In Reply

Letters to the Editor The Safety of Antirheumatic Drugs by Dr. med. Johanna Mucke, Prof. Dr. med. Dr. h. c. Hans-Uwe Simon, and Prof. Dr. med. Gerd Rüdiger Burmester in issue 6/2022

In response to the valuable suggestions for our article, we would like to point out the following (1):

Methotrexate (MTX)—We agree that various analyses have shown an increased risk of infections with low-dose MTX therapy. Fortunately, the risk of pneumonia or severe infections in the studies cited was low to moderate. In addition, the CIRT study, which was also cited, revealed an only slightly increased risk of mild infections in patients with cardiovascular risk factors but without an inflammatory rheumatic disease. There was no increased risk of serious infections or pneumonia. The aspect of correct intake of MTX is very important and should be emphasized in patient information. Misadministration such as erroneous daily intake instead of weekly intake is rare, but it is potentially life-threatening. Comprehensive information should also be provided for patients as well as for specialists.

Non-steroidal anti-inflammatory drugs (NSAIDs)—In principle, the cardiovascular risk of NSAIDs should not be underestimated. However, patients with inflammatory rheumatic diseases were underrepresented in the cited works, and studies on rheumatoid arthritis (RA) report either no increase in cardiovascular risk (2) or, for axial spondyloarthritis (axSpa), a reduction in cardiovascular risk, with NSAID therapy (3). This is explained by the good anti-inflammatory effect of NSAIDs in axSpa. For RA, NSAIDs are usually a short-term treatment option to reduce the time it takes for disease-modifying antirheumatic drug (DMARD) therapy to take effect and if glucocorticoids are contraindicated. For axSpa, on the other hand, NSAIDs are the therapy of first choice due to their good effects (4). Glucocorticoids have been shown to have no effect here. The use of NSAIDs should be dependent on the indication: while anti-inflammatory use does not appear to be associated with an increased risk of cardiovascular events, other substances should be considered for purely analgesic purposes.

Biologics—Serious infections are defined as those that require intravenous antibiotic therapy and/or hospitalization, or that are fatal. A systematic search of the literature found no substantial differences between the biologics in terms of the rate of severe infections (5). When considering the frequency of infections, it must be taken into account that susceptibility to infections is generally increased in RA due to comorbidities, high disease activity, and co-medication, especially with glucocorticoids. The infection rate has fallen significantly thanks to modern, glucocorticoid-saving medication and due to consistently addressing high disease activity. Good overviews can be found in the works cited by the German Rheumatism Research Centre (DRFZ). The risk score calculator of the DRFZ allows a practical assessment of the risk of infection (www.biologika-register.de/rabbit/risikoscore-fuer-infektionen/).

DOI: 10.3238/arztebl.m2022.0186

Dr. med. Johanna Mucke
Policlinic and Hiller Research Unit for Rheumatology
University Hospital Duesseldorf
Heinrich-Heine University Düsseldorf, Germany

Prof. Dr. med. Dr. h. c. Hans-Uwe Simon
Institute of Pharmacology, University of Bern, Switzerland

Prof. Dr. med. Gerd Rüdiger Burmester
Department of Rheumatology and Clinical Immunology, Charité – University Medicine Berlin
Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany

Conflict of interest statement:

Dr. Mucke has received consulting fees from Abbvie, Amgen, AstraZeneca, BMS, Celgene, Gilead, GSK, Novartis, Lilly, Medac, and Mylan, presentation fees from Abbvie, BMS, Celgene, Chugai, Gilead, GSK, Jannssen, Lilly, and Novartis, and reimbursement of travel expenses and conference fees from Abbvie, Celgene, Novartis, and AstraZeneca.

Prof. Burmester has received consulting and lecture fees from Abbvie, Amgen, BMS, Galapagos, Janssen, Lilly, MSD, Novartis, Pfizer, Roche, and Sanofi, and reimbursement of travel expenses and conference fees from Abbvie and Pfizer. He is a current or former member of the advisory boards of Abbvie, Amgen, BMS, Galapagos, Janssen, Lilly, MSD, and Pfizer.

Prof. Simon declares that no conflict of interest exists.

References

1. Mucke J, Simon HU, Burmester GR: The safety of antirheumatic drugs. Dtsch Arztebl Int 2022; 119: 81–7

2. Bhala N, Emberson J, Merhi A, et al.: Vascular and upper gastrointestinal effects of non-steroidal anti-inflammatory drugs: meta-analyses of individual participant data from randomised trials. Lancet 2013; 382: 769–79

3. Grigoriou A, Ibrahim F, Chaabo K, Scott DL, Steer S, Galloway J: Cardiovascular risk with NSAIDs in rheumatoid arthritis: an analysis using routinely collected data. Rheumatology (Oxford) 2016; 55: 763–4

4. van der Heijde D, Ramiro S, Landewé R, et al.: 2016 update of the ASAS-EULAR management recommendations for axial spondyloarthritis. Ann Rheum Dis 2017; 76: 978–91

5. Sepriano A, Kerschbaumer A, Smolen JS, et al.: Safety of synthetic and biological DMARDs: a systematic literature review informing the 2019 update of the EULAR recommendations for the management of rheumatoid arthritis. Ann Rheum Dis 2020; 79: 760–70