Introduction
Systemic inflammatory rheumatic diseases are a group of chronic inflammatory diseases of unknown aetiology that affect the musculoskeletal system, but also other organ systems. They are characterised by an inadequate immune reaction of the human body (1,2). In medical treatment, the basis of therapy are non-steroidal anti-inflammatory drugs NSAIDs), glucocorticoids and drugs that modify the course of the disease (disease-modifying antirheumatic drugs, DMARDs) (3,4). The so-called conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) have been used in treatment for several decades, and due to the progress of science and a better knowledge of the pathophysiology of these diseases, the new generations of drugs, biological and targeted synthetic disease-modifying antirheumatic drugs (bDMARDs and tsDMARDs) were developed. Their effects are primarily achieved by blocking certain proinflammatory cytokines. In addition, some of them also inhibit the signal required for the activation of T lymphocytes or act on the depletion of B lymphocytes. Care should be taken when prescribing therapy because, although these drugs act specifically and selectively on the immune system, they reduce the general defence function of the body, so patients are more susceptible to infections, but also to some malignant diseases such as lymphoma, skin cancer, breast cancer or melanoma. Due to the immune background in pathogenesis and the predominantly immunosuppressive approach in the treatment of systemic autoimmune diseases, the risk of malignancy is increased (5). Chronic inflammation can contribute to the process of tumorigenesis (6). It has been proven in animal models that tumour necrosis factor alpha (TNF-α) can inhibit, but also promote tumour development depending on the dose and biological conditions (7). The connection between biological therapy and the development of malignant diseases is the topic of continuous interest of many researchers, considering the pronounced immunomodulatory effect of biological drugs during their long-term use. Tumour necrosis factor inhibitors (TNFi) are associated with a variety of potentially dangerous adverse effects, but the risks must be interpreted in the context of the beneficial effects that are experienced with TNFi use. It is important to keep in mind that conventional drugs used for the treatment of inflammatory rheumatic diseases come with their own harmful effects, just like the disease itself (8). A list of biological DMARDs used in the treatment of inflammatory rheumatic diseases is shown in Table 1. In this paper, which is part of the master’s thesis written at the School of Medicine of the University of Zagreb, the available medical literature (with a special emphasis on more recent works) from the most important databases was analysed, covering the topic of the risks for the development of malignant diseases in patients with rheumatic diseases who were treated with biological DMARDs.
Risk of developing malignant diseases
According to data from the literature, patients suffering from rheumatoid arthritis (RA) have a 10–15% higher total risk of developing some malignancies compared to the general population, for example lung cancer and lymphoma (standardized incidence ratio 1, 2–4), non-melanoma skin cancers (SIR 1–3) and possible melanoma and leukaemia (9). The increased risk may be related to the simultaneous use of other drugs, but also the result of chronic, poorly controlled inflammation (10). On the other hand, due to the chronic use of NSAIDs, including cyclooxygenase-2 (COX-2) inhibitors, a lower incidence of colon adenocarcinoma and breast cancer is noted (11). According to some studies, methotrexate, which is often used in combination with TNF-alpha inhibitors may also be associated with an increased risk of developing lymphoma (5). Many of the conducted studies do not include a sufficient number of subjects in order to obtain a reliable result about a higher risk for the development of a malignant disease. Unlike RA, which was the topic of numerous studies in relation to the impact of TNF-alpha inhibitors, when it comes to other autoimmune diseases, as well as some biological drugs, the data on the increased risk are still insufficient. We must highlight the paper written by Kwan et al. in 2020, in which the risk for the development of a malignant disease in patients with seronegative spondyloarthropathies (SnSpA) was analysed (12). It is a systematic review article and meta-analysis that included 14,245 patients. Demographic and pathogenetic differences between patients with seronegative spondyloarthropathy (SnSpA) and RA are highlighted. Patients with SnSpA, especially those with the axial form of the disease, are mainly affected much earlier than patients with RA. In addition to that, considering the treatment guidelines, they were previously exposed to biological therapy. The pathophysiological aspect is also significant, considering the role of Th17 cells in the development of the disease, but also in tumorigenesis. The authors analysed the risk for the development of malignant disease depending on the type of SnSpA, which can be axial (e.g. ankylosing spondylitis, AS and non-radiographic axial spondyloarthritis, nr-axSpA) or peripheral (e.g. psoriatic arthritis, PsA or enteropathic arthritis, EA) and on therapy (biological drug vs. csDMARD and other types of biological drugs, TNF-alpha inhibitors, IL-17 inhibitors and others). Despite a comprehensive and detailed analysis, ultimately no increased risk was proven in patients with SnSpA, both with the disease itself and with biological therapy, regardless of the biological drug. The paper notes the need for trials that would include patients in a longer follow-up period. With psoriasis, independent of the development of PsA, an increased risk for the development of non-melanoma skin cancers, lymphomas and lung cancers has been described. There is speculation about the effect of IL-17, which promotes angiogenesis, but is also a mediator in immune defence processes against tumours. An increased risk for the development of the above-mentioned tumour diseases, including bladder tumours, in patients with psoriasis is also described in another review from 2020, but no connection with biological therapy was found, nor was there an increased risk for the development of tumours in patients with psoriatic arthritis (13). In studies that researched the risk of malignancy in inflammatory rheumatic diseases, SIR was predominantly used, which is obtained by comparing the recorded and expected incidence of malignancy, the relative risk (RR) and the odds ratio (OR). The advantage of using RR over SIR is higher specificity in the analysis of the risk associated with the therapy.
Studies of overall risk for malignant disease
The results of the studies published so far are conflicting. Some speak in favour, and others against the increased overall risk for the development of a malignant disease, regardless of its site. Initial concern about a possible association between TNF-alpha inhibitors and malignancy was based on a report by the Food and Drug Administration (FDA) from the United States of America (USA) which was published in 2002 and which included 26 cases of lymphoma, predominantly non-Hodgkin’s lymphoma (NHL) in patients with RA and Crohn’s disease who were treated with etanercept (ETN) or infliximab (IFX). Lymphoma remission was verified in 2 of the mentioned 26 patients after discontinuing the use of TNF-alpha inhibitors. However, in the aforementioned report, data were presented without comparison with a control group (14). A subsequent FDA report further raised concerns over the alleged association between malignancies and the listed drugs in children and adolescents treated for juvenile idiopathic arthritis (JIA) and inflammatory bowel disease (IBD) (8). The FDA analysis indicated a total of 48 cases of malignant diseases in a 10 year period (1998–2008) in patients treated with TNF-alpha inhibitors. Almost half of the 48 patients suffered from lymphoma (Hodgkin and non-Hodgkin type), and the rest had leukaemia, melanoma and solid tumours. Based on these reports, a meta-analysis was performed that included 9 clinical studies with a total of 3,493 RA patients who were treated with TNF-alpha inhibitors, drugs such as adalimumab (ADA) or infliximab (IFX). The results showed that the risk of developing malignancy in patients treated with these drugs was 3.3 times higher than in patients on placebo (OR 3.3; 95% confidence interval (CI, 1.2–9.1) (15). The frequency of cancer was higher in patients treated with higher doses of drugs. Out of the 26 malignant diseases registered in patients treated with TNF-alpha inhibitors, 15 had solid tumours. Only one solid tumour was recorded in the control group (patients on placebo).
Contrary to the aforementioned, other studies have shown that there is no increased risk for the development of malignant tumours in RA patients treated with TNF-alpha inhibitors compared to conventional therapy or the general population. The safe use of ADA in RA, PsA, AS, JIA and IBD was demonstrated in a study that included data from 71 clinical trials (16). This study included 23458 patients treated with ADA. The risk of developing tumours in patients treated with ADA, regardless of the inflammatory rheumatic disease for which they were treated, was almost the same as in the reference general population. The SIR for RA was 0.93 (95% CI, 0.82–1.06), for AS it was 0.51 (95% CI, 0.16–0.19), and for PsA it was 0.68 (95% CI, 0.22–1.59). Not a single incidence of cancer was recorded among patients with JIA. Considering the age of the affected population, JIA is certainly of particular interest when it comes to the risk of developing malignant diseases. According to data from the Swedish registry from 2019, for all cancers, regardless of their site, the HR was 1.4 (95% CI, 0.7–2.9), and for lymphoproliferative diseases the HR was 3.6 (95% CI, 1.1–11.2). The data indicate a mildly increased risk for the development of lymphoproliferative disease in patients with JIA, but not for other cancers. Also, the risk does not change depending on the treatment modality (17). In Sweden, a study was conducted in 2009 with the aim of assessing the overall risk for the development of cancer related to the use of TNFi (9). Data from the Swedish registers of biological drugs, rheumatic diseases and cancer were analysed, and the results showed that there was no difference in the risk of developing malignant diseases in patients treated with TNF-alpha inhibitors and csDMARDs (RR = 1.0; 95% CI 0.86–1.15). The study conducted on the basis of data from the Danish Registry for Biological Therapies in Rheumatology (DANBIO) in the period 2000–2008 yielded similar results (18). The data collected from 3347 RA patients who were treated with TNF-alpha inhibitors and 3812 RA patients who were not treated with biological therapy were compared, and overall, no increased risk of malignancy was found in patients treated with TNF-alpha inhibitors (RR=1.02; 95% CI 0.80–1.30). Compared to the general population, the risk of developing malignant diseases was slightly higher (SIR = 1.27; 95% CI 1.08–1.49). According to published meta-analyses and cohort studies on patients with RA, there are similar data for the drugs: abatacept, anakinra, rituximab (RTX) and tocilizumab (TCZ) (19–21). A higher incidence rate of solid or haematological neoplasm and skin cancer in patients on biological therapy compared to patients treated only with csDMARDs was not proven, except for an increased risk of developing squamous cell carcinoma with the use of abatacept (hazard ratio, (HR) was 2.12; 95% CI 1.14–3.95) (21). In a study from Finland, based on data from the national registry, the frequency of occurrence of malignant diseases in RA patients treated with TNF-alpha inhibitors (IFX, ETN, ADA), RTX or csDMARDs was analysed (22). Incidence rate (IR) of malignancy was the highest in patients treated with csDMARDs (IR = 12; 95% CI 8.6–17) and RTX (IR = 9.5; 95% CI 3.8–2.0), and the lowest in patients treated with IFX (IR = 5.8; 95% CI 2.8–11). Comparing biological drugs and csDMARDs, the risk of developing a malignant disease is lower with biological drugs, with the exception of RTX. However, as it was concluded in the study, after adjusting the data according to age and gender, no statistically significant difference was found in the rate of incidence of malignant diseases during treatment with any combination of drugs, and the only risk factor associated with the development of a malignant disease was age.
The safety of secukinumab, which is increasingly used in the treatment of SnSpA, PsA and psoriasis, has been investigated in several large studies. The 2021 study included data from 49 clinical trials that included a total of 14,519 patients whose follow-up was performed over a five-year period (23). The results showed that there is no increased risk for the development of malignant disease (SIR 0.99; 95% CI 0.82–1.19).
Risk for the development of haematological malignancies
Data on the association between TNF-alpha inhibitors and the risk of developing haematological malignancies in patients suffering from systemic inflammatory rheumatic diseases, especially lymphoma, are different. Some authors believe that chronic inflammation, and not its treatment, is associated with an increased risk of lymphoma in RA patients (24). Thus, data from the South Swedish Arthritis Treatment Group indicate a possible increased risk for the development of lymphoma (25). For the development of any malignant disease with the use of TNF-alpha inhibitors (ETN and IFX) the SIR was 1.1 (95% CI 0.6–1.8), and for the control group treated with csDMARDs it was 1.4 (95% CI 1.1–1.8). For lymphoma in the group treated with TNF-alpha inhibitors the SIR was 11.5 (95% CI 3.7–26.9), which is a significantly different result compared to the SIR for the group treated with csDMARDs, which was 1.3 (95 % CI 0.2–4.5). The previously mentioned retrospective cohort study in Sweden conducted on RA patients, which included more than 50,000 subjects, showed that RA patients have an increased risk of developing lymphoma (SIR 1.9) and leukaemia (SIR 2.1) compared to the general population (24). Data collected from the Swedish national registries of patients with AS and PsA in the period 2001–2011 did not show an increased risk for the development of lymphoma in patients with AS compared to the general population (HR 0.9; 95% CI 0.5 – 1.6), while a slightly increased risk was found in patients with PsA (HR 1.2; 95 % CI 0.9–1.7) (26). By comparing PsA patients treated with TNF-alpha inhibitors to patients treated with MTX or sulfasalazine, it was revealed that the risk was slightly higher with conventional therapy (HR 1.7; 95% CI 1.0–3.1).
A study from Japan conducted on a sample of 5,573 patients analysed the safety profile of TCZ in the treatment of patients suffering from inflammatory rheumatic diseases (27). In analysing the number of recorded malignancies, it was revealed that only the incidence of lymphoma was significantly increased in patients treated with TCZ compared to the general population (SIR = 3.13; 95% CI 1.82–5.39). The incidence of leukaemia was not higher compared to the general population (SIR 0.54; 95% CI 0.08–3.83).
A study was conducted in the USA based on data available from the National Databank for Rheumatic Diseases (5). Separate research revealed that neither IFX nor ETN were associated with an increased risk for lymphoma.
The RATIO registry in France was established with the aim of collecting data on all cases of opportunistic infections and lymphomas associated with the treatment with TNF-alpha inhibitors regardless of the underlying disease, and to identify risk factors and compare the risk among different biological drugs (28). Based on the analysis of data collected from 2004–2006 a case control was conducted in which 38 cases of lymphoma (29 non-Hodgkin lymphomas, 5 Hodgkin lymphomas and 2 Hodgkin-like lymphomas) were recorded in patients suffering from inflammatory rheumatic diseases treated with TNF-alpha inhibitors. The risk of developing lymphoma in these patients was elevated compared to the general population (SIR 2.4; 95% CI 1.7–3.2), almost the same as in those who were not treated with drugs of this group. Thus, the study failed to demonstrate an increased risk for the development of lymphoma in patients suffering from inflammatory rheumatic diseases treated with TNF-alpha inhibitors.
Risk for the development of solid malignant tumours
Most of the extensive studies published so far, mostly meta-analyses, which examined the safety of TNF-alpha inhibitor use, did not show a significantly increased risk for the development of solid tumours (5,29). In 20–50% of cases the risk is increased for cancers related to smoking and in 70% of cases there is an increased risk for all skin cancers except melanoma. In contrast, a reduced risk of developing breast cancer by 20% and colorectal cancer by 25% is reported, which was explained in the aforementioned part of the paper.
Furthermore, according to BSRBR-RA data (the British Society for Rheumatology Biologics Register for Rheumatoid Arthritis) there is no increased risk for solid tumours in patients treated with TNFi compared to patients who were never treated with biological drugs (HR 0.83; 95% CI 0.64–1.07) (30). The study included 11,767 RA patients treated with TNF-alpha inhibitors and 3,249 RA patients treated with csDMARDs. A 2015 study by Swedish researchers found no increased risk for developing solid malignancies. In a clinical trial that lasted 11 years, a follow-up was performed on the population of RA patients treated with RTX. The aim of the trial was to determine the possible long-term consequences of this therapy. The most common solid tumour was breast cancer (0.14/100 patient-years; 95% CI 0.08–0.22) (31). The SIR for breast cancer was 0.63 (95% CI 0.79–0.90) suggesting no increased risk compared to previous epidemiological studies of the safety of RTX in RA (SIR = 0.84; 95% CI 0.79–0.90) (32).
Risk for the development of skin cancer and melanoma
Research conducted so far has shown an increased risk for the development of non-melanoma skin cancer (NMSC) in patients suffering from RA (33,34). According to the study results, the use of TNF-alpha inhibitors and prednisone increases the risk of developing NMSC, which is confirmed by the results of a recent meta-analysis from 2020 which included 123,031 patients (35). It is emphasized that there is a statistically significantly higher risk for the development of squamous cell carcinoma (SCC) in RA patients treated with TNF-alpha inhibitors. In contrast, a British study that analysed data from the British Society for Rheumatology Biologics Register for Rheumatoid Arthritis (BSRBR-RA) from 2001–2008 did not show an additional increased risk for NMSC when using drugs from the group of TNF-alpha inhibitors (36). The results of the study showed that the risk of developing basal cell carcinoma (BCC) and SCC is increased in RA patients compared to the general population, regardless of whether they were treated with TNF-alpha inhibitors (SIR 1.72; 95% CI 1.43–2.04) or csDMARDs (SIR 1.83; 95% CI 1.30–2.50). The previously mentioned systematic literature review and meta-analysis based on the data collected from various databases (MEDLINE, EMBASE, Cochrane Database of Systematic Reviews) and from the data published by rheumatology societies yielded very comprehensive results on the risk of treatment with TNF-alpha inhibitors and skin cancers (27). The results of 4 studies involving over 28,000 patients showed that patients treated with TNF-alpha inhibitors have a higher risk of developing BCC and SCC (RR 1.45; 95% CI 1.15–1.76). In addition to that, the study presented data for the development of invasive melanoma, according to which the relative risk for their development is higher in patients treated with TNF-alpha inhibitors (RR = 1.79; 95% CI 0.92–2.67). The European Medicines Agency (EMA) requested that research be conducted on possible adverse effects in order to better recognize the side effects of treatment with TNF-alpha inhibitors. A meta-analysis of data from 74 randomized clinical trials on TNF-alpha inhibitors was conducted, which included 15,418 patients. The results showed a significantly increased risk for the development of skin cancer in patients treated with TNF-alpha inhibitors (RR = 2.02; 95% CI 1.11–3.95) (37). The study of the Danish Registry for Biological Therapies in Rheumatology (DANBIO) compared data for 3347 patients treated with TNF-alpha inhibitors and 3812 patients who were not treated with biological drugs. Patients suffering from RA, PsA and AS were included in the study. The data showed that there is no significantly increased risk for the development of skin cancer in patients treated with TNF-alpha inhibitors compared to patients treated with csDMARDs (HR = 1.10; 95% CI 0.69–1.76), while the risk compared to the general population was still increased (SIR = 1.92; 95% CI 1.42–2.59) (18). A large prospective cohort study conducted in Sweden, in the period from 2001–2010, which included patients with RA, studied the risk of developing skin melanoma (38). In patients who did not receive biological therapy, 113 cases of invasive melanoma were recorded (HR 1.2; 95% CI 0.9–1.5). In the group of patients treated with TNF-alpha inhibitors, 38 cases of melanoma were recorded (HR 1.5; 95% CI 1.0–2.2), which indicates an increased risk for the development of invasive melanoma. The authors of the study conclude that patients with RA who were not treated with TNF-alpha inhibitors are not at a significant risk for developing invasive melanoma compared to the general population, while patients treated with TNF-alpha inhibitors are exposed to a 50% higher risk for developing invasive melanoma.
Risk for the development of new malignancies in patients with previously diagnosed malignancies
There are numerous studies whose goal was to determine whether there is an increased risk of developing another malignant tumour in RA patients with a previously diagnosed malignant disease if they are treated with biological drugs. The lack of data on this group of patients could not produce significant results, which is understandable because these patients are at an exceptional risk (5). In Great Britain, based on the data collected from the BSRBR-RA, a study was conducted that dealt with this very issue (39). This study included 14,000 patients with RA, and 293 of these patients suffered from primary cancer. In the group of patients treated with TNF-alpha inhibitors, patients who already suffered from melanoma developed a new cancer more frequently (3 out of 17 people, 18%) than patients treated with csDMARDs in whose case no incidence of new cancer was recorded. According to this study, there is no increased risk for the use of TNF-alpha inhibitors in patients with RA and malignant disease, although great caution is required in the use of this therapy. The authors conclude that it is possible that the results are not representative due to an error when determining the criteria for the inclusion of patients in the clinical trial and thus the selection of patients. Future studies will reveal whether a diagnosis of melanoma in itself represents an increased risk for the development of another malignancy.
Although the data from the existing studies are actually few, they still indicate that the use of TNF-alpha inhibitors does not affect the prognosis in patients who develop cancer during treatment. Another Swedish study found no difference in the risk of cancer progression or death in cancer patients, whether treated with TNF-alpha inhibitors or csDMARDs (RR = 1.1; 95% CI 0.8–1.6) (40).
Small molecules, inflammatory rheumatic diseases and the risk of developing malignancies
Although the main purpose of this paper was to analyse the risk for the development of malignancies in patients with inflammatory rheumatic diseases treated with biological DMARDs, we shall briefly review the conventional therapy with targeted synthetic tsDMARDs that is commonly used today. Janus kinase inhibitors (JAKi), baricitinib, upadacitinib, tofacitinib and filgotinib (the latter is not yet registered in the Republic of Croatia) and the phosphodiesterase-4 inhibitor, apremilast, are used in the treatment of inflammatory rheumatic diseases. According to the data published so far in the available medical literature, adjusted for age, gender, other demographic data and anamnestic specifics, no increased signals for the risk of developing malignant diseases were detected compared to biological drugs (41–44). More detailed analysis of the mentioned literature goes beyond the scope of this paper.
CONCLUSION
The introduction of biological therapy as a standard treatment modality for inflammatory rheumatic diseases significantly improved the quality of life of patients and the functional status of patients. The study included 14,000 patients with RA. Numerous epidemiological studies were conducted that investigated the safety of the use of biological drugs in patients with various inflammatory rheumatic diseases, precisely in the context of the risk of developing malignancy. Most of the studies available in the literature were conducted on TNF-alpha inhibitors, given that these are the drugs that have been in use the longest. The results are different depending on which biological drug was used and which site of the malignant disease was observed. According to the aforementioned research, there is a certain risk of developing a haematological disease, skin tumours, and the development of a new malignant disease in patients with a previously diagnosed malignant disease. However, it is particularly important to highlight the fact that the results of these studies should be interpreted very cautiously, taking into account, among other things, the type of research (e.g., descriptive study, cohort study, randomized trial, etc.), the method of data collection, sample size and possible sampling error. The question is the need for systematic screening for malignant diseases in patients with rheumatic diseases, for which there are currently no clear, i.e., generally accepted, guidelines. Bearing in mind the previously mentioned tumour diseases, it is possible to screen patients with an increased risk once a year (for example, ultrasound of the abdomen and lymph nodes, serum protein electrophoresis and serum immunofixation test, examination by a dermatologist). Considering that it is a matter of risk assessment on an individual level, it is the duty of the treating physician to adapt the diagnostic procedure depending on that risk. The effectiveness and good safety profile of biological drugs are unquestionable if they are used according to the guidelines of the national rheumatology societies, and thus the risks associated with their use are minimized.
Conflict of interest statement: The authors declare no conflict of interest.
REFERENCES / Literatura
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Table 1 Biologic disease modifying drugs used in rheumatology
Tablica 1. Biološki lijekovi koji se koriste u reumatološkim indikacijama
Abbreviations / Skraćenice: AS – ankylosing spondylitis / ankilozantni spondilitis, CAPS – cryopyrin-associated autoinflammatory syndrome / autoinflamatorni sindrom povezan s kriopirinom (engl. cryopyrin associated autoinflammatory syndrome), CRS – cytokine release syndrome / sindrom otpuštanja citokina (engl. cytokine release syndrome), FMF – familial Mediterranean fever / obiteljska mediteranska vrućica (engl. familial mediterranean fever), GCA – giant cell arteritis / gigantocelularni arteritis, GPA – granulomatosis with polyangiitis / granulomatozni poliangiitis, Ig – immunoglobulin / imunoglobulin, IL – interleukin, IV/i.v. – intravenous / intravenski, JIA – juvenile idiopathic arthritis / juvenilni idiopatski artritis, jPsA – juvenile psoriatic arthritis / juvenilni psorijatički artritis, MPA – microscopic polyangiitis / mikroskopski polinagiitis, nr-axSpA – non-radiographic axial spondyloarthritis / neradiografski aksijalni spondiloartritis, PO/p.o. – peroral / peroralno, PsA – psoriatic arthritis / psorijatični artritis, RA – rheumatoid arthritis / reumatoidni artritis, SC/s.c. – subcutaneous / supkutano.