DÄ internationalArchive6/2022The Safety of Antirheumatic Drugs

Review article

The Safety of Antirheumatic Drugs

Dtsch Arztebl Int 2022; 119: 81-7. DOI: 10.3238/arztebl.m2022.0064

Mucke, J; Simon, H; Burmester, G R

Background: Drug therapy for rheumatic diseases has changed fundamentally in recent decades with the introduction of many new agents. As these drugs may have to be taken for many years, and many of them are of similar efficacy, the safety profiles of the individual substances play an important role in therapeutic decision-making.

Method: This review is based on pertinent literature retrieved by a selective search on the safety profiles of selected antirheumatic drugs.

Results: Non-steroidal antirheumatic drugs, glucocorticoids, conventional disease-modifying drugs such as methotrexate, biological agents, and janus kinase (JAK) inhibitors are all used to treat rheumatic diseases. Register and trial data show that antirheumatic treatments are relatively safe. Infections, in particular, are much less common than initially expected. Cortisone administration is an exception because of its severe long-term sequelae. Biological agents are associated with severe infectious events at a rate of 4–5 events per 100 patient years. Screening before treatment with biological agents has been shown to lower the rate of tuberculosis from 564 to 95 cases per 100 000 patient years. JAK inhibitors have a good safety profile, with respect to infections as well, but there is evidence of their association with cardiovascular problems, malignancies, and thrombosis.

Conclusion: A suitable, safe antirheumatic drug can be chosen for each patient in consideration of individual risk profiles. Regular monitoring enables the early detection of adverse effects. The risk profile of JAK inhibitors, in particular, will be studied in further trials.

LNSLNS

The developments of the past two decades have fundamentally changed the drug treatment of rheumatic diseases. Apart from the classical conventional disease-modifying antirheumatic drugs (cDMARDs), a multitude of biologics including biosimilars (bDMARDs) and, more recently, Janus kinase (JAK) inhibitors, so-called targeted synthetic DMARDs (tsDMARDs), have become available as highly effective treatment options (Table 1). Thirty-nine percent of patients with rheumatoid arthritis (RA) in Germany now achieve remission, compared with 13% during the period 1994–1996 (1).

Disease-modifying drugs for inflammatory rheumatic joint disorders
Table 1
Disease-modifying drugs for inflammatory rheumatic joint disorders

As many of these treatment options are similarly effective, and the drugs are in some cases taken for many years, the safety profiles of the individual substances play an important role. The profiles include adverse effects and intolerances as well as long-term complications such as infections, malignancies, and cardiovascular events.

Long-term data enable comparison of the substances and facilitate statements on their safety profiles. Compared with the general population, patients with inflammatory rheumatic diseases, in particular RA, have an elevated risk of infections (2- to 2.5-fold) (2), lymphomas (2.5-fold) (3), and cardiovascular comorbidity (1.5-fold) (4). In particular, inadequately controlled disease activity is considered an independent risk factor. Better control of disease therefore most likely reduces the risk of the complications mentioned above.

In this article we present the safety profiles of the DMARDs commonly used for inflammatory joint diseases. Due to the multitude of drugs used, only the most important aspects can be touched upon. The most commonly occurring side effects are listed in Table 2; a comprehensive list can be found in the eTable.

The most commonly occurring side effects/adverse drug reactions with DMARDs (up to 1 of 10 every persons treated)
Table 2
The most commonly occurring side effects/adverse drug reactions with DMARDs (up to 1 of 10 every persons treated)
Side effects/adverse drug reactions to DMARD and indications for the interruption of the treatment
eTable
Side effects/adverse drug reactions to DMARD and indications for the interruption of the treatment

Non-steroidal antirheumatic drugs

Non-steroidal antirheumatic drugs (NSAIDs) are often used for rheumatic diseases. As the conventional NSAIDs have an effect on both cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2), their inhibition of COX-1 may lead to stomach and intestinal ulcers as well as hemorrhage if they are administered for long periods and in high amounts. Furthermore, they may prolong the bleeding time because thrombocyte aggregation is inhibited. Although the COX 2-specific drugs celecoxib and etoricoxib usually do not cause these problems, all NSAIDs affect the renal blood flow with potential cardiovascular complications. Likewise, NSAIDs are contraindicated during the third trimester of pregnancy. In inflammatory rheumatic disorders, they should be administered primarily in the early stage, to relieve the symptoms while waiting for a specific antirheumatic treatment to take effect, or later for postarthritic pain (5). An exception is the frequently extended use of NSAIDs as basic treatment for axial spondyloarthritis.

Glucocorticoids

Glucocorticoids (GC) have a strong anti-inflammatory and immunomodulatory effect. Their clinical efficacy in the treatment of RA is well documented (e6). Nevertheless, GC have adverse effects, e.g., infections, high blood pressure, insulin resistance, weight gain, osteoporosis, or even Cushing’s syndrome (e7). GC should therefore only be used, e.g., in RA, at an initial maximum dosage of 30 mg prednisolone equivalent with reduction to 5 mg within 8 weeks and in combination with DMARDs (e8, 6).

The advantages and disadvantages of treatment with GC must be weighed up on a case-by-case basis. At a low dosage (<5 mg prednisolone equivalent per day), the benefits may prevail (7), although here too studies have reported weight gain of 3–5 kg over a period of 2–3 years (e9, e10) and more frequent development of glaucoma (GC = 2 versus placebo = 0 cases in two years) (e10). The weight gain may, however, be caused by reduction of the inflammation, as the catabolic state is reduced during high disease activity. While higher GC doses distinctly increase the risk of infections, this effect could not be verified at low dosage in controlled trials (8). In observational studies, however, an increased risk of infection was frequently described when low doses of GC were taken (≤ 5 mg prednisolone per day) with a hazard ratio (HR) of 1.35 (95% confidence interval [1.19; 1.53] (9), whereby the effects between the studies were very heterogenous (8).

The advantages and disadvantages of GC therapy can best be evaluated by monitoring the patients individually (e8). This includes measurement of blood pressure and weight as well as diagnostic work-up for osteoporosis, cardiovascular disease, diabetes mellitus, and glaucoma. GC-related osteoporosis can be greatly reduced by treatment with calcium, vitamin D, and oral bisphosphonates (10). The administration of GC in the morning or at night with a slow-release tablet appears to be beneficial due to the circadian rhythm of cytokine release (e11).

In the medium term, the goal should be to discontinue GC therapy for rheumatic diseases, or at least to reduce the dose as far as possible (e8). A recent international study showed that this is possible in the majority of patients with RA (7).

Conventional disease-modifying antirheumatic drugs

Methotrexate

Methotrexate (MTX) continues to be the first-line treatment for RA and is also used to treat psoriatic arthritis as well as for secondary inflammatory arthritis. MTX is generally given in a dose of 10 to 25 mg (most commonly 15 mg) once a week. A subcutaneous injection shows higher persistence and better tolerance than oral therapy (11). The most commonly occurring side effects are gastrointestinal problems and general symptoms, which can be reduced by subcutaneous administration and by folic acid treatment on the following day but occasionally lead to discontinuation of treatment. Regular laboratory testing for early detection of the potential increases in liver function tests and changes in blood counts is necessary. Moderate alcohol consumption of <14 units (112 g; 100 mL wine contains approximately 10 g alcohol) per week does not increase the risk of transaminase elevation (12). MTX should not be used in patients with significant renal failure: it is eliminated renally, and with concomitant NSAID therapy, MTX toxicity can be anticipated due to a reduction in tubular MTX secretion. Leflunomide is an alternative in such a situation. MTX pneumonitis occurs only rarely and is probably due to hypersensitivity (e12). In a systematic literature search, the frequency of MTX pneumonitis was estimated at 0.43% (13). A reduction in the risk of interstitial lung disease during MTX treatment was documented in a multicenter case–control study (odds ratio [OR] 0.43 [0.26; 0.69]) (14). Even systematic reviews were unable to identify a causal connection between the intake of MTX and the development of an interstitial lung disease (ILD) in RA patients (15).

The data on the risk of infection during MTX treatment are contradictory. Some studies show a slightly increased risk of infection, while a number of meta-analyses and systematic reviews found no increased risk in RA patients being treated with MTX (16, 17). The risk of malignancy appears not to increase – with the exception of a general increase (HR 2.05 [1.28; 3.28] in the risk of skin cancer, in particular squamous cell carcinoma (18). The greatest risk factor in this regard is inadequately controlled disease activity (19). The intake of MTX is contraindicated during pregnancy and breast-feeding. According to the manufacturers’ product information, treatment should be discontinued 6 months prior to pregnancy.

Sulfasalazine

Overall, sulfasalazine is regarded as a very safe DMARD. The blood count must be monitored regularly because of the increased risk of cytopenia. Due to the sulfonamide content, attention should be paid to any signs of allergy. There is no increased risk of infection or malignancy during treatment with sulfasalazine (20). Reversible oligospermia may occur.

Leflunomide

Leflunomide is an alternative should MTX be contraindicated. The risk profile is similar, with the same rates of hepatotoxicity and gastrointestinal intolerance as with MTX, so equally regular laboratory tests are required (e2, e13). Moreover, there is an elevated risk of arterial hypertension as well as distal axonal polyneuropathy, which is reversible if the therapy is swiftly discontinued (21). There are hardly any data on the risk of infection during leflunomide therapy. A Cochrane review show no significant differences between placebo and leflunomide with regard to infections (e2). The risk of malignancy risk does not appear to be increased during treatment with leflunomide (20). Leflunomide has a long half-life, with the active metabolites remaining in the body for up to 2 years. If necessary—in the case of toxicity or pregnancy, for example—the residence time can be greatly reduced by the administration of cholestyramine.

Hydroxychloroquine

Hydroxychloroquine (HCQ) is generally well tolerated and is used especially in systemic lupus erythematosus (SLE). The most significant side effects include retinal toxicity and polyneuropathy, which is rare but increases in frequency with increasing duration of treatment. It is therefore recommended to perform optical coherence tomography to screen for retinopathy at the outset of therapy and, if the result is normal, to repeat the screening annually for 5 years after commencing treatment (22). The maximum HCQ dose should not exceed 5 mg/kg body weight (23). Furthermore, HCQ is known to bear an increased risk of cardiotoxicity and especially conduction disorders, increasing with the cumulative dose. In addition, intake of HCQ may lead to prolongation of the QT interval and also cause cardiomyopathy. These complications are, however, very rare. A study on more than 4000 patients revealed only three cases of QT syndrome (24). Regular creatine kinase (CK) determination and, if appropriate, electrocardiography (ECG) should, however, be included in the monitoring program (e14). There is no increased risk of infection during HCQ treatment (25).

Biologics

Biologics are substances that are produced biotechnologically or with the aid of genetically modified organisms. Monoclonal antibodies and genetically engineered cytokine or receptor antagonists are used frequently in rheumatology. As a rule, biologics are tolerated very well. The side effects include serious infections, with a rate of approximately four to five events per 100 patient-years. The degree of risk depends on underlying risk factors such as smoking, concurrent treatment with glucocorticoids, age, and concomitant diseases (26). The German RABBIT register for the long-term observation of therapy with biologics in adult patients with rheumatoid arthritis has developed a calculator for easy risk assessment (27).

By means of intensive screening prior to biological therapy, the rate of tuberculosis has been reduced by more than 80% (from 564 to 95 cases per 100 000 patient-years [28]). Nowadays, tuberculosis screening includes a thorough exposure history, an interferon gamma test, and chest radiography. If there is any indication of latent tuberculosis, prophylactic therapy with isoniazid or rifampicin should ensue. In addition, the screening program features routine tests for current or previous hepatitis B or C (29).

Often (in up to 10% of cases), there are minor infectious events, injection site reactions, skin inflammation and, especially with tumor necrosis factor (TNF) inhibitors and interleukin (IL)-6 receptor inhibitors, transaminase elevations and leukopenia (also with abatacept). Urinary tract infections are also reported. Occasional patients have central and peripheral demyelinating diseases, including multiple sclerosis, optic neuritis, and Guillain–Barré syndrome or a lupus-like syndrome (particularly with TNF blocker treatment). Use of IL-6 receptor inhibitors may be followed by neutropenia without a clear association with infections, and diverticulitis, which may lead to intestinal perforation, can occur particularly with tocilizumab. IL-6 blockade generally leads to normalization of C-reactive protein, which stays in the normal range despite infection. The patients and treating physicians should be informed about this in order to prevent misinterpretations and incorrect treatments for infectious events.

Particular attention is currently being paid to rituximab, as this very well tolerated drug can lead to problems during the COVID-19 pandemic: Due to the absence of B-cells, a humoral immune response to SARS-CoV-2 is established either insufficiently or not at all, so that a COVID-19 infection may become severe (30). The success of COVID vaccination is also often limited, and this should be factored into the vaccination strategy (31). Nevertheless, rituximab treatment should be carried out as indicated in the case of life-threatening illnesses such as vasculitides. The procedure with regard to COVID vaccinations is outlined in recent statements from the German Society for Rheumatology (dgrh.de/ Start/Wissenschaft/Forschung/COVID-19/Stellungnahme-Covid-19-Auffrischimpfung.html).

The preparations secukinumab and ixekizumab, which block the cytokine IL-17, are generally very well tolerated. Occasionally, oral candidiasis develops. Inflammatory bowel disaese may be demasked, so such treatment should be avoided in patients with these conditions. The IL-23 blockers ustekinumab and guselkumab, which to date have not been associated with infectious incidents, are very well tolerated.

Registry data show that bDMARDs do not increase the risk of malignant diseases (32, 33). Analysis of a large number of treatment studies showed that TNF blockade (with adalimumab) may be associated with a survival advantage relative to the general population (34). Apart from the general inhibition of inflammation, the good monitoring conditions in clinical studies and a healthy cohort effect have been discussed as possible causes, the latter because patients with considerable comorbidities are not recruited to controlled clinical studies. This effect has to be considered in comparative analyses of other substances such as the JAK inhibitors with TNF-inhibitors.

Janus kinase inhibitors

An additional advance in the development of antirheumatics is the deployment of JAK inhibitors. These small molecules prevent conveyance of the signals from cytokines via their receptors to the cell nucleus. The JAK signal transmission chains are important for many biological reactions, e.g., in interferons, many cytokines, and growth factors. Four kinases are distinguished: JAK-1, JAK-2, JAK-3, and TYK-2. Four JAK inhibitors are currently approved for use in rheumatology: tofacitinib (JAK-1, JAK-2, and JAK-3), baricitinib (JAK-1 and JAK-2), and the JAK-1-selective inhibitors upadacitinib and filgotinib. Further studies are needed to show whether the differing JAK selectivity is also associated with various safety aspects (35). A common factor in all JAK inhibitors is that, considering their very good efficacy and short half-life, they exhibit an overall good safety profile also regarding infections. An important issue is, however, increased susceptibility to herpes zoster, for which the risk is twice as high as with biologics or cDMARDs (32). Patients with inflammatory rheumatic diseases should therefore be vaccinated against herpes zoster as soon as possible.

Creatine kinase and transaminases may be elevated, but this is generally not clinically relevant. Elevation of lipids may also occur. Overall, on the basis of treatment studies and initial large observational studies, the safety profile of the JAK inhibitors does not differ from the biologics. Surprisingly, however, a controlled treatment study in patients with cardiovascular risk factors (ORAL Surveillance) (36) found an increased risk of cardiovascular events (HR 1.43 [0.94; 2.18]) and certain malignancies (HR 1.48 [1.00; 2.19]) compared with the TNF blockers adalimumab and etanercept (37). It is currently uncertain whether the risk really is increased due to the JAK inhibitors in this particular patient population (smoking, hypertension, diabetes), or whether the TNF blockers exert a protective effect. Registry data show that there is no increased risk of infection due to JAK inhibitors in patients aged over 70 years (38). Apart from herpes zoster, another aspect of the JAK inhibition was the occurrence of deep vein thrombosis and pulmonary embolism, which occurred in a randomized controlled study with baricitinib (five cases in the baricitinib arm versus no cases in the placebo arm) (39) and with the higher dose of tofacitinib in the ORAL Surveillance study (HR 6.0 [1.8; 20.3]) (36). No similar signals were found with the selective JAK-1 inhibitors. The overall study program also showed no definitive signals for baricitinib and tofacitinib. In addition, it must be taken into account that RA in itself is associated with an approximately 1.5-fold tendency towards thrombosis (40). In any case, decisions regarding the indications for JAK inhibition following deep vein thrombosis or pulmonary embolism, or if there are risk factors, should be weighed very carefully. In these situations JAK inhibition should be carried out only after inadequate response to cDMARDs and bDMARDs and after detailed discussion with the patient.

Conclusion

The administration of cDMARDs and the use of bDMARDs and JAK inhibitors are relatively safe treatments, provided that the contraindications are observed. In particular, the risk of infection is much lower than initially assumed. Glucocorticoids are the substances with the largest and most severe side effect profile and should be used with caution.

Acknowledgments

The research in the laboratories of H.U.S. is supported by the Swiss National Fund (310030_184816) and by a Russian government program for the recruitment of leading researchers (# 075–15–2021–600).

Conflict of interest statement

Dr. Mucke has received consulting fees from Abbvie, Amgen, AstraZeneca, BMS, Celgene, Gilead, GSK, Novartis, Lilly, Medac, and Mylan, as well as presentation fees from Abbvie, BMS, Celgene, Chugai, Gilead, GSK, Janssen, Lilly, and Novartis. She has received travel expenses and reimbursement of 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. He has received reimbursement of travel expenses and conference fees from Abbvie and Pfizer. He has been/is a member of the advisory boards of Abbvie, Amgen, BMS, Galapagos, Janssen, Lilly, MSD, and Pfizer.

Prof. Simon declares that no conflict of interest exists.

Manuscript submitted on 25 August 2021, revised version accepted on 22 November 2021

Translated from the original German by PoliLingua and David Roseveare.

Corresponding author
Prof. Dr. med. Gerd Rüdiger Burmester
Medizinische Klinik mit Schwerpunkt Rheumatologie
und Klinische Immunologie, Charité – Universitätsmedizin Berlin,
Freie Universität Berlin und Humboldt-Universität zu Berlin
Charitéplatz 1, 10117 Berlin, Germany
Gerd.Burmester@charite.de

Cite this as:
Mucke J, Simon HU, Burmester GR: The safety of antirheumatic drugs. Dtsch Arztebl Int 2022; 119: 81–7. DOI: 10.3238/arztebl.m2022.0064

Supplementary material

eTable
www.aerzteblatt-international.de/m2022.0064

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e11.
Buttgereit F, Doering G, Schaeffler A, et al.: Efficacy of modified-release versus standard prednisone to reduce duration of morning stiffness of the joints in rheumatoid arthritis (CAPRA-1): a double-blind, randomised controlled trial. Lancet 2008; 371: 205–14 CrossRef
e12.
Roubille C, Haraoui B: Interstitial lung diseases induced or exacerbated by DMARDS and biologic agents in rheumatoid arthritis: a systematic literature review. Semin Arthritis Rheum 2014; 43: 613–26 CrossRef MEDLINE
e13.
Curtis JR, Beukelman T, Onofrei A, et al.: Elevated liver enzyme tests among patients with rheumatoid arthritis or psoriatic arthritis treated with methotrexate and/or leflunomide. Ann Rheum Dis 2010; 69: 43–7 CrossRef MEDLINE PubMed Central
e14.
Fiehn C, Ness T, Weseloh C, et al.: [Safety management of the treatment with antimalarial drugs in rheumatology. Interdisciplinary recommendations based on a systematic literature search]. Z Rheumatol 2020; 79: 186–94 CrossRef MEDLINE
e15.
Conaghan P, Cohen S, Burmester G, et al.: Benefit–risk analysis of upadacitinib compared with adalimumab in the treatment of patients with moderate-to-severe rheumatoid arthritis. Rheumatol Ther 2021. https://doi.org/10.1007/s40744-021-00399-5 (last accessed on 10 January 2022) CrossRef
Policlinic and Hiller Research Unit for Rheumatology, University Hospital Duesseldorf, Heinrich-Heine-University Duesseldorf: Dr. med. Johanna Mucke
Institute of Pharmacology, University of Bern: Prof. Dr. med. Dr. h.c. Hans-Uwe Simon
Institute of Biochemistry, Brandenburg Medical School, Neuruppin: Prof. Dr. med. Dr. h.c. Hans-Uwe Simon
Department of Clinical Immunology and Allergology, Sechenov University, Moscow, Russia: Prof. Dr. med. Dr. h.c. Hans-Uwe Simon
Institute of Fundamental Medicine and Biology, Kazan University, Russia: Prof. Dr. med. Dr. h.c. Hans-Uwe Simon
Department of Rheumatology and Clinical Immunology, Charité – Universitätsmedizin Berlin, Freie Universität Berlin und Humboldt-Universität zu Berlin: Prof. Dr. med. Gerd-Rüdiger Burmester
Disease-modifying drugs for inflammatory rheumatic joint disorders
Table 1
Disease-modifying drugs for inflammatory rheumatic joint disorders
The most commonly occurring side effects/adverse drug reactions with DMARDs (up to 1 of 10 every persons treated)
Table 2
The most commonly occurring side effects/adverse drug reactions with DMARDs (up to 1 of 10 every persons treated)
Side effects/adverse drug reactions to DMARD and indications for the interruption of the treatment
eTable
Side effects/adverse drug reactions to DMARD and indications for the interruption of the treatment
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e11.Buttgereit F, Doering G, Schaeffler A, et al.: Efficacy of modified-release versus standard prednisone to reduce duration of morning stiffness of the joints in rheumatoid arthritis (CAPRA-1): a double-blind, randomised controlled trial. Lancet 2008; 371: 205–14 CrossRef
e12.Roubille C, Haraoui B: Interstitial lung diseases induced or exacerbated by DMARDS and biologic agents in rheumatoid arthritis: a systematic literature review. Semin Arthritis Rheum 2014; 43: 613–26 CrossRef MEDLINE
e13.Curtis JR, Beukelman T, Onofrei A, et al.: Elevated liver enzyme tests among patients with rheumatoid arthritis or psoriatic arthritis treated with methotrexate and/or leflunomide. Ann Rheum Dis 2010; 69: 43–7 CrossRef MEDLINE PubMed Central
e14.Fiehn C, Ness T, Weseloh C, et al.: [Safety management of the treatment with antimalarial drugs in rheumatology. Interdisciplinary recommendations based on a systematic literature search]. Z Rheumatol 2020; 79: 186–94 CrossRef MEDLINE
e15.Conaghan P, Cohen S, Burmester G, et al.: Benefit–risk analysis of upadacitinib compared with adalimumab in the treatment of patients with moderate-to-severe rheumatoid arthritis. Rheumatol Ther 2021. https://doi.org/10.1007/s40744-021-00399-5 (last accessed on 10 January 2022) CrossRef