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, immunotherapyall 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.
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 patients rheumatoid arthritis in the perioperative period include not only the possibility of surgical complicationssuch as increased systemic and local infections, impaired wound healing, and bleedingbut 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 surgeryand 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.
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 receptorpositive, progesterone receptorpositive, human epidermal growth factor receptor 2negative 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.
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Management Considerations in Cancer Patients With Rheumatoid Arthritis - Cancer Network