Disease-Modifying Antirheumatic Drugs (Dmards) and Drug Interactions in Dentistry

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European Review for Medical and Pharmacological Sciences 2021; 25: 2834-2842 Disease-Modifying Antirheumatic Drugs (DMARDs) and drug interactions in dentistry

C. MUÑOZ-MARTÍNEZ, M. SEGURA-PUERTAS, G. GÓMEZ-MORENO

Department of Medically Compromised Patients in Dentistry, School of Dentistry, University of Granada, Granada, Spain

Abstract. – OBJECTIVE: Rheumatoid arthri- main symptoms. Its prevalence is five out of every tis is a chronic autoimmune disease. Treatment 1000 adults, affecting more women (aged 30-50 aims to reduce and improve its signs and symp- years) than men1,2. toms. Hence, Disease-Modifying Antirheumat- RA is the chronic inflammation of the synovial ic Drugs (DMARDs) are the treatment of choice. membrane and can advance to a point at which The objective of this study was to identify po- it destroys articular cartilage and juxta-articular tential interactions between DMARDs and the drugs most frequently prescribed in dentistry in bone. In addition, the patient suffers multiple order to avoid adverse reactions. organ disorders, swelling, pain, and joint rigidi- MATERIALS AND METHODS: This literature ty. After RA first appears, progressive articular review sets out to define possible adverse reac- destruction advances rapidly, causing deformed tions provoked by pharmacological interactions joints and unalterable physical abnormalities. between DMARDs and the drugs commonly pre- Appropriate diagnosis and treatment play in- scribed in dentistry. A search was conducted in PubMed by searching the names of drugs dispensable roles in dealing with this disease. used in dentistry, “drug interactions,” “rheuma- Ongoing research and developments in science toid arthritis,” and “dentistry”, “hydroxychlo- and technology have achieved major advances in roquine”, “leflunomide”, “methotrexate”, “sul- the remission of RA at early stages or in reducing fasalazine”, “adalimumab”, “anakinra”, “etaner- activity in established RA1. cept”, “abatacept”, “infliximab” and “rituximab”. RESULTS: Diagnosis of RA is by a set of criteria estab- It was found that most DMARDs lished by the American College of Rheumatology show potential interactions with many drugs used in dentistry, including various antibiotics, and the European League Against Rheumatism analgesics, anesthetics, antifungals, and corti- in 2010. When published, these criteria included costeroids. one or two novelties, such as the non-inclusion CONCLUSIONS: It is clinically important for of rheumatoid nodules, erosive changes observed oral health clinicians to be aware of possible radiographically, and symmetric arthritis. Diag- drug interactions between DMARDs and the nostic tests consist principally of determining drugs commonly prescribed in dentistry to prevent potential adverse reactions and avoid en- the presence of antibodies. Rheumatoid factor is dangering the patient. not characteristic of RA alone, while anti-citrullinated protein antibodies are more specific to Key Words: RA. Around 50-80% of persons with RA pres- DMARDs, Drug interactions, Dentistry, Non-steroi- ent rheumatoid factor, anti-citrullinated protein dal anti-inflammatories (NAIDS), Antibiotics, Antifun- gals, Acetaminophen. antibodies, or both. Other factors are globular sedimentation rates and reactive C protein levels, whose values increase with active RA. These factors are used to monitor the case, its activity, Introduction and response to medication. It is important to perform a differential diagnosis to distinguish The term rheumatism is 2,500 years old and RA from systemic erythematosus lupus, systemic comes from Ancient Greek, originally meaning sclerosis, or psoriatic arthritis3. “a flow of current”. This name alludes to the mul- Regarding the established treatments for RA, tiple joints that it affects. Rheumatoid arthritis Disease-Modifying Anti-Rheumatic Drugs (RA) is an autoimmune disease of a chronic and (DMARDs) are currently the leading treat- inflammatory character, synovitis being one of its ment and the subject of this literature review.

2834 Corresponding Author: Gerardo Gómez-Moreno, DDS, Ph.D, MS; e-mail: [email protected] Disease-Modifying Antirheumatic Drugs (DMARDs) and drug interactions in dentistry

DMARDs are a set of drugs that interfere in the hydroxychloroquine, leflunomide, methotrexate, signs and symptoms of RA, delaying or detaining sulfasalazine, adalimumab, anakinra, etanercept, the alterations suffered by the joints. DMARDs abatacept, infliximab, and rituximab. As the arti- are classified as biological or synthetic depending cles found were few or non-existent (depending on on provenance but can also be classified accord- the drug searched for), manualsearches were done ing to their route of administration, as synthetic in official websites: Drug Interactions Checker DMARDs are administered orally, while biolog- (https://www.drugs.com/drug_interactions.html) ical DMARDs are administered intradermally and the National Center for Biotechnology Infor- or intravenously1,4,5. Treatment with non-steroidal mation (https://www.ncbi.nlm.nih.gov). anti-inflammatories (NSAIDs) or analgesics only allows an improvement of the symptoms but does not halt the advance of the disease or the damage Results it causes, so these may be used as additional treatment of the symptoms or while diagnosis is Table I shows the number of known potential being established. drug interactions with DMARDs of clinical sig- This systematic literature review aimed to nificance. These drug combinations should not identify potential interactions between DMARDs be administered as the risk of the interaction out- and the drugs most commonly used in dentistry; weighs the benefits. They include potential inter- it also aims to establish preventative measures to actions regarded as major, moderate or minor be- avoid adverse reactions derived from these drug tween DMARDs and the drugs most commonly interactions. prescribed in dentistry identified in the searches (Table II), which are as follows.

Materials and Methods Hydroxychloroquine Major interactions have been described be- An electronic search was conducted in the tween hydroxychloroquine and antibiotics be- PubMed and MEDLINE databases for articles longing to the macrolide group (azithromycin, reporting potential pharmacological interactions clarithromycin, and erythromycin), antifungals between the drugs used to treat rheumatoid ar- (fluconazole and ketoconazole), and one analgesic thritis (DMARDs) and the drugs most commonly (tramadol). Hydroxychloroquine administered at prescribed in dentistry. The following search the same time as azithromycin, clarithromycin, terms were applied alone or in combination: erythromycin, fluconazole, and ketoconazole can drug interactions, dentistry, rheumatoid arthritis, lead to secondary effects, such as increased and/

Table I. Number of potential drug interactions of each DMARD. Number of Number of Number of Number of major moderate minor drug interactions DMARDs interactions interactions interactions in dentistry

Hydroxychloroquine 179 247 4 9 Leflunomide 451 90 7 11 Methotrexate 121 457 16 24 Sulfasalazine 41 159 7 7 Adalimumab 228 152 7 5 Anakinra 34 302 7 3 Etanercept 228 152 7 4 Abatacept 33 67 7 0 Infliximab 231 163 7 4 Rituximab 36 83 7 0 Tofacitinib 269 205 8 13 Baricitinib 239 107 6 9 Golimumab 228 152 7 5 Certolizumab 228 153 7 3 Tocilizumab 40 218 7 2 Sarilumab 41 159 7 1

2835 C. Muñoz-Martínez, M. Segura-Puertas, G. Gómez-Moreno

Table II. Potential interactions regarded as major or moderate between DMARDs and the drugs most commonly prescribed in dentistry. DMARDs Major interactions Moderate interactions

Hydroxychloroquine Azithromycin, Clarithromycin Carbamazepine, Itraconazole Erythromycin, Fluconazole Metronidazole Ketoconazole, Tramadol Leflunomide Acetaminophen, Acetylsalicylic acid Metronidazole Azithromycin, Clarithromycin, Erythromycin Carbamazepine, Clotrimazole, Fluconazole Ketoconazole, Methylprednisolone Methotrexate Amoxycillin, Penicillin G, Penicilin V, Acetaminophen, Azithromycin Diclofenac, Ibuprofen, Ketoprofen, Ketorolac, Carbamazepine, Clarithromycin Naproxen, Nitrous oxide, Omeprazole Clotrimazole, Cortisone, Erythromycin, Ethanol, Fluconazole Hydrocortisone, Itraconazole Ketoconazole, Tetracyclines Sulfasalazine Prilocaine Acyclovir, Diclofenac, Ibuprofen, Ketoprofen, Ketorolac Naproxen Adalimumab Cortisone, Hydrocortisone, Methylprednisolone Carbamazepine, Metronidazole Anakinra Carbamazepine, Hydrocortisone Methylprednisolone Etanercept Cortisone, Hydrocortisone Carbamazepine, Metronidazole Abatacept Infliximab Cortisone, Hydrocortisone Carbamazepine, Metronidazole Rituximab Tofacitinib Carbamazepine, Clarithromycin, Cortisone Diclofenac, Erythromycin Hydrocortisone, Fluconazole, Itraconazole Ibuprofen, Ketoprofen, Naproxen Ketoconazole Baricitinib Cortisone, Hydrocortisone, Methylprednisolone Acetylsalicylic acid, Diclofenac, Ibuprofen Ketoprofen, Naproxen Tramadol Golimumab Cortisone, Hydrocortisone Carbamazepine, Metronidazole Midazolam Certolizumab Cortisone, Hydrocortisone Metronidazole Tocilizumab Metronidazole, Carbamazepine Sarilumab Carbamazepine or irregular heartbeat, which can lead to serious As for moderate interactions between hydroxy- problems and even fatality. Patients presenting chloroquine and the drugs used in dentistry, ad- congenital long QT syndrome, conduction disor- verse reactions can occur with carbamazepine, ders, some heart diseases, or electrolyte disorders itraconazole, and metronidazole. While carbamaz- may be more susceptible to these adverse effects. epine can boost the level and effects of hydroxy- If the patient has a history of convulsions, is in a chloroquine, itraconazole reduces them. Moreover, period of abstinence from drug or alcohol con- if the patient is in treatment for epilepsy, the sumption, is elderly, or has some effect on the interaction with carbamazepine administered in central nervous system, the interaction between dentistry to treat trigeminal neuralgia may cause hydroxychloroquine and tramadol can occasion- a reduction in the efficacy of treatment. The inter- ally cause convulsions. It is advisable for the pa- action with metronidazole can increase the risk of tient to avoid activities that require mental agility nerve damage. If the patient presents weakness, until it becomes clear how he/she will react to pain, numbness, burning or a tingling sensation at these drugs6. the extremities, he/she should see the doctor6.

2836 Disease-Modifying Antirheumatic Drugs (DMARDs) and drug interactions in dentistry

Leflunomide anemia, infection, or blood disorders. It is nec- Leflunomide is the DMARD that shows the essary to adjust the dose if the patient suffers highest number of interactions with the drugs fatigue, dizziness, fainting, unusual bleeding commonly prescribed in dentistry: analgesics episodes, fever, shivering or other flu symp- (acetaminophen, acetylsalicylic acid), antibiot- toms. Interaction with NSAIDs will boost their ics (azithromycin, clarithromycin, erythromy- effects. It is recommended to supervise the dos- cin), anticonvulsants such as carbamazepine es of both drugs whenever the patient presents (used to treat trigeminal neuralgia), antifun- ulcers or sores, mucositis, pain or swelling of gals (clotrimazole, fluconazole, ketoconazole) the joints, yellowish skin color, dark urine, diz- and corticosteroids such as methylprednisolone7. ziness or fainting, bruising or unusual bleeding, Leflunomide can provoke hepatic damage or convulsions, infection, and flu-like symptoms. problems and administer it with other drugs that Special care must be taken whenever the patient affect the liver and increase the risk of hepatic presents any renal disease8. disorders. Depending on the dose administered, Methotrexate can have moderate interactions leflunomide may remain in the blood for some with various antifungals, analgesics, corticoste- time, so reactions may occur even though the roids, and antibiotics. Interactions may occur administration has come to an end. It is advis- with acetaminophen, azithromycin, carbamaze- able for the patient to avoid or minimize alcohol pine, clarithromycin, clotrimazole, corticotropin, consumption during treatment7. The signs and cortisone, erythromycin, fluconazole, hydrocorti- symptoms of hepatic damage that may appear sone, itraconazole, ketoconazole, or tetracyclines. are fever, shivering, pain or swelling in the Taking any of these drugs together with metho- joints, bleeding or unusual bruising, cutane- trexate can affect the liver. If the patient presents ous eruptions, itching, loss of appetite, fatigue, signs and/or symptoms of hepatic damage, he/she nausea, vomiting, abdominal pain, dark colored should be referred to a doctor8. Interactions with urine, light colored feces and/or yellowish skin corticosteroids are different and increase levels in and eyes7. the blood, causing a decrease in blood cell counts, The use of methylprednisolone together with bruising and easy bleeding, unusual feelings of leflunomide can cause severe infections. More- weakness, mouth ulcers, nausea, vomiting, black over, leflunomide has more interaction with alco- feces or blood in feces, urinating with less fre- hol, which may cause secondary effects such as quency than usual, or not urinating at all. The reddening, head and neck palpitations, throbbing same occurs with tetracyclines, but blood levels headache, difficulty breathing, nausea, vomiting, can increase or decrease, as can the secondary sweating, thirst, pains in the chest, increased effects. Methotrexate also has a moderate inter- heartbeat, palpitations, low blood pressure, dizzi- action with ethanol causing hepatic problems, ness, blurred vision, and confusion. and so alcohol consumption should be reduced or Leflunomide has a moderate interaction with minimized8,9. metronidazole, which can cause nerve damage, this being an important secondary effect. Patients Sulfasalazine with high arterial blood pressure must be moni- Sulfasalazine presents interactions with the tored during dental treatment as metronidazole local anesthetic prilocaine. Signs and symptoms alone raises blood pressure7. may occur within hours of administrating prilocaine. The patient should seek medical atten- Methotrexate tion if he/she presents grayish discoloration of This drug has interactions with antibiotics the skin, mouth or nail beds, nausea, headache, (amoxycillin and penicillin G/V), NSAIDs (di- dizziness, fatigue, difficulty breathing, rapid or clofenac, ibuprofen, ketoprofen, ketorolac, and shallow breathing, rapid heartbeat, palpitations, naproxen), anesthetics (such as nitrous oxide) anxiety or confusion10. or proton pump inhibitors (such as omeprazole). All sulfasalazine’s moderate interactions occur When amoxycillin or penicillin are prescribed in combination with NSAIDs: diclofenac, ibupro- for severe infections, they are usually admin- fen, ketoprofen, ketorolac, and naproxen. These istered in high doses, which will provoke an interactions affect mainly the renal system caus- interaction with methotrexate. The appearance ing nausea, vomiting, loss of appetite, increased or increase in secondary effects such as nausea, or decreased miction, sudden weight increase or vomiting, or oral ulcers promote the onset of decrease, retention of liquids, swelling, difficul-

2837 C. Muñoz-Martínez, M. Segura-Puertas, G. Gómez-Moreno ty breathing, muscle cramps, fatigue, dizziness, bamazepine, antibiotics (clarithromycin), cortico- confusion, and irregular heartbeat. Sulfasalazine steroids (corticotropin, cortisone, hydrocortisone) also interacts with acyclovir with similar effects or antifungals (fluconazole, itraconazole, keto- to NSAIDs10. conazole)14. Carbamazepine can reduce the effects of the Adalimumab tofacitinib, while clarithromycin, itraconazole This is a drug of biological origin that interacts (used to treat fungal throat infection), fluco- with corticosteroids: cortisone, hydrocortisone, nazole, and ketoconazole increase them, with and methylprednisolone. Interactions with these the appearance of secondary effects (low blood drugs can cause severe infections, with even a cell counts, anemia, severe infections, and high risk of fatality. If the patient presents any signs blood lipid levels)14. With cortisone, hydrocorti- or symptoms of the following and is taking both sone and methylprednisolone, there is a possibil- types of medication, he/she should seek emer- ity of severe infection, and patients may suffer gency medical attention at once: fever, shiver- additional adverse effects such as diverticular ing, diarrhea, sore throat, muscle pain, difficulty disease, bleeding or gastrointestinal perforation. breathing, blood in the phlegm, weight loss, red The signs and symptoms that these complications or inflamed skin, body sores, pain or a burning present are abdominal pain, fever, vomiting or sensation when urinating11. nausea. Moderate interactions take place with carba- As for moderate interactions with tofacitinib, mazepine and metronidazole. Interaction with care should be taken whenever the following are carbamazepine can reduce the levels and effects administered: diclofenac, ibuprofen, ketoprofen, of the adalimumab. In combination with metroni- or naproxen. These produce adverse effects in dazole, there is a risk of nerve damage11. the gastric system, producing intense abdominal pain, fever, nausea or vomiting. Lastly, the anti- Etanercept biotic erythromycin can eliminate the effects of Etanercept can interact with cortisone and hy- tofacitinib14. drocortisone, leading to potentially major infections, with the usual signs and symptoms: fever, Baricitinib diarrhea, muscle pain, and weight loss, among Baricitinib can interact with the following others12. corticosteroids prescribed as a part of dental Moderate interactions with etanercept are the treatment: cortisone, hydrocortisone, and methyl- same as those between adalimumab and carba- prednisolone. These interactions provoke severe mazepine, and it is advisable to adjust the dose infections, which may even be lethal. In some carefully. The same occurs with metronidazole. cases of cortisone, hydrocortisone, and meth- The patient should seek medical attention if he/ ylprednisolone administration, interactions with she presents weakness, numbing, pain, burning baricitinib can produce additional adverse effects or tingling in the extremities as these could be with risks of diverticular disease or gastrointesti- signs and symptoms of nervous damage12. nal perforation15. Moderate interactions can occur with NSAIDs Infliximab (acetylsalicylic acid, diclofenac, ibuprofen, keto- Infliximab can produce interactions in combi- profen, naproxen) and tramadol, producing ad- nation with corticosteroids, cortisone, and hydro- verse gastrointestinal effects that increase the cortisone, increasing the risk of severe infection, risk of diverticular disease, bleeding or gastroin- which may be lethal if not dealt with in time. The testinal perforation15. signs and symptoms are the same as those cited above for interactions with adalimumab. As for Golimumab and Certolizumab moderate interactions, these are the same as with Golimumab and certolizumab interact in the adalimumab and etanercept with the same signs, same way with certain groups of corticosteroids3: symptoms and recommendations13. cortisone and hydrocortisone. These interactions can cause severe infections, and patients must seek Tofacitinib medical attention if any signs or symptoms appear. RA patients treated with tofacitinib can suffer Regarding moderate interactions, these can oc- problematic interactions when it is administered cur with golimumab in combination with carba- in combination with anticonvulsants such as car- mazepine, metronidazole, and midazolam. With

2838 Disease-Modifying Antirheumatic Drugs (DMARDs) and drug interactions in dentistry carbamazepine and midazolam, the effects of the ventional synthetic DMARD), which is not the drugs will be reduced, but with metronidazole, DMARD that presents the most interactions with the interaction increases the possibility of ner- drugs used in dentistry1,4,5. Nevertheless, the in- vous damage16,17. teractions that do exist are serious and so special Metronidazole can produce a moderate inter- care must be taken whenever it is administered. action with certolizumab affecting the nervous Adverse reactions deriving from drug interac- system. In this case, the dose should be adjust- tions with methotrexate usually provoke hepatic ed or compatible alternatives prescribed. If the and gastrointestinal dysfunction. If the reactions patient presents weakness, numbness, burning are not resolved by one of the various alternatives or tingling sensations in the extremities, he/she such as vitamin B9 administration or adjusting should seek medical attention16,17. the dose, medication will have to be terminated in the following order: glucocorticoids, anti-inflam- Anakinra matories, and lastly DMARDs1. Anakinra can have moderate interactions with The present review was conducted in response corticosteroids, hydrocortisone and methylpred- to the uncertainties that arise in routine dental nisolone, increasing the risk of severe infection. clinical practice whenever a patient is diagnosed If the patient presents signs and symptoms of with RA and seeks dental treatment21-25. Informa- infection as described above, he/she should seek tion about pharmacological interactions between medical attention. Anakinra can also interact DMARDs and drugs used in dentistry is fairly with carbamazepine, reducing the effects of both scarce. DMARDs are immunosuppressants and drugs18. so patients taking this medication and attending the dental clinic for some treatment involving Tocilizumab other drugs already suffer a higher risk of bleed- Moderate interactions may be produced by ing and infection. In this sense, it is advisable to tocilizumab in combination with carbamazepine, look into the patient’s complete medical history leading to a reduction in carbamazepine lev- to identify any renal or hepatic pathologies the els. Monitoring and adjustment of the dose are patient may have presented, especially when the recommended, particularly when tocilizumab treatment for RA consists of drugs belonging to administration is suspended. This drug also in- the DMARD group. If the RA patient attending teracts with metronidazole, affecting the nervous the dental clinic requires some analgesic, we system19. should always ask whether he/she is taking corticosteroids or mononuclear antibodies in order to Sarilumab revise the dose and avoid overdosing. A moderate interaction can be produced when It is a known fact that methotrexate has ad- sarilumab and carbamazepine are administered verse effects on liver function and provokes the simultaneously, reducing the effects of the lat- appearance of mouth ulcers8,23. It is contraindi- ter20. cated for patients with any renal insufficiency or Regarding slight pharmacological interactions patients with hepatitis C. Leflunomide also has between DMARDs and the drugs used in den- adverse hepatic and gastrointestinal effects7. It is tistry, none have been reported. There is also a advisable to consider prescribing azithromycin group of DMARDs that have been found not to in combination with these two DMARDs (le- interact with the drugs commonly used in dentist- flunomide/methotrexate), or failing this, to adjust ry, although they interact with drugs prescribed methotrexate or leflunomide doses carefully3. in other medical fields. These are abatacept and When hydroxychloroquine or sulfasalazine are rituximab, both of biological origin11. being prescribed, the dentist must pay special attention to the gastrointestinal system. With biological DMARDs (adalimumab, certolizumab, Discussion etanercept, golimumab and infliximab) patients should be screened for latent tuberculosis by When RA is diagnosed, basic treatment con- means of a Mantoux test or thorax radiograph to sists of assessing the situation at once before ascertain presence or absence of the disease, as a articular destruction occurs to avoid arthritis propensity to develop TB and other opportunistic and halt the advance of the disease. The standard infections are among the adverse effects of this treatment is to prescribe methotrexate (a con- group of drugs11-13,17,18.

2839 C. Muñoz-Martínez, M. Segura-Puertas, G. Gómez-Moreno

Hydroxychloroquine action against folic acid. For this reason, folic Among the possible pharmacological interac- acid supplements are usually administered to tions that can occur with hydroxychloroquine, avoid the appearance of adverse reactions. These special care should be taken when administering reactions mainly affect the hepatic and gastroin- antifungals and antibiotics, as the interaction testinal systems8. produced can affect the heart rate, especially The hepatoxicity that can appear as a result in patients presenting cardiac pathologies. The of these interactions is due to the fact that they dentist must bear in mind the possible incidence can reduce the excretion of methotrexate through of convulsions resulting from its interaction with their effect on the renal tubules23. The same can tramadol. To manage moderate interactions, re- occur with penicillin22. The mechanism of action vising the doses of the drugs prescribed is rec- of NSAIDs is transferred to any drugs linked to ommended, especially when prescribing metro- proteins and endangers renal function, increasing nidazole, as there is a risk of the interaction levels of free methotrexate, which usually attach- causing nervous damage6,9. Hydroxychloroquine es to 50-60% of albumin. This group of NSAIDs accumulates in the liver, reaching much higher includes ibuprofen, ketoprofen, and naproxen. levels than in blood plasma. As these are often used in dentistry, their prescription must be applied with caution, or they Leflunomide should be replaced by other NSAIDs9. Due to the Drug interactions with leflunomide are numer- hepatoxicity caused, liver enzyme (SGOT and ous and relevant to dentistry. Special care must SGPT) levels increase4. Moreover, methotrexate be taken to avoid the possible hepatic damage presents an interaction with nitrous oxide, and so that these interactions can cause. There is also a the anesthesiologist should be consulted to assess strong possibility of severe infection when leflun- the indication or contraindication of inhalation omide is administered simultaneously to methyl- sedation in dental treatment. prednisolone, and patients must be monitored for Liver damage that may be caused by metho- any signs or symptoms. It is advisable to seek an trexate’s potential moderate interactions, which alternative to prescribing metronidazole to avoid should be taken into account before prescribing damage to the nervous system through its inter- it. Any appearance of the signs and symptoms action with leflunomide7. of gastrointestinal damage is a clear signal that a Leflunomide also has a potential interaction medical check-up is necessary. with alcohol, so the dentist must take care not to Little information is available about one pos- prescribe any mouthwash containing alcohol7. sible interaction between methotrexate administered at the same time as bisphosphonates. Methotrexate One clinical case reports a patient who, after When patients are taking methotrexate, special treatment with methotrexate, began treatment care must be taken as this DMARD interacts for osteonecrosis of the jaw with bisphos- with various drugs producing severe infections, phonates. A wound that would not close was mucositis, pain or swelling in the joints, yellow observed, which led to the suspension of the skin discoloration, dark urine, dizziness or faint- methotrexate, which seemed to tip the balance ing, bruising or unusual bleeding, or convulsions. towards slow healing. In spite of the efficacy of One of the secondary effects is the appearance this drug, its use is restricted by the secondary of mouth ulcers4, which is due to a lack of folic effects it causes26. acid or overdosing; it has been noted in various clinical cases that increasing the dose to the point Sulfasalazine of overdose causes the appearance of ulcers in Special care is recommended when prescribing different parts of the oral cavity23. Prescription sulfasalazine and prilocaine as it increases the of mouthwashes containing chlorhexidine and risk of methemoglobinemia, a situation that leads benzylamine hydrochloride at sufficient doses to reductions of oxygen in vital organs and tissues will resolve the ulcers completely. Folic acid sup- due to reduced oxygen transportation in blood. plements are also recommended23, as it has been This drug also presents moderate interactions shown that the onset of adverse effects partly with many NSAIDs commonly used in dentistry depends on factors that include a lack of folates1. to relieve pain. It is recommended to prescribe Methotrexate acts by controlling lymphocyte and an alternative to these NSAIDs to avoid possible synoviocyte proliferation through an antagonist adverse reactions10.

2840 Disease-Modifying Antirheumatic Drugs (DMARDs) and drug interactions in dentistry

Adalimumab should be taken regarding the latter, as NSAIDs Interactions with adalimumab produce severe aspirin and tramadol also have adverse effects on infection which unless managed can even lead to the digestive system15. death. Nerve damage is likely to occur through its interaction with metronidazole, and the dentist Golimumab and Certolizumab should bear this in mind whenever prescribing Like other drugs used to treat RA, interac- adalimumab11. tions with golimumab and certolizumab can cause major infections that are potentially le- Etanercept thal. It is recommended to avoid prescribing Adverse effects can occur with etanercept’s metronidazole with either of these drugs, as interactions with cortisone and hydrocortisone, moderate interactions can cause damage to the including a propensity to potentially severe infec- nervous system16,17. tion. In addition, there is a risk of nerve damage through its interaction with metronidazole. Doses Anakinra should be revised if treatment with carbamaze- The patient should be warned that infection pine begins, as there is also a risk of interaction12. can occur and if any signs or symptoms appear, he/she should seek medical attention18. Infliximab The potential moderate interactions and ad- Tocilizumab verse effects that infliximab can cause are the Damage to the nervous system can occur when same as with adalimumab, both belonging to the tocilizumab is taken simultaneously with met- same family of medicines2. The drug acts against ronidazole, and so an alternative should be pre- tumor necrosis factor (TNF) and is now used scribed in dental treatment19. to treat more than ten immunological diseases, including Kawasaki disease, psoriasis, Crohn’s Sarilumab disease, and ulcerative colitis. Therefore, these A possible interaction with carbamazepine can systemic diseases must be identified in the -pa reduce the effects of sarilumab20. tient’s medical history to assess the risk of drug interactions in dental treatment13. Conclusions Tofacitinib Interactions with tofacitinib take the form of In summary, secondary effects, ranging from increases or decreases in the drugs levels and slight to severe, can occur due to interactions effects. This is very important due to the fact that between the drugs prescribed in dentistry and an increase can led to overdose and secondary those prescribed to treat RA. Dentists need to be effects, while a decrease will interrupt the desir- aware of these interactions to prevent the appear- able effects of the drug in managing RA. This ance of possible adverse reactions that endanger happens when it is administered together with the patient. anticonvulsants such as carbamazepine, which reduces tofacitinib levels. But the antibiotic clarithromycin and antifungals fluconazole, itracon- Conflict of Interest azole, and ketoconazole increase them. There is The Authors declare that they have no conflict of interests. also a possibility of major infection through other interactions. Special care should be taken when prescribing NSAIDs as they have moderate interactions with tofacitinib, adversely affecting the References gastrointestinal system14. 1) Aletaha D, Smolen JS. Diagnosis and manage- Baricitinib ment of rheumatoid arthritis: a review. JAMA The corticosteroids used in dentistry can inter- 2018; 320: 1360-1372. act with baricitinib, provoking severe infection. 2) Tanaka Y. Rheumatoid arthritis. Inflamm Regen 2020; 40: 20. Interactions can also damage bone marrow, the 3) Wasserman AM. Diagnosis and management of immune system or even cause diseases of the co- rheumatoid arthritis. Am Fam Physician 2011; 84: lon or gastrointestinal perforations. Special care 1245-1252.

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