nanobody
(ALX-0061) Seamless "First-in-Human" Phase I/II POC Study in Patients with Active RA On Stable MTX Treatment" (Abstract No. 1307). - Völlig unklar, ob und was sich daraus für Vorteile in der Praxis ergeben könnten.

Sarilumab
Sarilumab ist ein Anti-IL-6-MAB. 2011 wurde eine Phase 2 Studie vorgelegt. Link: http://rheumatologe.blogspot.de/2011/12/sarilumab-for-treatment-of-rheumatoid.html 
Was gibt es Neues? Eine Studie schaute aufs Hämoglobin. Eine Studie erzählte etwas über akute Phase Proteine. Was ist aus der Phase 2 Studie geworden? Wo ist die Phase 3 Studie? Hier will man Zeit gewinnen, bis man sich darüber klar geworden ist, was man eigentlich will.

Olokizumab
Olokizumab targets interleukin-6 (IL-6).
R. Fleischmann and colleagues presented: "A Pilot Study Investigating the Tolerability and Pharmacodynamic Effect of Single Intravenous / Subcutaneous Doses of Olokizumab, an Anti-Interleukin-6 Monoclonal Antibody, in Patients with Rheumatoid Arthritis (Abstract No. 1339). They concluded: "These results provided the rationale for a further study to investigate the clinical efficacy of olokizumab in RA."
Das heißt also, dass es Hinweise gibt, die für weitere Studien sprechen.

Biosimilars
Biosimilars werden die Biologika genannt, die ein Zweithersteller nachahmt. Es werden jedoch auch Risiken gesehen, dass nämlich das Folgeprodukt doch nicht völlig identisch ist.
In Südkorea werden bei Celltrion Biosimlars bereits hergestellt. Studien zur Zulassung laufen. Wir sind gespannt, wann diese Präparate zur Verfügung.
    CT-P13 TNF (entspricht Infliximab / Phase III) - dieses Jahr in den USA, 2014 hier bei uns
    CT-P10 CD-20 (entspricht Rituximab / ?)
    CT-P17 TNF (wahrscheinlich Etanercept / ?)
Wir hatten wir eine internationale Diskussion zu Rituximab und mein Freund Dr. Shashank Akerker, der in Mumbai seine rheumatologische Praxis hat und auf einem der Bilder oben zu sehen ist, berichtete über ein Biosimilar, das in Indien bereits verfügbar ist und eingesetzt wird.
Reditux ist ein Biosimilar von Rituximab Reditux ist nur in Indien erhältlich / zugelassen.

Secukinumab
X. Baraliakos and colleagues tested secukinumab (IL-17A inhibition) in a proof-of-concept (PoC) trial and showed via MRI, that secukinumab may reduce spinal inflammation (Abstract No. 574). - Der Wirkstoff wird also noch bei M. Bechterew, wahrscheinlich nicht mehr bei rheumatoider Arthritis weiterverfolgt.

NNC0109-0012 NNC0109-0012 (anti-IL-20 mAb) is a novel human monoclonal IgG4 antibody.
L. SEnolt and colleagues presented: "Clinical Responses and Patient Reported Outcomes to NNC0109-0012 (anti-IL-20 mAb) in Rheumatoid Arthritis (RA) Patients Following 12-Weeks Dosing and 13 Weeks Follow up: Results From a Phase 2a Trial" (Abstract No. 836). Wird sicherlich weiterverfolgt.

NNC0114-0005
NNC0114-0005 is a recombinant anti-IL-21 monoclonal antibody. IL-21 is produced by activated T-cells.
St. Ignatenko and colleagues presented: "First in Human Study with Recombinant Anti-IL-21 Monoclonal Antibody in Healthy Subjects and Patients with Rheumatoid Arthritis" (Abstract No. 1279). Conclusions included: "The improvements in DAS28-CRP for patients with RA at the highest dose level may suggest biologic and clinical activity of NNC0114-0005." Ich bin mir nicht so sicher, ob dieser Wirkstoff eine Zukunft hat.

Small molecules
Small molecules oder kleine Moleküle sind die neueuste Entwicklung. Aber hier wird es kompliziert.
Ich versuche es mit Sprachen zu erklären. Von Zelle zu Zelle spricht man eine andere Sprache als in der Zelle. Und in der Zelle spricht man in verschiedenen Dialekten mit dem Zellkern, der wiederum in einer eigenen Sprache Anweisungen gibt.
Von Zelle zu Zelle sind es die Zytokine, wie z.B TNF-alpha oder die Interleukine. Diese Nachricht wird in der Zellwand durch Kinasen übersetzt. Daraufhin wird im Zellkern aus der Erbinformation wie aus einem Buch eine Anweisung ausgelesen und geht aus dem Zellkern wieder hinaus (mRNA). Für uns sind nun die Kinasen von Bedeutung.
Die Komplexität der Vorgänge lässt sich sehr gut an diesem Bild verfolgen: http://www.google.de/imgres?start=88&hl=de&biw=1339&bih=741&gbv=2&tbm=isch&tbnid=Q0BrIqPJmA8SpM:&imgrefurl=http://www.ask.com/wiki/Wnt_signaling_pathway&docid=rhMiIQ4y3e1e7M&imgurl=http://rpmedia.ask.com/ts%253Fu%253D/wikipedia/commons/thumb/2/29/Signal_transduction_v1.png/500px-Signal_transduction_v1.png&w=500&h=367&ei=cBlvT9ftPOmm4gSolaHAAg&zoom=1&iact=rc&dur=93&sig=111244820799203899031&page=5&tbnh=155&tbnw=211&ndsp=22&ved=1t:429,r:9,s:88&tx=94&ty=81  
Aus der Komplexität ergibt sich auch, dass Fehlschläge erst sehr viel später als bei anderen Medikamenten auffallen können.

Januskinasen
Kommen wir nun zu den Januskinasen. Hier z.B. ist eines dieser Bilder zu den Januskinasen: http://www.google.de/imgres?hl=de&biw=1339&bih=741&gbv=2&tbm=isch&tbnid=613r8cUmWWed7M:&imgrefurl=http://www.cellsignal.com/reference/pathway/Jak_Stat_IL_6.html&docid=F7WEmbTdfA9a_M&imgurl=http://www.cellsignal.com/reference/pathway/images/Jak_Stat_IL_6.jpg&w=700&h=597&ei=3RhvT5iuMPPP4QTui-W_Ag&zoom=1&iact=hc&vpx=367&vpy=135&dur=1262&hovh=207&hovw=243&tx=129&ty=122&sig=111244820799203899031&page=1&tbnh=125&tbnw=147&start=0&ndsp=26&ved=1t:429,r:1,s:0 http://oncochat.typepad.com/.a/6a00d8342ae08153ef01348768e87e970c-popup 

Baricitinib
Baricitinib (also known as INCB28050, LY3009104) is an oral JAK1 and JAK2 inhibitor. Die Studien zeigen ein Präparat, dass ein Potential hat, auf den Markt zu gelangen.
To sum it up: Baricitinib, we’re waiting for you!

GLPG0634
GLPG0634 is selective inhibitor of Janus kinase 1 (JAK-1). With JAK-inhibitors it seems that JAK-2-driven side effects limit the use of non-selective JAK-inhibitors. GLPG0634 has a 30-fold selectivity for JAK-1 over JAK-2 in human whole blood.
Dies spricht dafür, dass dieses Molekül auch eine Chance hat. Aber da der Teufel im Detail steckt, werden wir uns noch eine Weile gedulden müssen.

Dekavil
Dekavil - “F8-IL10 is a fusion protein in which the cytokine is fused with the antibody F8 specific to the alternatively-spliced EDA domain of fibronectin, a marker of angiogenesis.” Sehr geringe Fallzahl!
Dekavil ist ein guter Name, aber die Firma scheint die Studien nicht genügend schnell voranzutreiben.

Tofacitinib
Tofacitinib wurde einige Tage vor dem ACR 2012 von der FDA für die USA zugelassen und zwas unter dem Namen Xeljanz. .
Xeljanz Black kommt allerdings mit einer box warning auf den Markt: opportunistische Infektionen, Tuberkulose, Krebs, Lymphom.

MOR103
(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”. Dies war eine late breaking Studie, also eine Studie, die so interessant ist, dass man sie noch nachträglich zugelassen hat. Die Firma hatte zuvor Studien nur auf der eigenen Webseite veröffentlicht und kommt nur aus dem Nichts, so dass ich einen Marketing-Trick dahinter vermute. Das Medikament muss sowieso noch in einer größeren Studie getestet werden.

Fostamatinib
Concerning fostamatinib (a SYK inhibitor), how far have we come during the the time since EULAR 2012? Any date for launching the drug? Link: http://rheumatologe.blogspot.de/2012/07/fostamatinib-at-eular-2012.html.
I was surprised seeing a rat CIA study on fostamatinib (P. Pine et al. No. 329). Nothing more! Perhaps asking for a date when fostamatinib is to be launched was a bit premature. But is there any drug in sight?
More details are here: http://rheumatologe.blogspot.de/2012/12/fostamatinib-at-acr-2012-in-washington.html.
Hier war ich nun etwas enttäuscht. Ich hatte früher bereits Schwierigkeiten vermutet. Aber jetzt weren bestimmte Studien nicht weiter verfolgt und man kommt mit einer Tierstudie zurück. Wir werden auch sehen, wie es sich weiter entwickelt.

Zusammenfassend können wir auf eine Reihe von klassischen DMARDs, die TNF-alpha-Inhibitoren, Biologika mit weiteren Angriffspunkten sowie dem ersten "small molecule" Xeljanz zugreifen; bald wird die Palette durch Biologika von bekanntem oder neuem Angriffspunkt, Biosimilars und weiteren small molecules erweitert werden.