The German Society for Rheumatology recently published guidelines for the sequential therapy of rheumatoid arthritis (RA). These recommendations were developed as a transition from the 2010 EULAR (EUropean League Against Rheumatism) recommendations to the national clinical practice and are based on an updated systematic literature research and expert discussion. While most EULAR recommendations have remained unchanged, some were modified based on new evidence from randomized, controlled trials, current clinical practice, or national drug approval status. The guidelines also include a treatment algorithm for sequential therapy of RA with disease-modifying agents including biologics.
Die Deutsche Gesellschaft für Rheumatologie (DGRh) hat jüngst eine S1-Leitlinie zur sequenziellen medikamentösen Therapie der rheumatoiden Arthritis veröffentlicht. Die Empfehlungen beruhen auf einer Bewertung der EULAR (EUropean League Against Rheumatism) Recommendations vor dem Hintergrund der landesüblichen klinischen Praxis auf der Basis einer aktualisierten systematischen Literaturrecherche und eines Expertenurteils. Während sich viele EULAR-Empfehlungen in der deutschen Version unverändert finden, ergaben sich für einige Änderungen auf der Grundlage neuer Evidenz aus randomisierten kontrollierten Studien, derzeitiger klinischer Praxis oder des nationalen Medikamentenzulassungsstatus. Konkretisiert werden die Empfehlungen durch einen überarbeiteten Therapiealgorithmus mit Basistherapeutika einschließlich Biologika. Der vorliegende Kommentar soll – auch für englischsprachige Leser – die Gemeinsamkeiten und Unterschiede der deutschen Empfehlungen 2012 und der EULAR Recommendations von 2010 erläutern.
On the verge of this year’s German Society of Rheumatology congress in Bochum, the new German guidelines for the medical treatment of rheumatoid arthritis have been published . Based on the 2010 EULAR recommendations (EUropean League Against Rheumatism)  and subsequent evidence from an additional systematic literature research  and expert consensus, they provide not only information concerning state-of-the-art treatment of rheumatoid arthritis (RA) but also a modification of the hitherto common treatment algorithm in Germany .
Although the predominant part of the single EULAR recommendations remains unchanged, recent data from the current systematic literature research resulted in distinct rephrasing of the original EULAR recommendations (Tab. 1, Tab. 2). In addition, differences in the German statuary order and a somewhat different status of approval have been followed. These new guidelines have been approved by a committee of national experts and the executive committee of the German Society of Rheumatology, who have discussed and voted upon the final set of the recommendations.
The national experts agreed to leave the overarching principles and the first two EULAR recommendations without modification. They refer to the quickest-possible diagnosis and treatment of rheumatoid arthritis at its best in accordance with the patient and the rheumatologist, targeting early remission and with respect to direct and indirect costs. Furthermore, it was beyond any doubt that according to recommendation 3, methotrexate should be part of the first treatment strategy.
In case of methotrexate contraindication or intolerance, leflunomide and sulfasalazine are considered part of the first treatment strategy in both recommendations. However, injectable gold is not recommended in the current German guidelines. The main reason for not following the EULAR recommendation in this aspect and despite the available high-level evidence for the efficacy of injectable gold was the decreasing experience of the rheumatologists and the considerable side effects in long-term use.
In contrast to previous decisions, EULAR recommendation 5 took for the first time a firm stand towards a DMARD monotherapy (disease-modifying antirheumatic drug) rather than a combination therapy of synthetic DMARDs. In fact, no clinical study has demonstrated a significant advantage of combination therapy over monotherapy in the absence of glucocorticoids. Nevertheless, the EULAR recommendation also states that while in DMARD naïve patients the balance of efficacy and toxicity favors monotherapy, the respective evidence is inconclusive in DMARD inadequate responders. Here, the German guidelines only state the lacking evidence for the advantage of combination therapy and recommend a monotherapy explicitly for DMARD naïve patients. In DMARD inadequate responders, a clear recommendation remains to be determined by reason of missing evidence.
EULAR and German guidelines conform that adding glucocorticoids to DMARD monotherapy or combination therapy is beneficial for the patient. As evidence concerning doses and duration of glucocorticoid-bridging therapy is not available, both recommendations remain general and lack a more specific advice.
The EULAR recommendation 7 emphasizes the importance of prognostic factors for the further treatment decisions. A biological DMARD can be added to a synthetic DMARD if poor prognostic factors are present in DMARD inadequate responders. Otherwise, a switch to another synthetic DMARD strategy should be considered. At this point, the German guidelines strongly recommend a combination treatment of several DMARDs in DMARD inadequate responders but also allow a biological DMARD as part of the combination therapy if poor prognostic factors are present. The conclusion of both guidelines is similar, even if the order of the German statements accentuates the possibility to primarily utilize the full potential of synthetic DMARD combination.
According to the available evidence and the approval as first biological agents, the initiation of a biological therapy was mainly equalized with the initiation of a TNF (tumor necrosis factor) inhibitor in EULAR recommendation 8. This priority status of TNF inhibitors has been withdrawn in the German guidelines as the more recent biologic DMARDs abatacept and tocilizumab provided equivalent evidence for their efficacy and safety and are also approved as first-line biological agents. As indirect treatment comparison show similar efficacy for all biologic agents except for anakinra, no specific agents are recommended at this point for preferable first line therapy.
The switch to a second biologic treatment after an inadequate response to the first biological therapy remains identical in the EULAR and German guidelines—as second TNF inhibitor, abatacept, rituximab or tocilizumab are possible agents without a specific ranking. However, full efficacy and safety data for a change to a defined second biologic agent following abatacept or tocilizumab are still lacking.
In the case of rheumatoid arthritis refractory to several DMARDs and biologic agents, azathioprine, cyclosporin A and cyclophosphamide are specifically recommended by EULAR due to existing evidence on their efficacy, of course with respect to their individual toxicity. However, German recommendation 10 has been rephrased to a more general statement in order to also enable the application of other treatment options with the necessary reduction of evidence level to expert opinion.
The final recommendations conform to the EULAR statements, even if recommendations 12 and 13 are combined in the German guidelines—specific suggestions concerning the procedure in case of a sustained remission are not provided due to the lack of evidence. Intensive treatment strategies and treatment adjustment considering structural progression, comorbidities and safety concerns are self-evident. EULAR recommendation 14 refers to DMARD naïve patients again and creates the possibility to begin a biologic agent in combination with MTX as a first treatment strategy in individual patients with poor prognostic factors. By reason of order, this exceptional case was included and discussed in recommendation 3 of the German guidelines.
The aligned treatment algorithm summarizes the recommendations and represents the current practice subjected to the different strategy steps in the course of the disease (Fig. 1).
Taken together, the new 2012 German recommendations provide an update of the current evidence for the medical treatment on rheumatoid arthritis on the basis of the 2010 EULAR recommendations, providing an evidence-based real-life set of recommendations for the use in the daily practice of every rheumatologist in (and outside) of Germany.
Krüger K, Wollenhaupt J, Albrecht K et al (2012) S1-Leitlinie der DGRh zur sequenziellen medikamentösen Therapie der rheumatoiden Arthritis 2012: adaptierte EULAR Empfehlungen und aktualisierter Therapiealgorithmus. Z Rheumatol 71:592–603
Smolen JS, Landewe R, Breedveld FC et al (2010) EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs. Ann Rheum Dis 69:964–975
Albrecht K, Krüger K, Müller-Ladner U, Wollenhaupt J (2012) Systematische Literaturrecherche für die S1-Leitlinie zur sequentiellen medikamentösen Therapie der rheumatoiden Arthritis. Z Rheumatol 71:604–618
Wollenhaupt J, Alten R, Backhaus M et al (2009) Aktualisiertes Therapieschema der Rheumatoiden Arthritis. Ergebnisse eines Konsensusprozesses deutscher Rheumatologen. Akt Rheumatol 34:234–239
This article is distributed under the terms of the Creative Commons Attribution License which permits any use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited.
Conflict of interest
On behalf of all authors, the corresponding author states the following: speakers honoraria from Abbott (K.A.); honoraria for consultation, speaking honoraria, and/or reimbursement of travel costs from Abbott, BMS, MSD, Mundipharma, Pfizer, UCB, Roche (K.K.); honoraria from Abbot, BMS, Chugai, MSD, Pfizer, Roche, UCB (U.M.-L.); honoraria from Abbott, BMS, Chugai, MSD, Pfizer, Roche, UCB (J.W.).
©The Authors (2013) This article is published with open access at Springerlink.com.
About this article
Cite this article
Wollenhaupt, J., Albrecht, K., Krüger, K. et al. The new 2012 German recommendations for treating rheumatoid arthritis. Z. Rheumatol. 72, 6–9 (2013). https://doi.org/10.1007/s00393-012-1093-6