Rheumatoid arthritis is a common inflammatory disease that requires treatment with immunosuppressants to control symptoms and avoid joint destruction. Managing cancer in patients with concomitant rheumatoid arthritis poses special challenges that require close coordination of care between oncologists and rheumatologists. Potential clinical issues needing special consideration include: 1) perioperative management in patients undergoing cancer surgery, which often requires discontinuation of antirrheumatic therapy; 2) use of immunosuppressant therapies for rheumatoid arthritis, especially biologic agents that inhibit cytokine and immune pathways, which conceivably could affect immune-mediated antitumor responses (the issues are different in patients with active cancer vs those with a past history of cancer and no recurrences); 3) management in the palliative care setting; and 4) use of cancer immunotherapy, such as checkpoint inhibitor agents, in patients with pre-existing rheumatoid arthritis. We explore these clinical issues in case-based scenarios. In all cases, clinical decision making must include a careful weighing of risks and benefits of both cancer treatments and antirrheumatic therapies, with attention given to prognosis and life expectancy, quality of life, and patient preferences.
Rheumatoid arthritis is the most common inflammatory arthritis, affecting 1% of the general population. It is a chronic disease in which inflammation of the synovium leads to bony erosions and joint destruction. The etiology of rheumatoid arthritis remains unclear, but its development likely requires a high-risk genetic background and an environmental trigger, leading to autoimmune dysregulation and an autoinflammatory response; the latter can affect not only the joints, but also other organs and systems. Patients with rheumatoid arthritis usually require treatment for the duration of their lifespan. Drugs used to treat rheumatoid arthritis fall primarily into three general categories: nonsteroidal anti-inflammatory drugs (NSAIDs), glucocorticoids, and disease-modifying antirrheumatic drugs (DMARDs); DMARDs can be synthetic drugs or biologic agents targeting specific cytokines or other molecules involved in the regulation of the immune response (Table). DMARDs can suppress the inflammatory response, primarily by downregulating the immune system.
Patients with cancer and concomitant rheumatoid arthritis are at increased risk for morbidity and mortality, in part because of their therapeutic needs.[1] Immunosuppressant drugs used to treat rheumatoid arthritis can increase the risk of infection in patients undergoing surgery, or in those receiving chemotherapy. In addition, there are concerns that chronic immunosuppression from these therapies could result in downregulation of immune antitumor responses. It has been proposed that the use of biologic therapies for rheumatoid arthritis may conceivably increase the risk of malignancy, or of tumor progression in patients with a coexisting cancer. Patients with rheumatoid arthritis already have an increased risk of certain types of cancer, specifically lymphoma and lung cancer, likely as a result of their chronic inflammatory state.[2] There is no evidence so far that rheumatoid arthritis therapies increase the risk of developing non-skin solid tumors.[3,4] There is some controversy as to whether biologic agents, specifically tumor necrosis factor (TNF) inhibitors, may increase the risk of nonmelanoma skin cancer, melanoma, and lymphoma; any increased risk, however, appears to be small.[3,4] Whether this class of agents may accelerate tumor progression in patients with pre-existing cancer remains debatable. While in theory this could be possible, the data are scarce, since patients with cancer are typically excluded from clinical trials of these immunosuppressive therapies, and few case series or observational studies have addressed the issue.
Cancer patients may undergo tumor resection, chemotherapy, radiation treatment, or, more recently, immunotherapy-all of which can make their management more challenging if they have concomitant rheumatoid arthritis. Coordination of care with a rheumatologist will be essential, especially if the patient has active rheumatoid arthritis or is receiving concomitant antirrheumatic therapy. Here we present practical approaches to the management of patients with cancer and rheumatoid arthritis at various stages of their malignancy.
Case 1
A 62-year-old man develops abdominal pain and hematochezia. He undergoes colonoscopy and is found to have a nonobstructing adenocarcinoma in his ascending colon. Staging scans do not show evidence of metastatic disease. He is scheduled to undergo a laparoscopic hemicolectomy. The patient has a 15-year history of rheumatoid arthritis, currently well controlled on hydroxychloroquine, methotrexate, and 7.5 mg daily of oral prednisone; he has been treated with this regimen continuously for the last 5 years. He also takes ibuprofen as needed for pain control.
The primary concerns in the management of this patient’s rheumatoid arthritis in the perioperative period include not only the possibility of surgical complications-such as increased systemic and local infections, impaired wound healing, and bleeding-but also problems that more directly involve his rheumatoid arthritis, such as the risk of postoperative arthritis flares, and difficulties in rehabilitation if his antirrheumatic therapies are discontinued.
Nonselective NSAIDs are used by many patients with rheumatoid arthritis as part of their daily drug regimen, or on an as-needed basis. Inhibition of cyclooxygenase (COX)-1 results in decreased production of prostaglandins and thromboxane, ultimately reducing the inflammatory response and platelet aggregation. Because of their antiplatelet effect, bleeding is the most feared side effect of NSAIDs in the perioperative setting, and NSAIDS should be held for a total of 5 half-lives of the drug in question prior to surgery-and in the case of aspirin, for 7 to 10 days, since aspirin binds to COX irreversibly, inactivating platelets for the remainder of their life.
Rheumatoid arthritis patients frequently take glucocorticoids as part of their drug regimen. Chronic glucocorticoid use is associated with surgical site infections and poor wound and bone healing. It is therefore recommended that patients slowly taper their glucocorticoid dose as tolerated throughout the preoperative period. Suppression of the hypothalamic-pituitary-adrenal axis is common in patients receiving long-term glucocorticoid therapy. The axis is considered to be functional if the daily dose of oral prednisone (or equivalent) is ≤ 5 mg. Patients who have been on ≥ 20 mg of prednisone daily for 3 weeks or longer may have significant adrenal suppression. Under normal circumstances, the human body produces 5 to 10 mg of cortisol daily. In the perioperative period, daily cortisol production can range from 50 to 200 mg.[5] It is therefore necessary to give supplemental corticosteroids perioperatively to avoid acute adrenal insufficiency, which can lead to hypotension and shock in patients who are likely to have adrenal suppression as a result of prolonged glucocorticoid therapy.
Although data on hydroxychloroquine use in the perioperative period are limited, a retrospective study of 367 orthopedic surgeries in 204 patients with rheumatoid arthritis found no increased risk of systemic or surgical site infections in patients treated with hydroxychloroquine.[6] This was corroborated in a subsequent study.[7] Due to its low toxicity profile, hydroxychloroquine can be continued throughout the perioperative period.
A number of studies have examined the safety of methotrexate in the postoperative period. A clinical trial evaluated 388 patients with rheumatoid arthritis who were randomized to continuation of methotrexate or to discontinuation from 2 weeks prior to 2 weeks following surgery.[8] The results did not show an increased infection rate in patients who continued methotrexate. Another study retrospectively evaluated 121 patients with rheumatoid arthritis who had undergone total joint arthroplasty; the investigators found no significant differences in postoperative infections or wound healing complications between those who continued on methotrexate and those who did not.[9] Although the evidence would suggest that methotrexate is safe in the perioperative period, most studies included patients undergoing orthopedic surgery, and the results may not be representative of all surgical procedures. Discontinuing methotrexate for just 1 week prior to surgery and 1 week after surgery can minimize the risk of rheumatoid arthritis flares, and seems a reasonable approach in the face of uncertainty for nonorthopedic surgery outcomes.
Data for other DMARDs are scarce. One study showed a decrease in surgical site infections in patients who were taking sulfasalazine throughout the postoperative period.[10] Other researchers have suggested that sulfasalazine be held on the day of surgery because the glomerular filtration rate can decrease during surgery and this drug is primarily excreted by the kidneys.[11] There are limited data regarding the perioperative use of leflunomide, but a study in patients with rheumatoid arthritis who underwent total hip replacement showed no difference with respect to wound healing and infection rate between those who continued leflunomide and those in whom it was held.[12]
There are few data on the use of most biologic agents and Janus kinase (JAK) inhibitors in patients with active cancer, because of concerns of possible suppression of tumor immunity. It is generally recommended that these agents be discontinued in patients with a recent diagnosis of cancer, so most patients will have stopped biologics before surgery.
Case 2
A 44-year-old woman with seropositive rheumatoid arthritis, on triple-DMARD therapy (methotrexate, sulfasalazine, and hydroxychloroquine), presents with a 1.5-cm nodule on her right breast, and no suspicious regional lymph nodes. Biopsy confirms an estrogen receptor–positive, progesterone receptor–positive, human epidermal growth factor receptor 2–negative ductal carcinoma. Her rheumatoid arthritis medications are stopped. The patient would like to undergo lumpectomy followed by radiation therapy but is concerned about the possible adverse effects of radiotherapy in women with rheumatoid arthritis.
A few studies have evaluated the risk of radiation therapy in patients with cancer and connective tissue diseases, especially scleroderma and lupus erythematosus. The evidence is limited; still, while some studies show an increase in the incidence of early and late adverse events in patients with rheumatoid arthritis, this risk appears to be small, and the majority of patients do not have any major complications.[13-15]
The patient decides to undergo lumpectomy followed by radiation therapy, and she experiences no complications. She declines adjuvant chemotherapy and starts treatment with oral tamoxifen, returning to her full-time job. Two months later, she develops severe polyarthritis of her hands, elbows, and knees, which has a major impact on her quality of life. She starts treatment with oral prednisone. Six weeks later she starts triple-DMARD therapy, which had been an effective treatment before her cancer diagnosis. After 4 months, she shows no improvement and is obliged to take a temporary leave from her job; she would like to discuss an alternative therapy for her rheumatoid arthritis.
Decision making about antirrheumatic therapy in patients with concomitant rheumatoid arthritis and cancer requires careful risk stratification with respect to the cancer type, its stage, and its prognosis[1]; patient preferences with regard to risk and outcome uncertainty must also be considered. In this situation, had this patient not had a recent diagnosis of cancer, it would be appropriate to consider a biologic therapy for her rheumatoid arthritis, according to recommendations from the American College of Rheumatology (ACR).[16] However, this woman is young and has a recent cancer diagnosis with an excellent prognosis; thus, it would be desirable to choose an agent with a low likelihood of affecting tumor immunity. This is particularly important because the patient declined adjuvant chemotherapy, which can be effective in eliminating micrometastases.
Most commonly, patients with rheumatoid arthritis in whom traditional DMARD therapy fails are treated with TNF inhibitors. However, there is insufficient evidence regarding the safety of these agents in patients with cancer, primarily because they are typically excluded from clinical trials. Two observational studies assessed the risk of cancer recurrence in patients with rheumatoid arthritis treated with TNF inhibitors compared with traditional DMARDs and found no differences in recurrence rates; however, the numbers were small, and these studies did not include any patients who were within 5 years of their cancer diagnosis.[17,18] Another case series reported that 8 of the included patients received TNF inhibitors within 5 years of cancer diagnosis, with no recurrences.[19] A recent larger observational study showed that patients with rheumatoid arthritis who started therapy with TNF inhibitors after a diagnosis of breast cancer were not at increased risk for recurrence, but the median time from diagnosis to therapy initiation was 9 years (more than 5 years for 85% of the patients).[20] These results are reassuring in that in selected patients with a history of treated cancer and no recurrence, TNF inhibitors appear to be safe when used several years after completion of therapy. However, for patients with a more recent cancer diagnosis, uncertainty remains.
Several factors should be taken into consideration when making decisions about rheumatoid arthritis therapy in patients with a history of cancer. The baseline risk of recurrence varies depending on how aggressive the original cancer was. Moreover, although the risk of recurrence decreases over time, for some cancer types, such as breast cancer, there is a risk even decades later. No study has examined the likelihood of cancer recurrence for specific rheumatoid arthritis therapies. However, most of the concerns have centered on TNF inhibitors, primarily because of their mode of action and limited evidence showing an increase in the risk of lymphoma, melanoma, and nonmelanoma skin cancers with these agents.
Because this patient has failed to respond to therapy with combination DMARDs, it is appropriate to initiate treatment with a biologic agent, but TNF inhibitors would not be the best choice. An appropriate alternative would be rituximab, which is an effective therapy for rheumatoid arthritis, and which has been used for many years in the treatment of lymphoma, with no evidence of increased recurrence in patients with prior solid tumors. Other biologic agents and JAK inhibitors have not been sufficiently evaluated in this setting to offer a recommendation.
Case 3
A 56-year-old woman with a history of stage IA lung adenocarcinoma was treated with right upper lobectomy and lymph node dissection 7 years ago. She is doing well, with no evidence of disease. Two years ago, she developed rheumatoid arthritis, which was initially well controlled with NSAIDs, weekly oral methotrexate, and daily hydroxychloroquine. Six months ago, she developed progressively worsening polyarthritis involving the knees, wrists, metacarpophalangeal joints, and proximal interphalangeal joints; this arthritis has proven refractory to therapy, including a trial of corticosteroids. Her pain is now limiting her ability to work as a hairdresser. She has heard about biologic therapies for rheumatoid arthritis, and she is eager to start a new treatment.
According to ACR guidelines, this patient is a candidate for biologic DMARDs.[16] As reviewed previously, most observational studies evaluating the use of biologic therapy in patients with rheumatoid arthritis and a history of a solid tumor diagnosed and treated several years earlier do not show an increased risk of recurrence.[17-20] Based on the available data, and primarily on consensus expert opinion, the ACR recommendations suggest that in patients in whom solid malignancies have been treated with curative intent and who presently have no evidence of disease, any agents, including TNF inhibitors, can be used.[16] The patient in this case has established rheumatoid arthritis with high disease activity, which is worsening despite treatment with nonbiologic DMARDs. Because it has been 7 years since her cancer treatment and she has had no recurrences, it would be reasonable to treat her rheumatoid arthritis with biologic therapy.
However, even for patients with a history of successfully treated cancer, one must take into consideration tumor type, biology, stage, treatment received, and prognosis. A woman with an early diagnosis of stage I lung cancer will have a worse prognosis, with a higher recurrence rate, than a woman with an early-stage estrogen receptor–positive breast cancer, even if both are treated with curative intent.
In this case, it would be appropriate to present the patient with the various available options and the associated uncertainties. Since no biologic agent for rheumatoid arthritis is substantially better than the rest, any choice could be appropriate.
Case 4
A 56-year-old man in whom rheumatoid arthritis was diagnosed 4 years ago has been receiving methotrexate and etanercept (a TNF inhibitor), with an excellent response and no evidence of active arthritis. He presents with new back pain and weight loss. MRI of the lumbar spine reveals lesions suspicious for metastasis. Subsequent scans reveal a pancreatic mass encasing the superior mesenteric artery, and numerous hepatic lesions. Histopathology confirms metastatic pancreatic adenocarcinoma. His rheumatoid arthritis treatment is discontinued, and he starts palliative chemotherapy with gemcitabine. Within 2 months, he develops significant exacerbation of his rheumatoid arthritis, with painful synovitis of several joints that is affecting his quality of life and ability to perform activities of daily living. He starts treatment with oral prednisone but reports only mild improvement. He would like to restart his last rheumatoid arthritis treatment that worked so well for him.
Current ACR guidelines include recommendations for managing rheumatoid arthritis in patients with previously treated malignancies; however, no specific recommendations exist for patients with active cancer.[16] Because some DMARDs and all biologic agents can suppress the immune system to varying degrees, there is a theoretical risk that they may hinder cancer treatment. In patients with active malignancy who are undergoing chemotherapy, potentiated immunosuppression may result in increased toxicity, especially cytopenias, and worsened outcomes. In addition, there is a concern that tumor progression will be accelerated. The general consensus has been that treatment with all biologics should be held in patients with active malignancy who are undergoing chemotherapy.[16] Nevertheless, a patient’s stage of disease, overall prognosis, concomitant cancer therapy, and individual preferences should be taken into consideration. In patients with metastatic disease, the goal of treatment is not curative but palliative. Therefore, the risk associated with rheumatoid arthritis treatment should be weighed against its potential benefit, since undertreating rheumatoid arthritis can significantly diminish quality of life. For a patient such as the one presented here, whose rheumatoid arthritis was previously well controlled, who is receiving palliative therapy, and whose life expectancy is short, it is reasonable to resume rheumatoid arthritis treatment, after carefully presenting him with the potential benefits and risks.
KEY POINTS
- Therapeutic decisions in cancer patients with concomitant rheumatoid arthritis need to consider risk-benefit ratios of different therapies with respect to cancer prognosis, quality of life, and patient preferences.
- Some antirrheumatic biologic therapies may impair immune-mediated antitumor responses and therefore require careful consideration when their use is contemplated in patients with active cancer.
- For patients with a history of cancer and no recurrences, antirrheumatic therapy appears to be safe, with no evidence that it increases recurrence rates.
- Data are limited on the use of immune checkpoint inhibitors in cancer patients with pre-existing rheumatoid arthritis; in about half of the cases reported, patients had a disease flare.
- Comanagement by oncologists and rheumatologists can reduce the risk of complications and improve symptom control and quality of life in patients with active arthritis.
It is worth noting that many patients with rheumataoid arthritis and cancer may notice improvement of their arthritis during chemotherapy, especially with the use of immunosuppressant agents, such as cyclophosphamide (which is also used to treat autoimmune disorders). In some instances, this could influence the choice of a specific anticancer drug. In patients with active rheumatoid arthritis who are starting chemotherapy, it is advisable to wait for a few weeks before considering antirrheumatic treatment, since their joint symptoms may improve with cancer therapy.
Case 5
A 67-year-old woman has a history of melanoma resected from her left thigh 3 years ago. The patient has a history of rheumatoid arthritis, and her disease is well controlled with methotrexate and oral prednisone. She presents for follow-up with right upper quadrant abdominal pain. Imaging reveals multiple liver lesions; biopsy confirms metastatic melanoma. Her rheumatoid arthritis treatment is discontinued. Her oncologist is considering therapy with an immune checkpoint inhibitor but is concerned about her history of rheumatoid arthritis.
Immune checkpoint inhibitor therapy is associated with myriad immune-related adverse events (irAEs) that can affect different organs, can be serious, and can occasionally be fatal.[21] There have been concerns regarding the use of these agents in patients with pre-existing autoimmune disease, who have typically been excluded from clinical trials out of fear of increased or more severe irAEs, or disease flare.[22] There are few reports of patients with rheumatoid arthritis receiving checkpoint inhibitors. Overall, approximately 50% of patients with rheumatoid arthritis who received checkpoint inhibitor therapy and for whom results have been reported experienced flares or had irAEs.[22,23] Management of rheumatoid arthritis flares during cancer immunotherapy also poses a challenge because immunosuppression could potentially counteract the tumor therapeutic effects of checkpoint inhibitors.
For this patient it would be important to consider whether there are alternative therapies for her melanoma. If checkpoint inhibitors are the best option, and given that her comorbid rheumatoid arthritis would typically not be life-threatening, a consideration of the risks and benefits should be presented to her, including a careful explanation of the potential efficacy of immunotherapy in melanoma. Before starting immunotherapy, it is recommended that prednisone be discontinued, possibly tapering it over a couple of weeks to avoid concomitant immunosuppression during the initial courses of therapy; the patient’s rheumatoid arthritis can be managed instead with NSAIDs and pain control. There are no evidence-based recommendations for patients who may experience a rheumatoid arthritis flare during checkpoint inhibitor therapy, given the scarcity of data. However, an approach similar to that used to manage irAEs can be implemented, with initial treatment with glucocorticoids, which can be adjusted according to the severity of symptoms and response. Discontinuation of the checkpoint inhibitor is recommended for severe arthritis that limits activities of daily living. For patients who do not respond to glucocorticoids or who are unable to taper their dose, therapy with conventional DMARDs, or biologics, might be indicated.
Summary
Patients with cancer and concomitant rheumatoid arthritis pose special challenges. Many therapies for rheumatoid arthritis can increase the risk of adverse events during cancer therapy because they are immunosuppressive. Moreover, the effects of these drugs on tumor progression and recurrence is uncertain. Lastly, cancer immunotherapy has revolutionized the treatment of various cancers; however, it poses a dilemma when considered for use in patients with autoimmune diseases such as rheumatoid arthritis, because of the potential for increased toxicity or disease flare. Moreover, concomitant immunosuppressive treatment of the underlying disorder could blunt the potential anticancer benefits of immunotherapy. Given the many factors that must be weighed when making therapeutic decisions in patients with rheumatoid arthritis and cancer at different stages of their oncologic disease, careful consideration needs to be given to risk stratification, potential risk-benefit ratios, and individual patient preferences.
Financial Disclosure:Dr. Suarez-Almazor participated in an Advisory Board for Bristol-Myers Squibb on the use of immune checkpoint inhibitors to treat patients with cancer and concomitant autoimmune disease. The other authors have no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.
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