Member of the Indexed in EMBASE/Scopus/Excerpta Medica

(1)

Journal für

Mineralstoffwechsel &

Muskuloskelettale Erkrankungen

Krause & Pachernegg GmbH • Verlag für Medizin und Wirtschaft • A-3003 Gablitz

Member of the Indexed in EMBASE/Scopus/Excerpta Medica

Homepage:

www.kup.at/

mineralstoffwechsel

Online-Datenbank mit Autoren- und Stichwortsuche

Österreichische Gesellschaft für Rheumatologie Österreichische Gesellschaft

für Orthopädie und Orthopädische Chirurgie Offizielles Organ der

Österreichischen Gesellschaft zur Erforschung des Knochens

und Mineralstoffwechsels

News-Screen Rheumatologie Lunzer R

Journal für Mineralstoffwechsel &

Muskuloskelettale Erkrankungen

2016; 23 (2), 59-62

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Unsere Räucherkegel fertigen wir aus den feinsten Kräutern und Hölzern, vermischt mit dem wohlriechenden Harz der Schwarzföhre, ihrem »Pech«. Vieles sammeln wir wild in den Wiesen und Wäldern unseres Bio-Bauernhofes am Fuß der Hohen Wand, manches bauen wir eigens an. Für unsere Räucherkegel verwenden wir reine Holzkohle aus traditioneller österreichischer Köhlerei.

www.waldweihrauch.at

»Feines Räucherwerk

aus dem «

» Eure Räucherkegel sind einfach wunderbar.

Bessere Räucherkegel als Eure sind mir nicht bekannt.«

– Wolf-Dieter Storl

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59

J MINER STOFFWECHS MUSKULOSKELET ERKRANK 2016; 23 (2)

News-Screen Rheumatologie

R. Lunzer

 Th e EULAR Points to Consider for Use of Antirheumatic Drugs Before Pregnancy, and During Pregnancy and Lactation

Skorpen CG, et al. Ann Rheum Dis 2016; 75: 795–810.

Abstract

A European League Against Rheumatism (EULAR) task force was established to define points to consider on use of antirheumatic drugs before pregnancy, and during pregnancy and lactation. Based on a systematic literature review and pregnancy exposure data from several registries, statements on the com- patibility of antirheumatic drugs during pregnancy and lactation were developed. The level of agreement among experts in regard to statements and propositions of use in clinical practice was established by Delphi voting. The task force defined 4 overarching principles and 11 points to consider for use of antirheumatic drugs during pregnancy and lactation. Compatibili- ty with pregnancy and lactation was found for antimalarials, sul- fasalazine, azathioprine, ciclosporin, tacrolimus, colchicine, in- travenous immunoglobulin and glucocorticoids. Methotrexate, mycophenolate mofetil and cyclophosphamide require discon- tinuation before conception due to proven teratogenicity. In- sufficient documentation in regard to fetal safety implies the dis- continuation of leflunomide, tofacitinib as well as abatacept, rituximab, belimumab, tocilizumab, ustekinumab and anakin- ra before a planned pregnancy. Among biologics tumour necrosis factor inhibitors are best studied and appear reasonably safe with first and second trimester use. Restrictions in use ap- ply for the few proven teratogenic drugs and the large proportion of medi cations for which insufficient safety data for the fetus/child are available. Effective drug treatment of active inflammatory rheumatic disease is possible with reasonable safety for the fetus/child during pregnancy and lactation. The dissemina- tion of the data to health professionals and patients as well as their im plementation into clinical practice may help to improve the management of pregnant and lactating patients with rheumatic disease.

Kommentar

Hilfreicher und schưner Übersichtsartikel für die klinische Routine, wenn Patientinnen mit Kinderwunsch oder bereits erfolgter Empfängnis zur Vorstellung kommen. Der frei zu- gängliche Artikel belegt das derzeitige (!) empfohlene Vorge- hen bei Patientinnen unter einer Biologikatherapie basierend auf wissenschaft lichen Daten und Informationen aus Regis- tern. Sicherlich sind die Evidenzlevels „nur“ B und tlw. auch C und D, aber als Unterstützung für das individuel le Vorge- hen hilfreich. Auch auf die postpartale Stillperiode wird ein- gegangen. Von der Expertengruppe wird explizit unter Punkt 6 auf die beiden TNF-α-Blocker Cimzia® und Enbrel® verwie-

sen: „Among b-DMARDs continuation of tumour necrosis fac- tor (TNF) inhibitors during the fi rst part of pregnancy should be considered. Etanercept and certolizumab may be considered for use throughout pregnancy due to low rate of transplacental passage.“

 Cancer Risk in Patients with Spondylo- arthritis Treated with TNF Inhibitors:

A Collaborative Study from the ARTIS and DANBIO Registers

Hellgren K, et al. Ann Rheum Dis 2016 [Epub ahed of print].

Abstract

Background: Safety data on cancer risks following tumour necrosis factor α inhibitors (TNFi) in patients with spondyloarthritis (SpA) (here defined as ankylosing spondylitis (AS), undifferentiated spondarthropaties (SpA UNS), psoriatic arthritis (PsA)) are scarce. Our objective was to assess risks for cancer overall and for common subtypes in patients with SpA treated with TNFi compared with TNFi-nạve patients with SpA and to the general population. Methods: From the Swedish (Anti- Rheumatic Therapy in Sweden (ARTIS)) and Danish (DANBIO) biologics registers, we assembled 8703 (ARTIS = 5448, DAN- BIO = 3255) patients with SpA initiating a first TNFi 2001–2011.

From the Swedish National Patient and Population Registers we assembled a TNFi-nạve SpA cohort (n = 28,164) and a Swe dish age-matched and sex-matched general population comparator cohort (n = 131 687). We identified incident cancers by link- age with the nationwide Swedish and Danish Cancer Registers 2001–2011, and calculated age-standardised and sex-standardised incidence ratios as measures of relative risk (RR). Results:

Based on 1188 cancers among the TNFi-nạve patients with SpA, RR of cancer overall was 1.1 (95 % CI 1.0 to 1.2). Based on 147 cancers among TNFi initiators with SpA, RR versus TNFi-nạve was 0.8 (95 % CI 0.7 to 1.0) and results were similar for AS and PsA when analysed separately. Site-specific cancer RRs: prostate 0.5 (95 % CI 0.3 to 0.8), lung 0.6 (95 % CI 0.3 to 1.3), colorec- tal 1.0 (95 % CI 0.5 to 2.0), breast 1.3 (95 % CI 0.9 to 2.0), lym- phoma 0.8 (95 % CI 0.4 to 1.8) and melanoma 1.4 (95 % CI 0.7 to 2.6). Conclusions: In patients with SpA, treatment with TNFi was not associated with increased risks of cancer, neither overall nor for the six most common cancer types.

Kommentar

Die Registerdaten aus Nordeuropa zeigen jetzt auch gesondert

für den Formenkreis der SpA/PsA, dass kein erhưhtes Risiko

für Karzinome vorliegt (Prostata, Lunge, kolorektal, Mamma,

Lymphom, Melanom). Der Beobachtungszeitraum: 10 Jahre,

bei etwa 8700 Patienten.

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News-Screen Rheumatologie

60 J MINER STOFFWECHS MUSKULOSKELET ERKRANK 2016; 23 (2)

 Effi cacy of First-Line Tocilizumab Th erapy in Early Polymyalgia Rheuma- tica: A Prospective Longitudinal Study

Devauchelle-Pensec V, et al. Ann Rheum Dis 2016 [Epub ahed of print].

 Tocilizumab for Induction and Main- tenance of Remission in Giant Cell Arteritis: A Phase 2, Randomised, Dou- ble-Blind, Placebo-Controlled Trial

Villiger PM, et al. Lancet 2016; 387: 1921–7.

Abstract

Background: Giant cell arteritis is an immune-mediated dis- ease of medium and large-sized arteries that affects mostly peo- ple older than 50 years of age. Treatment with glucocorticoids is the gold-standard and prevents severe vascular complications but is associated with substantial morbidity and mortality. To- cilizumab, a humanised monoclonal antibody against the in- terleukin-6 receptor, has been associated with rapid induction and maintenance of remission in patients with giant cell arteritis. We therefore aimed to study the efficacy and safety of tocilizumab in the first randomised clinical trial in patients with newly diagnosed or recurrent giant cell arteritis. Methods: In this single centre, phase 2, randomised, double-blind, placebo- controlled trial, we recruited patients aged 50 years and older from University Hospital Bern, Switzerland, who met the 1990 Ameri can College of Rheumatology criteria for giant cell arteritis. Patients with new-onset or relapsing disease were randomly assigned (2:1) to receive either tocilizumab (8 mg/kg) or placebo intravenously. 13 infusions were given in 4 week intervals un- til week 52. Both groups received oral prednisolone, starting at 1 mg/kg per day and tapered down to 0 mg according to a standard reduction scheme defined in the study protocol. Allocation to treatment groups was done using a central computerised randomisation procedure with a permuted block design and a block size of three, and concealed using central randomisation gener- ated by the clinical trials unit. Patients, investigators, and study personnel were masked to treatment assignment. The primary outcome was the proportion of patients who achieved complete remission of disease at a prednisolone dose of 0.1 mg/kg per day at week 12. All analyses were intention to treat. This trial is reg- istered with ClinicalTrials.gov, number NCT01450137. Results:

Between March 3, 2012, and Sept 9, 2014, 20 patients were randomly assigned to receive tocilizumab and prednisolone, and ten patients to receive placebo and glucocorticoid; 16 (80 %) and seven (70 %) patients, respectively, had new-onset giant cell arteritis. 17 (85 %) of 20 patients given tocilizumab and four (40 %) of ten patients given placebo reached complete remission by week 12 (risk difference 45 %, 95 % CI 11–79; p = 0.0301). Re- lapse-free survival was achieved in 17 (85 %) patients in the tocilizumab group and two (20 %) in the placebo group by week 52 (risk difference 65 %, 95 % CI 36–94; p = 0.0010). The mean survival-time difference to stop glucocorticoids was 12 weeks in favour of tocilizumab (95 % CI 7–17; p < 0.0001), leading to a cumulative prednisolone dose of 43 mg/kg in the tocilizumab group versus 110 mg/kg in the placebo group (p = 0.0005) af- ter 52 weeks. Seven (35 %) patients in the tocilizumab group and five (50 %) in the placebo group had serious adverse events. In- terpretation: Our findings show, for the first time in a trial set-

ting, the efficacy of tocilizumab in the induction and maintenance of remission in patients with giant cell arteritis.

Kommentar

Diese beiden aktuellen Beiträge zeigen eine relevante neue Th erapieoption (Ergänzung!) bei der PMR/RZA auf. Nach 12 Wochen war der primäre Endpunkt einer PMR-Aktivi- tät Score ≤ 10 bei allen Patienten erreicht, außerdem die be- eindruckende steroidsparende Wirkung von Tocilizumab – bis zu 70 %. Kritisch bewertet wurde das verzögerte Ansprechen der Tozilizumab-Th erapie (in 4 Wochen nur 45 %, gegenüber dem klassischen Kortison doch 71 % [Dasgupta B et al., 2012].

Auch waren die Nebenwirkungen von Tocilizumab vor allem bezüglich Neutropenien (70 %) und Infektionen (25 %) be- trächtlich, wenngleich auf das höhere Alter der PMR-Patien- ten und die damit verbundenen Komorbiditäten zu verweisen sind.

Somit ergibt sich eine Empfehlung als Second-Line-Option bei Patienten mit refraktärem oder wiederkehrendem Krank- heitsverlauf und/oder Toxizität von Glukokortikoid.

 Effi cacy and Safety of Baricitinib in Japanese Patients with Active Rheuma- toid Arthritis Receiving Background Methotrexate Th erapy: A 12-Week, Double-Blind, Randomized Placebo- Controlled Study

Tanaka Y, et al. J Rheumatol 2016; 43: 504–11.

 Rheumatoid Arthritis: RA-BEACON Illuminates Baricitinib

Ummarino D. Nat Rev Rheumatol 2016; 12: 313.

 Baricitinib in Patients with Refractory Rheumatoid Arthritis

Genovese MC, et al. N Engl J Med 2016; 374: 1243–52.

Abstract

Background: In phase 2 studies, baricitinib, an oral Janus kinase 1 and 2 inhibitor, reduced disease activity in patients with rheumatoid arthritis who had not previously received treatment with biologic disease-modifying antirheumatic drugs (DMARDs).

Methods: In this phase 3 study involving 527 patients with an inadequate response to or unacceptable side effects associated with one or more tumor necrosis factor inhibitors, other biologic DMARDs, or both, we randomly assigned the patients in a 1:1:1 ratio to baricitinib at a dose of 2 or 4 mg daily or placebo for 24 weeks. End points, tested hierarchically at week 12 to control type 1 error, were the American College of Rheumatol- ogy 20 % (ACR20) response (primary end point), the Health As- sessment Questionnaire-Disability Index (HAQ-DI) score, the

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61

J MINER STOFFWECHS MUSKULOSKELET ERKRANK 2016; 23 (2) 28-joint Disease Activity Score based on C-reactive protein level

(DAS28-CRP), and a Simplified Disease Activity Index (SDAI) score of 3.3 or less (on a scale of 0.1 to 86.0, with a score of 3.3 or less indicating remission). Comparisons with placebo were made first with the 4-mg dose of baricitinib and then with the 2-mg dose. Results: Significantly more patients receiving baricitinib at the 4-mg dose than those receiving placebo had an ACR20 response at week 12 (55 % vs. 27 %, P < 0.001). Differ- ences between the higher-dose baricitinib group and the placebo group were also significant for the HAQ-DI score and the DAS28-CRP but not for an SDAI score of 3.3 or less. Adverse- event rates through 24 weeks were higher for patients receiving the 2-mg dose of baricitinib and those receiving the 4-mg dose than for patients receiving placebo (71 % and 77 %, respectively, vs. 64 %), including infections (44 % and 40 %, vs. 31 %).

The rates of serious adverse events were 4 %, 10 %, and 7 % in the three groups, respectively. Two nonmelanoma skin cancers and two major adverse cardiovascular events, including a fatal stroke, occurred in the higher-dose group. Baricitinib was associated with a small reduction in neutrophil levels and increases in serum creatinine and low-density lipoprotein cholester- ol levels. Conclusions: In patients with rheumatoid arthritis and an inadequate response to biologic DMARDs, baricitinib at a daily dose of 4 mg was associated with clinical improvement at 12 weeks.

Kommentar

Die Beiträge zu Baricitinib häufen sich und werden bald unse- re DMARD-Bandbreite erweitern. Dieser orale (!) Janus-Kina- se-Hemmer zeigt eine Wirksamkeit in der Monotherapie auf

„Biologika-Niveau“ – bei rheumatoider Arthritis. Auch gibt es zwei Dosierung, sodass auf individuelle Situationen Rück- sicht genommen werden kann. Weitere Vorteile sind auch in der HWZ von doch nur 10–15 Stunden zu sehen. Natürlich sind die klassischen Nebenwirkungen zu erwähnen und auch weiter zu beobachten, wie zum Beispiel Infektionen (Herpes zoster). Somit interessante und gute Th erapieoption auf „ora- ler“ Seite!

 Adalimumab, Etanercept, Infl iximab, Certolizumab Pegol, Golimumab, Tocilizumab and Abatacept for the Treatment of Rheumatoid Arthritis Not Previously Treated with Disease-Mod- ifying Antirheumatic Drugs and Aft er the Failure of Conventional Disease- Modifying Antirheumatic Drugs Only:

Systematic Review and Economic Eval- uation

Stevenson M, et al. Health Technol Assess 2016; 20: 1–610.

Abstract

Objectives: Rheumatoid arthritis (RA) is a chronic inflammato- ry disease associated with increasing disability, reduced quality of life and substantial costs (as a result of both intervention ac-

quisition and hospitalisation). The objective was to assess the clinical effectiveness and cost-effectiveness of seven bio logic disease-modifying antirheumatic drugs (bDMARDs) compared with each other and conventional disease-modifying antirheumatic drugs (cDMARDs). The decision problem was divided into those patients who were cDMARD naive and those who were cDMARD experienced; whether a patient had severe or moderate to severe disease; and whether or not an individual could tolerate methotrexate (MTX). Data Sources: The following databases were searched: MEDLINE from 1948 to July 2013;

EMBASE from 1980 to July 2013; Cochrane Database of System- atic Reviews from 1996 to May 2013; Cochrane Central Regis- ter of Controlled Trials from 1898 to May 2013; Health Tech- nology Assessment Database from 1995 to May 2013; Database of Abstracts of Reviews of Effects from 1995 to May 2013; Cu- mulative Index to Nursing and Allied Health Literature from 1982 to April 2013; and TOXLINE from 1840 to July 2013. Stud- ies were eligible for inclusion if they evaluated the impact of a bDMARD used within licensed indications on an outcome of interest compared against an appropriate comparator in one of the stated population subgroups within a randomised controlled trial (RCT). Outcomes of interest included American College of Rheumatology (ACR) scores and European League Against Rheumatism (EULAR) response. Interrogation of Early Rheu- matoid Arthritis Study (ERAS) data was undertaken to assess the Health Assessment Questionnaire (HAQ) progression while on cDMARDs. Results: Sixty RCTs met the review inclusion criteria for clinical effectiveness, 38 of these trials provided ACR and/or EULAR response data for the NMA. Fourteen additional trials contributed data to sensitivity analyses. There was uncer- tainty in the relative effectiveness of the interventions. It was not clear whether or not formal ranking of interventions would result in clinically meaningful differences. Results from the analy- sis of ERAS data indicated that historical assumptions regarding HAQ progression had been pessimistic. The typical incremental cost per QALY of bDMARDs compared with cDMARDs alone for those with severe RA is > £40,000. This increases for those who cannot tolerate MTX (£50,000) and is > £60,000 per QALY when bDMARDs were used prior to cDMARDs. Values for in- dividuals with moderate to severe RA were higher than those with severe RA. Results produced using EULAR and ACR data were similar. The key parameter that affected the results is the assumed HAQ progression while on cDMARDs. When historic assumptions were used typical incremental cost per QALY values fell to £38,000 for those with severe disease who could tolerate MTX. Conclusions: bDMARDs appear to have cost per QALY values greater than the thresholds stated by the National Institute for Health and Care Excellence for interventions to be cost-effective. Future research priorities include: the evaluation of the long-term HAQ trajectory while on cDMARDs; the rela- tionship between HAQ direct medical costs; and whether or not bDMARDs could be stopped once a patient has achieved a stated target (e.g. remission).

Kommentar

Aufwendiger Beitrag zu den Kosten der modernen Basisthera- pien, und vielleicht doch der Hinweis, dass die Biologika wirt- schaft lich von Bedeutung sind. Die Kosten sind hoch – mit schwerer RA > 40.000 £ (Pfund), kann sich aber auf £ 50.000–

60.000 erhöhen. In der Zusammenfassung wird aber – auf

HAQ-Daten bezogen – schon von einer insgesamt „kosten-

günstigeren und eff ektiven“ Option gesprochen, sodass sich

die biologischen DMARDs ökonomisch rechnen können.

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62 J MINER STOFFWECHS MUSKULOSKELET ERKRANK 2016; 23 (2)

 A Randomized, Double-Blind, Active- and Placebo-Controlled Effi cacy and Safety Study of Arhalofenate for Reduc- ing Flare in Patients with Gout

Poiley J, et al. Arthritis Rheumatol 2016 [Epub ahead of print].

Abstract

Ojective: Arhalofenate is a novel anti-inflammatory uricosuric.

The objective of the study was to evaluate the anti-flare activity of arhalofenate in gout patients. Methods: A 12-week, randomized, double-blind, controlled phase 2b study. Gout patients with ≥ 3 flares during the previous year, who had discontinued urate lowering therapy and colchicine and with a serum uric acid (sUA) ≥ 7.5 and ≤ 12 mg/dL were eligible. Patients were randomized (2:2:2:2:1) to daily arhalofenate 600 or 800 mg, allopurinol 300 mg, allopurinol 300 mg + 0.6 mg colchicine or placebo. The primary outcome was the flare incidence ( number of flares divided by time of exposure). sUA was a secondary outcome. Results: 239 gout patients were randomized and dosed.

The primary outcome comparing flare incidence between arhalofenate 800 mg and allopurinol 300 mg was achieved, with a 46 % decrease (0.66 versus 1.24, p = 0.0056). Arhalofenate 800 mg was also significantly better than placebo (p = 0.049) and not significantly different from allopurinol + colchicine (p = 0.091). Mean changes in sUA were –12.5 % and –16.5 % with arhalofenate 600 mg and 800 mg (p = 0.001 and p = 0.0001 versus placebo, respectively). There were no meaningful adverse events (AEs) differences between groups and no serious AEs re- lated to arhalofenate. One urolithiasis occurred on allopurinol 300 mg. No subjects on arhalofenate developed an abnormal serum creatinine > 1.5-fold pre-treatment value. Conclusion:

Arha lofenate, at 800 mg, significantly decreased gout flares when compared to allopurinol 300 mg. Arhalofenate was well tolerated and appeared safe. Arhalofenate is the first Urate-Low- ering Anti-Flare Therapy.

Kommentar

Arhalofenat war ursprünglich in der Diabetes-Th erapie als orale Option gedacht. Es zeigte sich aber neben der guten harnsäuresenkenden Komponente, dass Arhalofenat auch als

„Anfallsprophylaxe“ eingesetzt werden kann.

In dieser Arbeit konnte Arhalofenat alleine neben der harn- säureenkenden Komponente (46 %) auch eine gleich gute Re- duktion der Gichtattacken erzielen – vergleichbar mit Allopu- rinol + Colchizin (ohne Steroide oder NSAR!).

Die gute Wirksamkeit wird einem dualen Wirkmechanis- mus zugeschrieben: Zum einen, die IL-1β-Produktion als Re- aktion auf MSU-Kristalle zu senken, während andererseits gleichzeitig die in den proximalen Nierentubuli lokalisierten Urat-Transporter, die Harnsäureaufnahme, blockiert werden.

Wichtige Voraussetzung: Die Niere muss ausreichend funktio- nieren!

Korrespondenzadresse:

OA Dr. Raimund Lunzer Interne Abteilung

Krankenhaus der Barmherzigen Brüder Graz-Eggenberg A-8020 Graz, Bergstraße 27

E-Mail: [email protected]

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Ungekühlte Lagerung bis zu

4 Wochen

bei Raumtemperatur möglich

¹

Flexibilität

durch Halbwertszeit

von ca.

3 Tagen

¹

Keine

neutralisierenden Antikörper nachgewiesen

¹

Rheumatoide Arthritis

¹

Juvenile Idiopathische Arthritis (ab 2 Jahren)

¹

Morbus Bechterew

¹

Nicht-röntgenologische axiale Spondyloarthritis

¹

Psoriasis-Arthritis

¹

Plaque Psoriasis

(ab 6 Jahren)

¹

ENBREL ^® ist mehr als Etanercept

Pﬁ zer Corporation Austria Ges.m.b.H., Wien www.pﬁ zermed.at

Klinische Erfahrung

seit über

20 Jahren

²

REFERENZEN

1 ENBREL® in der aktuell gültigen Fachinformation 2 Pﬁ zer Data on ﬁ le

PP-ENB-AUT-0002/01.2016

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