There are life-saving treatments available for cancer and autoimmune disease, but they can often wreak havoc on the oral cavity. Here's an overview of common conditions, drugs, and side effects, and the role the dental hygienist plays in keeping these patients healthy.
Table of Contents
Cancer
Autoimmune disease
Chemotherapy agents
Methotrexate
Cyclophosphamide
Biotherapy agents
Rituximab
Infliximab
Belimumab
Prevention and management of oral side effects and the role of dental hygienist
Conclusion
Chemotherapy and biotherapy have been the most common treatments available for cancer and autoimmune diseases. In treatment of cancer, chemotherapy agents work by killing cancer cells, and biotherapy agents help immune system to fight cancer cells. In autoimmune disease, these agents suppress the immune system, which in turn helps in managing the disease. Unfortunately, the agents used in these therapies not only fight the diseased cells but also lead to the destruction of healthy cells in the body, resulting in systemic and oral complications.
Chemotherapy and biotherapy drugs cause long- or short-term side effects depending on the type of disease, drug used, and each patient’s health status. These therapy drugs affect the oral cavity by damaging the oral tissue, decreasing salivary gland function, and causing pH imbalance of the oral environment. The compromised state of the oral cavity results in complications during and after the therapy. The complications include difficulty in eating, drinking, and speaking, which eventually results in a prolonged recovery period. On the other hand, the patients with optimum health of the oral environment show deterrence to secondary infections of oral tissues and other systemic infections. Dental hygienists make beneficial contributions in preventing aforementioned complications by providing appropriate counseling and care to the patients. Dental hygienists recommend preventative measures such as good oral hygiene, oral rinses, nutritional supplements, and flossing, which make a marked difference in the overall health and recovery of cancer patients.
It has been reported that autoimmune diseases and cancer had a major impact on population in the United States. According to 2016 statistics, about 1,685,210 new cases of cancer have been diagnosed in the United States. The most common cancers reported were breast cancer, lung and bronchus cancer, melanoma of the skin, thyroid cancer, leukemia and pancreatic cancer. (1) According to the National Institute of Health, about 23.5 million people in the United States suffered from autoimmune disease and it had been continuously increasing. There were approximately 80 types of autoimmune diseases discovered; causes of many of these were still unknown. Some of the common autoimmune diseases included lupus erythematosus, multiple sclerosis, rheumatoid arthritis, and type I diabetes. (2) The Annual Report published by National Cancer Institute in March 2016 stated that the death rate of cancer had been declined by 1.8% in men and 1.4% among women. (1) Autoimmune diseases were not curable but managed successfully by different therapies. The increased survival rate of autoimmune and cancer patients was attributed to chemotherapy agents such as methotrexate and cyclophosphamide, and biotherapy agents such as rituximab, infliximab, and belimumab. In addition to the benefits these agents had, some adverse effects were also noted. Dental professionals played a vital role in providing preventive oral care to the patients which curtailed the adverse effects of these therapies and improved the quality of life.
Cancer
Cancer could occur anywhere in the body when uncontrolled division of some cells begins and metastasizes to other tissues. The normal growth, division, and replacement of damaged cells is disrupted when cells ignore the signals from brain to stop growing, and thus new cells continue to form and do not replace damaged cells. This survival of damaged cells and formation of extra cells results in the development of masses called tumors. Cancer cells are able to avoid the immune system, thus resulting in the infection and destruction of surrounding tissues. (3)
Autoimmune disease
The National Institute of Health estimates that 23 million Americans are affected by autoimmune diseases. Autoimmune disease develops when the immune system considers the body’s own cells and tissues as a foreign substance and starts killing them. It could occur only in one part of the body or could spread to multiple systems. For example, in rheumatoid arthritis, affects only joints; in systemic lupus, erythematosus several affects several systems of the body, such as skin, joints, kidneys, heart, nerves, blood vessels, and more. Genetics and environmental factors play a significant role in the occurrence of autoimmune disease, which causes physical impairment thus altering patient’s quality of life. (4) Autoimmune disease is mainly treated by suppressing the immune system, which in turn reduces symptoms and manages the disease. In the past, autoimmune diseases were treated with the use of analgesics, NSAIDS, and corticosteroids. Chemotherapy and biotherapy agents were traditionally used for cancer, but their immunosuppressant properties had also proven effective against autoimmune diseases. (4)
Systemic lupus erythematosus, considered a rare disease, mostly affects women between 15 to 50 years old. The cause of systemic lupus erythematosus is still unknown, but it was an autoimmune disease that causes damage to internal organs of the body. It is treated effectively by early diagnosis and helped by reduction of the symptoms. The National Institute for Health and Care Excellence (NICE), on May 10th 2016, recommended a biotherapy agent, belimumab, for adult patients with active systemic lupus erythematosus. The common symptoms of systemic lupus erythematosus include fatigue, fever, hair loss, chest pain, mouth sores, anemia, swelling in legs and ankles, rash on face and hands, muscle and joint pain. (5)
The treatment of rheumatoid arthritis focuses on the suppression of immune system with the help of biotherapy agents. The oral complications caused by these agents include oral thrush, metallic taste, soreness and burning sensation of tongue, difficulty swallowing, cold sores on lips, xerostomia, ulcers, gingival bleeding, oral pain, white spots or patches, itching of lips and tongue, halitosis, burning of lips, pain in the jaw, and swelling in glands. (6)
Chemotherapy agents
Every year approximately 650,000 patients in the United States who had cancer receive chemotherapy treatment. (7) There are more than 100 chemotherapy agents that are used alone or with other drugs to treat cancer. Chemotherapy agents are divided into groups such as alkylating agents (cyclophosphamide) and antimetabolites (methotrexate). Selection of these drugs depends on their chemical composition, benefits, and side effects. Selection of chemotherapy agents depends on factors such as type of cancer, patient’s age, and overall health. Treatment of cancer is more effective when a combination of chemotherapy drugs is used or combination of treatments such as chemotherapy and biotherapy is implemented. (8) Immunosuppressant properties of chemotherapy agents show promising results in the management of autoimmune disease by decreasing the neutrophil count in blood. (4)
About 40% of patients in one study showed signs of oral complications that postponed or lengthened the treatment, and increased the cost of the treatment and occurrence of oral and systemic secondary infections. (9) In addition to the destruction of the cancer cells, chemotherapy agents kill the healthy cells in the body and also lower the platelet and white cell count in the blood. The low platelet and white blood cells result in the increased risk of bleeding and infection in the body. (10) Most commonly, the destruction is seen in cells of the mouth, digestive tract, hair follicles, bone marrow, and reproductive system. The oral complications that occur during or after the chemotherapy treatment include mouth lesions, xerostomia, metallic taste, yellow or white coating on the tongue, pain in the mouth and gums, increased caries risk, bone loss, peeling or burning of the tongue, and bacterial infection. (11)
Methotrexate
Methotrexate is one of the commonly used drugs in the treatment of cancer and autoimmune diseases. It was first developed in 1940s for the treatment of cancer. The rationale was given in 1951 for the usage of methotrexate for treatment of rheumatoid arthritis (RA) because it controlled the proliferation of lymphocytes and other cells involved in RA. Clinical studies done in 1984 and 1985 validated the use of methotrexate in RA. Several studies have also suggested that low dose of methotrexate was anti-inflammatory rather than antiproliferative. (12)
The antimetabolite property of methotrexate impedes cell metabolism in the body. In treatment of cancer, it worked by reducing the development of cancer cells; in autoimmune disease, it slowed down the activity of the immune system. (13)
Methotrexate worked as a folate analogue and inhibits dihydrofolate reductase. Like normal body cells, malignant cells also require folate for their proliferation, and methotrexate stops rapid growth of cancerous cells by inhibiting their access to folate. (14)
Methotrexate is considered to be one of the safest drugs available for the treatment of autoimmune diseases. Among primary care physicians and patients, there is a widespread misconception that methotrexate was highly toxic. The reason for that misconception is based on the dosage, because in order to treat autoimmune disease 10 to 25mg of methotrexate was prescribed per week ,whereas doses prescribed for treating cancer are a hundred times larger. (14)
In addition to the benefits of methotrexate, there are also side effects. It could cause damage to the liver and make it susceptible to infection. Serious birth defects had also been associated with the use of the drug during pregnancy. Other common side effects included nausea, vomiting, diarrhea, mouth ulcers or sores, hair loss, and skin rashes. Another common complaint reported is called “methotrexate fog” in which patient experienced headache and fatigue. (14)
While taking methotrexate, certain precautions help minimize the side effects. Caffeine and alcohol avoidance is recommended, as these hinder the effectiveness of the drug; this precaution also prevents liver damage. Skin becomes sensitive because of methotrexate, so sun exposure is minimized. Blood work every eight to 12 weeks to check folate level is recommended. Folic acid or folate supplements are also sometimes prescribed. (15) Mouthwash containing lidocaine or salt water helps to alleviate pain caused by mouth ulcers or sores. (14)
Methotrexate is commonly used to treat rheumatoid arthritis, psoriasis, multiple sclerosis, lupus erythematosus, sarcoidosis, ectopic pregnancy and cancers of blood, bone, lung, breast, head and neck. (4)
Cyclophosphamide
Another widely and successfully is treat cancer and autoimmune diseases was cyclophosphamide. Clinical studies for the use of this drug were done in 1958 by Arnold and Bourseaux. In 1959, it was approved by the FDA as the cytotoxic anticancer agent. Cyclophosphamide is also used in the “conditioning” and “mobilization” procedures for blood and bone marrow transplantation. (16)
Cyclophosphamide is a cytotoxic agent and belongs to the class of alkylating agents. In cancer patients, it works by adding an alkyl group to the electronegative groups in the DNA of targeted cells. This inhibits the tumor cell growth by diminishing the ability of DNA strands to uncoil and replicate, which results in cell death. In autoimmune disease, cyclophosphamide kills and suppresses lymphocytes. In RA, it reduces the number of B cells and function of T cells. (17)
The toxicity of cyclophosphamide depends on the dosage and length of drug administration. This drug is usually prescribed for three to six months only, because use of the drug for more than six months caused chronic toxicity. The drug is administered orally or intravenously. The low to intermediate dosages tend to produce less acute toxic effects, and high dose causes more acute toxic effects. The high doses result in neutropenia, leukopenia, thrombopenia and anemia; however, the low doses rarely caused these conditions. The high doses of cyclophosphamide cause bone marrow suppression, hemorrhagic cystitis, and cardiac, gonadal and bladder toxic effects. High doses of cyclophosphamide for prolonged period of time can be carcinogenic. Bladder cancer, secondary acute leukemia, and skin cancer have been seen after the therapy with cyclophosphamide. The other common side effects associated with cyclophosphamide include nausea, vomiting, reversible hair loss, diarrhea, hyponatremia, headaches, dry and sore eyes, soreness of the hands and feet, skin rash, loss of appetite, tiredness, sore on the mouth or tongue, and skin color change. Cyclophosphamide also causes fertility problems in both men and women and serious birth defects. (16)
While taking cyclophosphamide, certain precautions need to be taken to reduce its side effects. It is important to have careful monitoring by the physician. Some vaccinations needed to be updated before the treatment begins, such as pneumovax, hepatitis B, tetanus booster and zostavax (shingles), because this medication suppresses the immune system. Effective birth control methods should be taken during the treatment to avoid pregnancy. (18)
The injection of Granulocyte-colony stimulating factor (G-CSF or GCSF) is prescribed by the physician to stimulate bone marrow to produce granulocytes and stem cells. After the administration of the drug, it is advisable to drink plenty of fluids to reduce bladder irritation. Cleaning of teeth and dentures twice a day with soft bristle toothbrush and using mouthwash regularly helped to reduce mouth sores or ulcers. Avoidance of tightly fitting socks, shoes, and gloves are advised to reduce soreness in the hands and feet. Skin can be sensitive due to cyclophosphamide, so sun protection is advised. (19)
Cyclophosphamide is used to treat certain cancers such as breast cancer, lung cancer, ovarian cancer, bone cancers, soft tissue sarcoma, retinoblastoma, neuroblastoma, multiple myeloma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, chronic lymphocytic leukemia, chronic myelogenous leukemia, acute myeloid leukemia and acute lymphoblastic leukemia. (20) The autoimmune diseases treated by cyclophosphamide included rheumatoid arthritis, lupus, systemic sclerosis (scleroderma), vasculitis and myopathies such as polymyositis and dermatomyositis. (15)
Biotherapy agents
The latest development in the treatment of cancer and autoimmune diseases is the introduction of biotherapy agents, which were made or derived from living organism. These agents boost or suppress the immune system, which in return helps the body to fight infections, cancer cells and other diseases. These agents are also able to directly kill the cancer cells. Biotherapy is also called biological therapy, biological response modifier therapy (BRM therapy), and immunotherapy. The significant difference between chemotherapy and biotherapy agents is that biotherapy agents help the immune system to fight tumor cells and chemotherapy agents directly kill the cancer cells. The two types of biotherapy agents are monoclonal antibodies and cytokines. Side effects commonly seen with the use of chemotherapy agents were not evident in biotherapy treatment. However, some side effects which were seen in biotherapy treatment were weight gain, nausea, vomiting, mouth sores, and fatigue. (21)
Rituximab
In the United States, one of the widely-used biotherapy agent is Rituximab, which works by binding on B cell surface receptors. The drug then kills B cells. The drug has been effectively used in the treatment of autoimmune diseases such as lupus and rheumatoid arthritis and certain type of cancers. (22)
One of the serious side effects of Rituximab is infusion reaction that resulted in death. Other common side effects includ rash, swelling of face, lips, tongue and throat, fatigue, and chest pains. Skin and mouth reactions result in sores on lips and inside the oral cavity, pustules, blisters, and peeling skin. (21)
The initial use of Rituximab was confined to the treatment of lymphoma, a type of B cell cancer, but later the drug was approved for patients with rheumatoid arthritis and lupus. Rituximab, a genetically engineered agent, was obtained from an antibody found in mice. The distinctive feature of this antibody is that it killed B cells. In a normal immune system, B cells were a major component but kept within balanced limits; in patients with lupus, B cells or lymphocytes are overactive. Rituximab administration reduces over activity of B cells in patients with lupus. (23)
Infliximab
Infliximab is used to treat rheumatoid arthritis, Crohn’s disease, ulcerative colitis, and plaque psoriasis. The possible side effects evident with the use of infliximab biotherapy agent include low blood cell count resulting in risk of infection, itching and hives, tingling and swelling in oral cavity, fever, chills, and nausea. Erythema multiforme (EM) has been reported following infliximab therapy. Dental hygienists have evaluate patients presenting with oral complications. (24)
Infliximab is a monoclonal antibody developed from cells of humans and mice. It works by blocking the activity of tumor necrosis factor alpha (TNF-alpha). Infliximab binds to and neutralizes TNF-alpha cell membranes thus preventing inflammation. (25)
Belimumab
Belimumab, a synthetic monoclonal antibody, was approved by FDA on March 9, 2011, as the first biological treatment for systemic lupus erythematosus (SLE). B lymphocyte stimulator (BLyS) or B cell-activating factor (BAFF) plays an important role in the pathogenesis of SLE. BLyS is responsible for the survival and function of B- cells in the body. The increase in the level of BLyS in the body increases the number of antibodies such as IgG, IgM and IgA. BLys is found bound in membranes and soluble form in the body. The soluble form is the active form in the body. Patients with SLE have shown an increased serum level of BLyS or BAFF; therefore its levels are monitored during the SLE to see the activity of the disease. Belimumab works by binding to BLyS and inhibiting its interaction with the receptors. This inhibition resulted in the decrease of B cell and autoantibody production in the body, which reduced autoimmune response. (26)
Belimumab is administered intravenously. Belimumab did not show any pharmacokinetic changes when used in combination with NSAIDs, antimalarials, corticosteroids, methotrexate, azathioprine, or mycophenolate mofetil. It is not recommended to use belimumab in combination with cyclophosphamide or other biological drugs, because studies have not been conducted yet to see the side effects of this combination. Live vaccines are also not recommended to be given in combination with belimumab. (26)
Side effects include infections, headache, rash, pyrexia, diarrhea, nausea, nasopharyngitis, bronchitis, insomnia, pain, neutropenia, and thrombocytopenia. The drug should be used with caution in patients such as pregnant women, nursing mothers, children, and geriatric patients. According to a clinical trial, some adverse effects have also been reported with the use of belimumab such as anaphylaxis, serious infections, death, severe depression, and suicide due to depression. (26)
Belimumab is only used to treat patients with active systemic lupus erythematosus (SLE) in combination with standard therapy. Studies had been conducted for the use of belimumab to treat patients with severe active lupus nephritis or severe active central nervous system lupus, but the effectiveness of the drug in these diseases was yet unclear. (27)
Prevention and management of oral side effects and the role of dental hygienist
The high dose of methotrexate (HDMTX) is an aggressive form of treatment used in some patients to treat cancer, but HDMTX use has shown renal toxicity, hepatotoxicity, or oral mucositis. To reduce the effects of renal toxicity and hepatotoxicity, it is recommended to increase hydration to aid in the excretion of methotrexate from the body. Before the administration of high dose methotrexate, avoidance of alcohol, control of hepatitis B and C infections, and measurement of bilirubin is recommended to make sure the liver is not inflamed and is functioning normally. Oral mucositis is also associated with the use of high dose methotrexate. It causes other oral infections and delays the chemotherapy process. Dental hygienists have effectively managed oral mucositis by accurate evaluation and early management. (28)
A clinical study was conducted on patients 16 years and younger who were treated with cyclophosphamide as an antineoplastic agent. The study took place at the Children’s Hospital of Westmead Australia between September 2007 and April 2009. One hundred and six patients participated in this study. These patients were closely examined for any oral soft-tissue abnormalities and dental caries. The DMFT index was used to examine dental caries. Saliva testing was also performed to examine the salivary gland function on 104 participants. The participants were categorized in three groups: very low, low, and normal salivary flow. Very low salivary flow was shown in 27.9% of the participants; 18.3% participants showed low salivary flow. According to the analysis, low salivary flow was 12.4 times more evident in patients who received cyclophosphamide than those who were on a different chemotherapy drug. Low salivary flow was associated with increased caries risk. Dental hygienists helped and monitored patients who were receiving cyclophosphamide because they were more susceptible to developing oral conditions. Careful and regular monitoring of these patients with appropriate oral hygiene education and introduction of salivary substitutes decreased the risk of dental caries and discomfort in chewing or swallowing. (29)
About 67% to 86% patients experienced oral pain due to oral mucositis caused by chemotherapy. Oral mucositis also affected the food intake ability of patient, increased their hospital stay, and also amplified their risk for secondary infections. Dental hygienists improved quality of life of these patients by preventing and managing oral mucositis and oral pain. Oral mucositis was prevented by keeping the mouth cold before, during, and after chemotherapy treatment. Oral therapy in which ice chips and ice water were applied to oral mucosa was referred as oral cryotherapy. Patient sucked on ice chips or rinsed with ice water to keep mouth cold. The constriction of blood vessels by oral cryotherapy reduced the effects of chemotherapy on oral mucosa. Oral cryotherapy had shown to reduce the occurrence of oral mucositis when used in combination with standard oral care. (30)
Patients with autoimmune diseases improved their quality of life by making changes in their lifestyle; healthcare professionals helped them by regular monitoring and management of disease. (5)
Conclusion
Studies have confirmed that patients going through chemotherapy and biotherapy showed both systemic and oral complications, which increased the hospitalization and recovery time. The side effects of the therapy agents varied with the dosage, route of administration, and type of the agent. Quick intervention helped to arrest any infection in its primary stage and prevented further damage. Dental hygienists need to be familiar with biotherapy and chemotherapy agents and their potential side effects to be able to educate patients accordingly.
According to the National Institute of Dental and Craniofacial Research (NIDCR), oral assessments before the cancer treatment were vital for the patient and oncology team. They helped in the diagnosis and treatment of any oral risks before or during the chemotherapy. (31)
Dental hygienists performed a comprehensive evaluation one month before the chemotherapy or biotherapy treatment began. It helped to eliminate any existing infections. Dental hygienists provided thorough prophylaxis and oral hygiene instructions every appointment, such as use of fluoride gel, nonalcohol mouthwash, jaw muscle exercises to treat jaw stiffness, and acidic foods avoidance. It was important to keep regular visits to dental office even after the completion of the therapies for early detection of any new infections, since the immune system stayed suppressed for a certain period following the therapy. Dental hygienists played a pivotal role before, during and after the chemo and bio therapy, thus making a marked difference in treatment management and improved quality of life of the patients.
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