The use of biologics such as anti–tumor necrosis factor and oral Janus kinase inhibitors have revolutionized the treatment of rheumatoid arthritis (RA). The risk of malignancies such as lymphomas, lung cancer, and nonmelanoma skin cancers (NMSCs) is greater in patients with RA compared with the general population. The incidence of all malignancy (excluding NMSC) was similar in tofacitinib users compared with the general population. The rates of overall and site-specific malignancies in patients with RA treated with tofacitinib are similar to what is expected in the RA population and not different from disease-modifying antirheumatic drugs and biologics.
Key points
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Janus kinase inhibitors have been shown to be effective for treatment of rheumatoid arthritis (RA).
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The risk of malignancy in patients with RA treated with tofacitinib is similar to what has been reported with disease-modifying antirheumatic drugs and biologics.
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The risk of malignancy with tofacitinib in the RA population was not dose related except for an increased risk of nonmelanoma skin cancers in the long-term extension studies with the 10-mg dose.
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Based on clinical trial and long-term extension data, the rate of malignancy in patients with RA treated with tofacitinib does not increase over time with treatment.
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Based on clinical trial and long-term extension data, the risk of malignancy with tofacitinib treatment is similar to what is expected in the RA population.
Introduction
The management of rheumatoid arthritis (RA) has dramatically transformed over the last 20 years. The use of early aggressive therapy targeting low disease activity and the development of biologic therapies has dramatically improved patient outcomes with slowing of structural damage, improved physical function, and prolonged survival.
However, biologic therapies have limitations; more than half of the patients continue to have active disease and require either subcutaneous or intravenous administration; they are associated with significant expense; and they can induce immunogenicity. Over the last 25 years, the intracellular signaling pathways involved in signal transduction from the cell surface to the nucleus after ligand-receptor binding have been identified. This improved understanding of these pathways has provided opportunities for development of small molecule therapies that could target these pathways modifying proinflammatory cytokine production. Multiple preclinical studies have shown benefit in inhibiting various intracellular kinases, such as p38 Map kinase, and SyK (spleen tyrosine kinases) but failed to show benefit in RA clinical trials.
In 2012, tofacitinib, an oral Janus kinase (Jak) inhibitor, was approved for RA treatment and other Jak inhibitors are under development, with baricitinib recently completing phase III trials in RA and selective inhibitors for Jak1 in phase II/III trials. Jaks are protein tyrosine kinases that bind the cytoplasmic region of transmembrane cytokine receptors and mediate signaling through type I and type II cytokine receptors. After receptor-ligand interaction, various Jaks are activated, resulting in tyrosine phosphorylation of the receptor and subsequent activation of STATs (signal transducer and activators of transcription), which act as transcription factors. Jak/STAT signaling mediates cellular responses to multiple cytokines and growth factors. These responses include proliferation, differentiation, migration, apoptosis, and cell survival, depending on the signal and cellular context. Activated STATs enter the nucleus and bind to specific enhancer sequences in target genes, affecting their transcription. Jaks consists of 4 types: Jak1, Jak2, Jak3, and Tyk2. The JAKs signal as pairs. Jak3 is primarily expressed in hematopoietic cells and is critical for signal transduction from the common gamma chain of the receptors for interleukin (IL)-2, IL-4, IL-7, IL-9, IL-15, and IL-21 on the plasma membrane to the nuclei of immune cells. Jak3 only signals in combination with Jak1. The cytokines are integral to lymphocyte activation, function, and proliferation. Jak3-knockout mice have defects in T and B lymphocytes and natural killer cells, with no other defects reported. Humans lacking Jak3 develop a severe combined immunodeficiency with a deficiency in natural killer cells and T lymphocytes. Tofacitinib is a more selective inhibitor of Jak3/Jak1 based on enzymatic/cellular assays, but at the serum levels that have been achieved it also has an impact on Jak2.
Jak1 and Jak2 were initially not considered as potential therapeutic targets because knocking out these kinases results in germline lethality. Baricitinib, which is a Jak1/Jak2 inhibitor, is in development for RA and has shown similar efficacy and safety to tofacitinib. Ruxolitinib, which has selectivity for Jak1/Jak2 is approved for myelofibrosis. Hormones like the cytokines erythropoietin, thrombopoietin, growth hormone, granulocyte-macrophage colony-stimulating factor, IL-3, and IL-5 all signal through Jak2. IL-6, IL-10, IL-11, IL-19, IL-20, IL-22, and interferons gamma, alfa, and beta signal through Jak1. Tyk2 facilitates signaling for IL-12, IL-23, and type 1 interferons. Tyk2 pairs with either Jak1 or Jak2 to facilitate signaling. At present, no specific Tyk2 inhibitors are under development for RA.
Tofacitinib was approved by the US Food and Drug Administration (FDA) for patients with RA with active disease despite methotrexate treatment at a dosage of 5 mg twice daily in combination with nonbiologic disease-modifying antirheumatic drugs (DMARDs) or as monotherapy. The American College of Rheumatology guidelines recommend the use for moderate to severe RA that is nonresponsive to conventional DMARDs, and additionally also recommended their continued long-term use in patients who attain clinical remission.
RA and other autoimmune conditions are chronic inflammatory states and are characterized by abnormalities of the immune system. Treatment of RA consists of medications that alter the upregulated immune system. The immune system is thought to play an important role in immune surveillance and protection from development of malignancy, with increased risk of certain malignancies, such as lymphomas, lung cancer, and nonmelanoma skin cancers (NMSCs), in patients with RA compared with the general population. The available information on Jak inhibition and the potential development of malignancies are reviewed here and the risk of malignancies is compared with that reported with biologic therapies.
Introduction
The management of rheumatoid arthritis (RA) has dramatically transformed over the last 20 years. The use of early aggressive therapy targeting low disease activity and the development of biologic therapies has dramatically improved patient outcomes with slowing of structural damage, improved physical function, and prolonged survival.
However, biologic therapies have limitations; more than half of the patients continue to have active disease and require either subcutaneous or intravenous administration; they are associated with significant expense; and they can induce immunogenicity. Over the last 25 years, the intracellular signaling pathways involved in signal transduction from the cell surface to the nucleus after ligand-receptor binding have been identified. This improved understanding of these pathways has provided opportunities for development of small molecule therapies that could target these pathways modifying proinflammatory cytokine production. Multiple preclinical studies have shown benefit in inhibiting various intracellular kinases, such as p38 Map kinase, and SyK (spleen tyrosine kinases) but failed to show benefit in RA clinical trials.
In 2012, tofacitinib, an oral Janus kinase (Jak) inhibitor, was approved for RA treatment and other Jak inhibitors are under development, with baricitinib recently completing phase III trials in RA and selective inhibitors for Jak1 in phase II/III trials. Jaks are protein tyrosine kinases that bind the cytoplasmic region of transmembrane cytokine receptors and mediate signaling through type I and type II cytokine receptors. After receptor-ligand interaction, various Jaks are activated, resulting in tyrosine phosphorylation of the receptor and subsequent activation of STATs (signal transducer and activators of transcription), which act as transcription factors. Jak/STAT signaling mediates cellular responses to multiple cytokines and growth factors. These responses include proliferation, differentiation, migration, apoptosis, and cell survival, depending on the signal and cellular context. Activated STATs enter the nucleus and bind to specific enhancer sequences in target genes, affecting their transcription. Jaks consists of 4 types: Jak1, Jak2, Jak3, and Tyk2. The JAKs signal as pairs. Jak3 is primarily expressed in hematopoietic cells and is critical for signal transduction from the common gamma chain of the receptors for interleukin (IL)-2, IL-4, IL-7, IL-9, IL-15, and IL-21 on the plasma membrane to the nuclei of immune cells. Jak3 only signals in combination with Jak1. The cytokines are integral to lymphocyte activation, function, and proliferation. Jak3-knockout mice have defects in T and B lymphocytes and natural killer cells, with no other defects reported. Humans lacking Jak3 develop a severe combined immunodeficiency with a deficiency in natural killer cells and T lymphocytes. Tofacitinib is a more selective inhibitor of Jak3/Jak1 based on enzymatic/cellular assays, but at the serum levels that have been achieved it also has an impact on Jak2.
Jak1 and Jak2 were initially not considered as potential therapeutic targets because knocking out these kinases results in germline lethality. Baricitinib, which is a Jak1/Jak2 inhibitor, is in development for RA and has shown similar efficacy and safety to tofacitinib. Ruxolitinib, which has selectivity for Jak1/Jak2 is approved for myelofibrosis. Hormones like the cytokines erythropoietin, thrombopoietin, growth hormone, granulocyte-macrophage colony-stimulating factor, IL-3, and IL-5 all signal through Jak2. IL-6, IL-10, IL-11, IL-19, IL-20, IL-22, and interferons gamma, alfa, and beta signal through Jak1. Tyk2 facilitates signaling for IL-12, IL-23, and type 1 interferons. Tyk2 pairs with either Jak1 or Jak2 to facilitate signaling. At present, no specific Tyk2 inhibitors are under development for RA.
Tofacitinib was approved by the US Food and Drug Administration (FDA) for patients with RA with active disease despite methotrexate treatment at a dosage of 5 mg twice daily in combination with nonbiologic disease-modifying antirheumatic drugs (DMARDs) or as monotherapy. The American College of Rheumatology guidelines recommend the use for moderate to severe RA that is nonresponsive to conventional DMARDs, and additionally also recommended their continued long-term use in patients who attain clinical remission.
RA and other autoimmune conditions are chronic inflammatory states and are characterized by abnormalities of the immune system. Treatment of RA consists of medications that alter the upregulated immune system. The immune system is thought to play an important role in immune surveillance and protection from development of malignancy, with increased risk of certain malignancies, such as lymphomas, lung cancer, and nonmelanoma skin cancers (NMSCs), in patients with RA compared with the general population. The available information on Jak inhibition and the potential development of malignancies are reviewed here and the risk of malignancies is compared with that reported with biologic therapies.
Overall malignancy risk in rheumatoid arthritis
As a background to understanding the risk of malignancy and Jak inhibition it is important to examine what is known about malignancy risk in RA and there are still gaps in the knowledge on this issue. It remains unclear whether the perceived risk for malignancies in RA is related to the underlying chronic inflammatory state, immunologic stimulation (suppression of T cells and malignant transformation of CD5 B cells), the use of biologics/nonbiologic DMARDs, or a result of a combination of the these factors. The overall risk of malignancy in adult patients with RA is thought to be similar to that of the general population, based on observational databases. Data using the general population as a comparator group in various RA studies in the United States were obtained from the Surveillance, Epidemiology and End Results (SEER) program of the National Cancer Institute database. In general, the overall pooled standardized incidence ratio (SIR) for malignancies in RA is 1.09 (95% confidence interval [CI], 1.06–1.13) compared with the general population. However, patients with RA seem to have a higher risk for certain site-specific malignancies such as lung cancer (SIR, 1.63; 95% CI, 1.43–1.87) and lymphoma (SIR, 2.08; 95% CI, 1.80–2.39) but a decreased risk of colorectal and breast cancer in patients with RA compared with the general population ( Table 1 ). Lymphoma was associated with the highest risk for malignancy, the pooled SIRs for lymphoma being 2.46 (95% CI, 2.05–2.96) with the risk of Hodgkin lymphoma (SIR, 3.21; 95% CI, 2.42–4.27) being numerically greater than that of non-Hodgkin lymphoma (SIR, 2.26; 95% CI, 1.82 to 2.81). There was no trend toward increased or decreased risk in RA for melanoma, cervical cancer, or prostate cancer.
| Malignancy | Pooled Data, Studies (N) | Pooled SIRs (95% CI) |
|---|---|---|
| Overall | 23 | 1.09 (1.06–1.13) |
| Lung cancer | 23 | 1.64 (1.51–1.79) |
| Lymphoma | 12 | 2.46 (2.05–2.96) |
| Hodgkin lymphoma | 14 | 3.21 (2.42–4.27) |
| Non-Hodgkin lymphoma | 17 | 2.26 (1.82–2.81) |
| Breast cancer | 19 | 0.86 (0.73–1.01) |
| Colorectal cancer | 23 | 0.78 (0.71–0.86) |
| Melanoma | 21 | 1.23 (1.01–1.49) |
The impact of biologics on the risk of malignancies in patients with RA has been controversial. Some of the studies suggest increased risk, whereas more recent population-based studies do not show any additional risk other than what already exists for patients with RA, noting the relationship of increased disease activity to development of lymphoid malignancy. Data from various large European and US registry studies indicated that treatment of patients with RA with tumor necrosis factor (TNF) inhibitors is not associated with increased risks of non–skin cancer malignancies (odds ratio [OR], 0.95; 95% CI, 0.85–1.05), particularly lymphoma (OR = 1.1; 95% CI, 0.70–1.51) compared with treatment with traditional DMARDs.
Protein tyrosine kinase inhibitors such as Jak inhibitors were originally developed for use in oncology. Imatinib, which is a protein tyrosine kinase inhibitor, has dramatically improved the outcomes for patients with chronic myelogenous leukemia, and other kinase inhibitors are used as treatment of renal cell carcinoma and small cell lung cancer. However, even though these therapies are used to treat cancer, concern over Jak inhibition and the significant impact on multiple cytokines with a potential for immunosuppression malignancy risk was a major issue monitored closely during the development program and postapproval for tofacitinib and more recently baricitinib. This article reviews the data available on malignancy risk and Jak inhibitor treatment of RA.
Overall malignancy in patients with rheumatoid arthritis exposed to tofacitinib
Data assessing the risks of malignancies among JAK inhibitor users in RA are primarily obtained from individual randomized control trials (RCTs) and meta-analysis of RCTs. Although RCTs ensure comparability in the development of malignancies between the users and the placebo group, the short-term follow-up makes it difficult to quantify the exact incidence of malignancies in individuals using these medications. The ideal mechanism to obtain accurate data to assess the incidence of malignancies in JAK kinase inhibitors is the use of patient-based registries. However, JAK inhibitors in the treatment of RA have become available only recently, necessitating the use of RCTs to estimate the malignancy risk.
The bulk of the information on malignancy risk and tofacitinib is derived from the data presented to the FDA at the Arthritis Advisory Committee in 2012 and subsequent publications from the long-term extension (LTE) database of patients continuing on treatment following the randomized clinical trials. Approximately 4800 patients participated in the clinical trials on dosages of either 5 mg twice a day or 10 mg twice a day. The overall rates of malignancy in patients with RA receiving tofacitinib were similar to those of the general population and comparable with other biologics ( Figs. 1 and 2 , Table 2 ). There was concern that there was a trend for a higher risk for malignancy development in the LTE on the 10-mg dose compared with the 5-mg dose even though the rates were not statistically different except for the rate of NMSC in the LTE. At the Arthritis Advisory Committee meeting concern was expressed because of a modestly increased incidence of all malignancies (excluding NMSC) over time, with incidence rates of malignancies of 0.79 per 100 patient-years in the first 6 months with a peak incidence (1.93 per 100 patient-years) in 24 to 30 months. However, the number of subjects on treatment at the later time point was small compared with the earlier time points and an increased risk over time has not been reported with longer-term follow-up.
| Malignancy | Total Patients Tofacitinib (N) | SIRs (95% CI) | IR/100 Patient-Years (95% CI) |
|---|---|---|---|
| Overall (excluding NMSC) | 5671 | 1.17 (0.96–1.41) | 0.85 (0.70–1.02) |
| Lung cancer | 5671 | 2.19 (1.39–3.29) | 0.19 (0.13–0.28) |
| Lymphoma | 5671 | 2.64 (1.27–4.86) | 0.08 (0.04–0.14) |
| Breast cancer | 5671 | 0.78 (0.47–1.22) | 0.18 (0.12–0.28) |
| NMSC | 5671 | NR | 0.53 (0.41–0.67) |
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