Journal of Investigative and Clinical Dentistry (2015), 6, 252–260
REVIEW ARTICLE Oral Medicine
Orofacial adverse effects of biological agents Eleni A. Georgakopoulou1 & Crispian Scully2 1 Department of Histology and Embryology, National and Kapodistrian University of Athens, Athens, Greece 2 UCL Eastman Dental Institute, London, UK
Keywords autoimmune, biological agent, drug, infection, ulcer. Correspondence Dr E. A. Georgakopoulou, Laboratory of Histology–Embryology, Molecular Carcinogenesis Group, Medical School, National and Kapodistrian University of Athens, 75 Mikras Asias Street, Goudi, Athens 11527, Greece. Tel: +30-210-7462346 Email: [email protected] Received 3 February 2014; accepted 20 March 2014.
Abstract Biological agents (BA) are increasingly used effectively in the treatment of a range of disorders, but to date, their application in diseases affecting the orofacial region has been fairly limited. Several orofacial adverse effects related to BA have been recently reported. However, the evidence for such adverse reactions is not always strong, and some of the adverse effects of BA have only been reported in case reports or case series. Most reactions to BA reported thus far have been in association with antitumor necrosis factor-a agents, which is not surprising, as these are the most widely-used BA. In the present study, the orofacial adverse effects are reported with various BA in order to sensitize clinicians to the possibilities. In addition, we briefly summarize the mode of action and indications of these BA. As the use and range of BA increases, the number and diversity of adverse effects might well increase. Despite the adverse effects of biological agents, these may often be less serious than the adverse effects of the more traditional immunosuppressive agents.
doi: 10.1111/jicd.12102
Introduction Generated by recombinant biotechnology, biological agents (BA) target immunocytes or their products. BA comprise a number of human (suffix “mab”), humanized (suffix “zumab”), or chimeric (mouse–human) (suffix “ximab”) monoclonal antibodies (mAb) or variant fusion proteins (suffix “cept”) that target immunocytes or specific steps in pro-inflammatory pathways. Biological agents often bind directly to T- or B-lymphocytes, granulocytes, antigen-presenting cells (dendritic cells, macrophages), or other immunocytes and mediators (cytokines, chemokines, growth factors, complement components) in order to deplete them, suppress their function, prevent their homing to lymphoid organs and inflammatory sites, or to induce anergy. The three main classes of BA are tumor necrosis factor (TNF)-a inhibitors (e.g. infliximab, etanercept, and adalimumab), inhibitors or mimickers of other cytokines or key proteins in cellular reactions (e.g. interleukin [IL] inhibitor ustekinumab, which inhibits IL-12 and IL-23), and lymphocyte modulators (T-lymphocyte modulators, 252
e.g. alefacept and efalizumab; or B-lymphocyte modulators, e.g. rituximab). Biological agents are currently licensed for use in rheumatological, gastrointestinal, dermatological, and other systemic diseases, some of which can have orofacial lesions.1–4 Several dozen therapeutic mAb are now marketed for a variety of indications, and as their number increases exponentially, reports of adverse effects are also increasing. Immunomodulatory mAb (and Fc-fusion proteins) are indicated predominantly for the treatment of inflammatory and autoimmune diseases, or used to prevent organ transplant rejection. Immunomodulatory mAb have an inherent risk for producing adverse immune-mediated drug reactions, such as infusion reactions, cytokine storms, immunosuppression, autoimmunity, and other disorders.5 Most reactions have been reported to be associated with anti-TNF-a agents, the most widely used BA, but as the use of BA increases, the number and diversity of adverse effects might well increase. Some of these adverse effects affect the orofacial region. Few oral medicine specialists are very familiar with the use of BA, but they are the specialists ª 2014 Wiley Publishing Asia Pty Ltd
Orofacial effects of biological agents
E. A. Georgakopoulou and C. Scully
who will be called to recognize and possibly treat the orofacial adverse effects of BA. In the present study, we summarize the orofacial adverse effects of BA reported; these have been mainly reported in case reports and case series (published in peer-reviewed journals). We also refer to the orofacial side-effects officially recorded in the US Food and Drug Administration (FDA) and European Medicines Agency factsheets (classified by drug category in Tables 1–3), and include a brief section that refers to the mode of actions and the therapeutic applications (official and off label) of BA that so far have proved to have relevant orofacial adverse effects.
Orofacial adverse effects of BA Oral ulceration A Caucasian patient with a 13-year history of Crohn’s disease (CD), and who had been treated with infliximab infusions, suffered severe recurrent oral and esophageal ulceration, as well as loss of efficacy of the agent with undetectable levels of infliximab due to the appearance of antibodies to infliximab.6 Adalimumab and dapsone were used to control oral, esophageal, and enteric lesions.
Twelve patients on efalizumab, after pancreatic islet transplantation for type 1 diabetes, developed mouth ulcers, anemia, leukopenia, diarrhea, and hypertransaminasemia.7 Six females with type 1 diabetes, transplanted with allogenic islets and treated with daclizumab, sirolimus, and tacrolimus, frequently developed transient mouth ulcers, diarrhea, edema, hypercholesterolemia, weight loss, and myelosuppression, but the effects of agents other than BA that might induce mouth ulceration could not be excluded in either Turgeon et al.’s7 study or Hirshberg et al.’s8 study. Oral ulceration is among the possible adverse effects of the IL-2R antibodies basiliximab and daclizumab;9,10 rituximab;11 and alemtuzumab, which are used for rheumatoid arthritis.12 Oral ulceration has been reported to be a common adverse effect of abatacept.13,14 Mucositis Mucositis (also referred to in drug factsheets as “stomatitis”) is a severe adverse effect of several antineoplastic treatments. It has been reported to be a common adverse effects of mAb cetuximab, panitumumab, pertuzumab and trastuzumab, which are used in the treatment of various epithelial malignancies.15 Mucositis is also an adverse effect of combined chemotherapy and iodine-131–tositumomab.16
Table 1. Reported oral adverse effects of anti-TNF Monoclonal antibody/ fusion protein
Targets
Applications
Adalimumab (Humira)
TNF-a
CD, RA, psoriasis
Etanercept (Enbrel)
TNF-a
CD, RA, psoriasis, sarcoidosis
Infliximab (Remicade)
TNF-a
CD, RA, psoriasis, sarcoidosis
Oral adverse effects TB Carcinoma? (Lichenoid reaction) Candidosis Erythema multiforme Candidosis Carcinoma? Sarcoid nodules (on face) Erythema multiforme Histoplasmosis Infections Lichen planus Mandibular osteomyelitis (following surgical extraction) Parotid swelling Ulceration Erythema multiforme
CD, Crohn’s disease; RA, rheumatoid arthritis; TB, tuberculosis; TNF, tumor necrosis factor.
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Erythema multiforme Cutaneous eruptions, which are seen in approximately 20% of patients treated with anti-TNF-a agents,17 can include vesiculobullous reactions, such as erythema multiforme (EM),17–19 pemphigoid, or pemphigus;20–22 such reactions might include oral involvement. EM can be a consequence of a class effect with TNF-a inhibitors; for example, a patient treated with adalimumab and etanercept for psoriasis developed EM with both agents.23 Adalimumab has been reported to cause EM reactions in patients with CD.17 For example, a 29-year-old male with colonic and perianal CD developed severe oral mucositis, peripheral rash and desquamation, fevers, and respiratory symptoms concomitant with a second dose of adalimumab after a 2-month break from adalimumab therapy. The patient responded to hydrocortisone, and therapy was changed to infliximab without any recurrence of the Stevens–Johnson syndrome.17 EM major has also been reported following treatment with infliximab.24 Ibritumomab tiuxetan also has a box-FDA warning for serious mucocutaneous adverse reactions, including major EM.25 Nevertheless, BA, such as TNF-a antagonists, are also emerging as treatments for toxic epidermal necrolysis (TEN).26 253
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Targets
Applications
Abciximab (ReoPro)
Glycoprotein II/IIIa
Coronary interventions
Basiliximab (Simulect)
IL-2R
Transplant rejection
Bevacizumab
VEGF
Cancers (various)
Cetuximab (Erbitux)
EGFR
Head and neck cancer
Daclizumab (Zenapax) Denosumab (Prolia) Interferons
IL-2R RANKL –
Panitumumab (Vectibix) Pertuzumab (Perjeta) Trastuzumab (Herceptin)
EGFR HER-2 ErbB2 (Her-2)
Transplant rejection Osteoporosis Viral hepatitis, Malignancies, Kaposi sarcoma, Multiple sclerosis, Chronic granulomatous disease, Chronic myeloid leukaemia, Renal cell carcinoma Cancers Breast cancer Breast cancer
Oral adverse effects
Table 2. Oral adverse effects of biological agents targeting or mimicking key proteins (cytokines, receptors, ligands)
Gingival bleeding Petechiae, Xerostomia Gingival swelling Ulcers Geographic tongue (?) Gingival bleeding Stomatitis Xerostomia Dysphagia mucositis (stomatitis) Pharyngitis Taste alterations Xerostomia Ulcers Osteonecrosis Dysgeusia Lichen planus Trigeminal neuropathy Xerostomia
Mucositis Stomatitis Dysgeusia Mucositis
EGFR, Epidermal growth factor receptor; HER, human epidermal growth factor receptor; IL, interleukin; RANKL, receptor activator of nuclear factor-KB ligand; VEGF, vascular endothelial growth factor.
Lichen planus and lichenoid reactions In their study, Worsnop et al. reported on a 32-year-old woman whose TEN was secondary to sulfasalazine was treated with infliximab. The patient then developed erosive lichen planus affecting the mouth and vulva.27 A similar reaction has been reported following adalimumab administration.28 Interferon has also been reported to trigger lichenoid reaction in patients with hepatitis C.29,30 Bacterial odontogenic infections The treatment of rheumatoid arthritis (RA) with an antiTNF-a agent plus methotrexate might predispose to Staphylococcus aureus carriage, although treatment with anti-TNF-a agents alone has not been associated with an increased S. aureus carriage rate.31 Anti-TNF-a therapy was not found to correlate with increased oral counts of
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microorganisms other than Candida.32 Patients with RA who are on anti-TNF-a medication appear to have lower indices of periodontal disease.33 Infliximab can have adverse effects, which could include diabetes mellitus, as well as a liability to infection. One report detailed the development of mandibular osteomyelitis after a surgical tooth extraction in a patient on infliximab.34 Two further cases of osteomyelitis of the jaw have been reported in patients on infliximab.35,36 Adalimumab given for the management of orofacial granulomatosis (OFG) was believed to be responsible for the development of perioral cellulitis in one report.37 The subsequent use of TNF-a blockade in OFG involves screening for labial S. aureus with antimicrobial treatment during therapy, as required.38 In Favero et al.’s39 study, etanercept given to a patient with RA was believed to be responsible for the development of septic arthritis related to Rothia dentocariosa.
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Orofacial effects of biological agents
E. A. Georgakopoulou and C. Scully
Table 3. Oral adverse effects of biological agents targeting B or T lymphocytes Monoclonal antibody/ fusion protein
Targets
Applications
Abatacept (Orencia) Gemtuzumab (Mylotarg)
CD80 & CD86 CD33
Rheumatoid arthritis, transplant rejection Acute myeloid leukemia
Ibritumomab (Zevalin)
CD20
Non-Hodgkin lymphoma
Rituximab (Mabthera)
CD20
Tositumomab (Bexxar)
CD20
Efalizumab (withdrawn)
CD11a
Non-Hodgkin lymphoma, rheumatoid arthritis Non-Hodgkin lymphoma Psoriasis
Oral adverse effects Ulcers Gingival Acute myeloid leukemia recurrence (not truly an adverse effect) Candidosis Dermatitis herpetiformis Desquamation Erythema multiforme Candidosis Ulcers
Mucositis (in combined chemotherapy) Ulcers
Tuberculosis Anti-TNF therapy has resulted in the reactivation of mycobacterial infections with orofacial manifestations.40– 42 In one report, Mycobacterium bovis was implicated.42
Fungal Candidosis Candidosis can be a complication of anti-TNF agents; two of 17 patients receiving TNF-a blocking agent infusions for the treatment of RA developed oral candidosis during treatment over the course of 1 year.43 There have also been reports of oropharyngeal candidosis.44 Oral candidosis has also been reported in some patients receiving ibritumomab and rituximab.25,45
Histoplasmosis Tumor necrosis factor-a antagonists, used in the management of RA and CD, have been implicated in the reactivation of histoplasmosis. In one study, oral histoplasmosis was reported in a 75-year-old-woman patient on infliximab.46
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Malignant disease A small number of cases of oral cancer have been reported in patients recently or actively receiving antiTNF-a agents,47,48 and another of severe oral epithelial dysplasia.49 Oral cancer has also been reported to coexist with rituximab therapy.50 Lymphomas have only rarely been reported. In their study, Deneau et al. reported on a child with active inflammatory bowel disease with oral ulceration, which resolved with infliximab therapy. However, the patient subsequently developed a fatal Epstein–Barr virus-associated natural killer⁄T-cell lymphoma.51 Uncommon orofacial adverse effects Allergic reactions are most likely to underlie the urticaria and angioedema seen with adalimumab. A rare salivary swelling reaction to infliximab has been reported,52 as has a granulomatous reaction after etanercept.53 The report of geographic tongue following therapy with bevacizumab, an mAb targeting a vascular endothelial growth factor protein, should probably be treated with skepticism, as erythema migrans is such a common genetic condition.54 Bad taste (dysgeusia) is a reported adverse effect of trastuzumab, cetuximab, and interferon,55 and xerostomia has been reportedly associated with abciximab, bevacizumab, cetuximab, and interferon.55–58 Gingival swelling can be an adverse effect of basiliximab,10 and gingival bleeding has been reported in patients on abciximab58 and bevacizumab.59 Osteonecrosis of the jaw is a well-documented adverse effect of denosumab.60 Trigeminal neuropathy has been reported following interferon treatment.61 The persistence of leukemic deposits on the gingival was also considered a failure of gemtuzumad in controlling a case of relapsed acute myeloid leukemia (AML).62 Anti-TNF BA Tumor necrosis factor, and more specifically, TNF-a inhibitors, are a relatively new class of injectable drugs, available for the treatment of RA and other chronic inflammatory conditions, including juvenile idiopathic arthritis, CD, psoriasis, and psoriatic arthritis. TNF inhibitors could have a strong anti-inflammatory effect, and show promise as a second-line treatment option where conventional disease-modifying drugs, such as diseasemodifying antirheumatic drugs, have failed.63 TNF inhibitors have also been used in oral medicine, as previously reported.64 These drugs might also be associated with a wide range of systemic adverse effects, such as infections and malignancies.65–67
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BA targeting or mimicking key proteins (cytokines, receptors, ligands) Basiliximab is a chimeric anti-IL-2 receptor mAb used to prevent acute renal transplantation rejection. It attaches to the alpha chain of IL-2 receptors (IL-2R-a) on the surface of activated T lymphocytes, and blocks their function. The most usual undesirable effects of basiliximab in adult patients are constipation, infections, pain, nausea, peripheral edema, hypertension, anemia, headache, hyperkalemia, hypercholesterolemia, raised serum creatinine, and hypophosphatemia.10 Daclizumab is another anti-IL-2 receptor antibody used to prevent acute transplant rejection, and appears to share a similar safety profile with basiliximab.68. Abciximab is the Fab section of the chimeric human– murine mAb 7E3.69 Abciximab binds to the platelet receptor glycoprotein IIb/IIIa, and inhibits blood clot formation. The drug has been used in angioplasty since the mid-1990s. The main adverse effects are bleeding and thrombocytopenia.70 Bevacizumab (Avastin; Genetech/Roche, San Francisco, CA, USA) is a VEGF inhibitor that blocks angiogenesis, and is approved for the treatment of metastatic colorectal cancer; non-squamous, non-small cell lung cancer; metastatic breast cancer; glioblastoma; and metastatic renal cell carcinoma.59 Bevacizumab has an FDA warning for arterial thromboembolic events, hypertension, reversible posterior leukoencephalopathy syndrome, proteinuria, infusion reactions, and ovarian failure.71 The most common adverse reactions, however, are epistaxis, headache, hypertension, rhinitis, proteinuria, taste alterations, dry skin, rectal hemorrhage, lacrimation disorders, back pain, and exfoliative dermatitis.59 Cetuximab is an anti-epidermal growth factor receptor (EGFR) used in the treatment of metastatic epithelial cancers (namely head and neck, colorectal, non-small cell lung cancer).72 Cetuximab’s common adverse effect is a severe, generalized acneiform eruption. Panitumumab is another EGFR competitor approved for the treatment of metastatic colorectal carcinoma, but has an FDA warning for severe dermatological toxicities.73 Trastuzumab is a humanized mAb targeting the extracellular domain of the human epidermal growth factor receptor (HER)-2/neu protein.74 It is approved for the treatment of HER-2 overexpressing breast cancer and HER-2-overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma. Severe adverse effects include congestive heart failure and cardiac dysfunction, and there are cases of patients who have developed leukemia.75 Pertuzumab is also a recombinant humanized mAb that is directed at the extracellular dimerization domain (subdomain II) of HER-2, and in so doing hinders the 256
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ligand-dependent heterodimerization of HER-2 with further HER family members, including EGFR, HER-3, and HER-4.76 Pertuzumab is approved for metastatic breast cancer in combination with trastuzumab and conventional chemotherapy, but has an FDA warning for fetal toxicity. Common adverse effects are febrile neutropenia and leukopenia.77 Denosumab is a human mAb that targets the receptor activator of nuclear factor-KB (RANK) ligand (RANKL). It is approved for the treatment of osteoporosis (patients at high risk of fracture), bone mass augmentation in men receiving androgen-deprivation therapy, non-metastatic prostate cancer, and for women receiving adjuvant aromatase inhibitor therapy for breast cancer.78 Denosumab blocks RANKL binding to RANK, inhibiting osteoclast growth and action, reducing bone resorption, and enhancing bone density. Denosumab’s severe adverse events include skin exanthemas and infections, decreased physiological bone turnover, and osteonecrosis of the jaw.60,79 Interferons are cytokines produced by immune cells and fibroblasts, part of the non-specific immune response. Interferon-recombinant products are used for various therapeutic purposes. Interferon-a is used in the treatment of viral hepatitis, certain types of hematological malignancies, and Kaposi’s sarcoma.80,81 Interferon-b is used in the treatment of multiple sclerosis.82 Interferon-c is used in chronic granulomatous disease, chronic myeloid leukemia, and renal cell carcinoma.83,84 Common adverse effects of interferons are flu-like symptoms and psychiatric disorders, and they could also trigger immunological phenomena.85,86 BA targeting B or T lymphocytes Zevalin (ibritumomab tiuxetan) is a CD20-directed radiotherapeutic antibody used for treating patients with indolent B-cell non-Hodgkin lymphomas.87 Zevalin has an FDA warning for serious mucocutaneous adverse reactions. Another radiolabeled monoclonal anti-B-cell antibody is iodine-131 tositumomab.16 Rituximab is an anti-CD20 mAb successfully used to treat patients with various lymphoid malignancies,88 and in RA. Rituximab’s serious adverse effects include infections (some fatal), cutaneous eruptions, multifocal leukoencephalopathy (PML), and tumor lysis syndrome.89–91 Rituximab is emerging as a reliable alternative treatment choice in pemphigus patients who do not respond to conventional treatment,91 but patients could develop antibodies against rituximab and become resistant to its therapeutic effect.91 Gemtuzumab ozogamicin is a semisynthetic end-product of calicheamicin, a cytotoxic antibiotic connected to a recombinant mAb directed against the CD33 antigen on ª 2014 Wiley Publishing Asia Pty Ltd
Journal of Investigative and Clinical Dentistry (2015), 6, 252–260
REVIEW ARTICLE Oral Medicine
Orofacial adverse effects of biological agents Eleni A. Georgakopoulou1 & Crispian Scully2 1 Department of Histology and Embryology, National and Kapodistrian University of Athens, Athens, Greece 2 UCL Eastman Dental Institute, London, UK
Keywords autoimmune, biological agent, drug, infection, ulcer. Correspondence Dr E. A. Georgakopoulou, Laboratory of Histology–Embryology, Molecular Carcinogenesis Group, Medical School, National and Kapodistrian University of Athens, 75 Mikras Asias Street, Goudi, Athens 11527, Greece. Tel: +30-210-7462346 Email: [email protected] Received 3 February 2014; accepted 20 March 2014.
Abstract Biological agents (BA) are increasingly used effectively in the treatment of a range of disorders, but to date, their application in diseases affecting the orofacial region has been fairly limited. Several orofacial adverse effects related to BA have been recently reported. However, the evidence for such adverse reactions is not always strong, and some of the adverse effects of BA have only been reported in case reports or case series. Most reactions to BA reported thus far have been in association with antitumor necrosis factor-a agents, which is not surprising, as these are the most widely-used BA. In the present study, the orofacial adverse effects are reported with various BA in order to sensitize clinicians to the possibilities. In addition, we briefly summarize the mode of action and indications of these BA. As the use and range of BA increases, the number and diversity of adverse effects might well increase. Despite the adverse effects of biological agents, these may often be less serious than the adverse effects of the more traditional immunosuppressive agents.
doi: 10.1111/jicd.12102
Introduction Generated by recombinant biotechnology, biological agents (BA) target immunocytes or their products. BA comprise a number of human (suffix “mab”), humanized (suffix “zumab”), or chimeric (mouse–human) (suffix “ximab”) monoclonal antibodies (mAb) or variant fusion proteins (suffix “cept”) that target immunocytes or specific steps in pro-inflammatory pathways. Biological agents often bind directly to T- or B-lymphocytes, granulocytes, antigen-presenting cells (dendritic cells, macrophages), or other immunocytes and mediators (cytokines, chemokines, growth factors, complement components) in order to deplete them, suppress their function, prevent their homing to lymphoid organs and inflammatory sites, or to induce anergy. The three main classes of BA are tumor necrosis factor (TNF)-a inhibitors (e.g. infliximab, etanercept, and adalimumab), inhibitors or mimickers of other cytokines or key proteins in cellular reactions (e.g. interleukin [IL] inhibitor ustekinumab, which inhibits IL-12 and IL-23), and lymphocyte modulators (T-lymphocyte modulators, 252
e.g. alefacept and efalizumab; or B-lymphocyte modulators, e.g. rituximab). Biological agents are currently licensed for use in rheumatological, gastrointestinal, dermatological, and other systemic diseases, some of which can have orofacial lesions.1–4 Several dozen therapeutic mAb are now marketed for a variety of indications, and as their number increases exponentially, reports of adverse effects are also increasing. Immunomodulatory mAb (and Fc-fusion proteins) are indicated predominantly for the treatment of inflammatory and autoimmune diseases, or used to prevent organ transplant rejection. Immunomodulatory mAb have an inherent risk for producing adverse immune-mediated drug reactions, such as infusion reactions, cytokine storms, immunosuppression, autoimmunity, and other disorders.5 Most reactions have been reported to be associated with anti-TNF-a agents, the most widely used BA, but as the use of BA increases, the number and diversity of adverse effects might well increase. Some of these adverse effects affect the orofacial region. Few oral medicine specialists are very familiar with the use of BA, but they are the specialists ª 2014 Wiley Publishing Asia Pty Ltd
Orofacial effects of biological agents
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health and quality of life. J Mass Dent Soc 2010; 59: 22–7. Oh Y-J, Park T-H, Choi Y-J et al. Abciximab (ReoPro)-induced thrombocytopenia diagnosed through measurement of heparin-dependent antibody. Korean Circ J 2009; 39: 75–8. Bevacizumab FDA LABEL. Cited 1 Feb 2014. Available from http:// www.accessdata.fda.gov/drug satfda_docs/label/2011/125085s225lbl. pdf Diz P, L opez-Cedr un JL, Arenaz J, Scully C. Denosumab-related osteonecrosis of the jaw. J Am Dent Assoc 2012; 143: 981–4. Read S, Crawford D, Pender M. Trigeminal sensory neuropathy induced by interferon-alpha therapy. Aust N Z J Med 1995; 25: 54. Sollecito TP, Draznin J, Parisi E et al. Leukemic gingival infiltrate as an indicator of chemotherapeutic failure following monoclonal antibody therapy: a case report. Spec Care Dentist 2003; 23: 108–10. Chang J, Girgis L. Clinical use of anti-TNF-alpha biological agents – a guide for GPs. Aust Fam Physician 2007; 36: 1035–8. O’Neill ID. Off-label use of biologicals in the management of inflammatory oral mucosal disease. J Oral Pathol Med 2008; 37: 575–81. Bongartz T, Sutton AJ, Sweeting MJ, Buchan I, Matteson EL, Montori V. Anti-TNF antibody therapy in rheumatoid arthritis and the risk of serious infections and malignancies. JAMA 2006; 295: 2275–85. Gardam MA, Keystone EC, Menzies R et al. Anti-tumour necrosis factor agents and tuberculosis risk: mechanisms of action and clinical management. Lancet Infect Dis 2003; 3: 148– 55. Taylor PC, Feldmann M. Anti-TNF biologic agents: still the therapy of choice for rheumatoid arthritis. Nat Rev Rheumatol 2009; 5: 578–82. van den Hoogen MW, Hilbrands LB. Use of monoclonal antibodies in renal transplantation. Immunotherapy 2011; 3: 871–80.
69 Starnes HB, Patel AA, Stouffer GA. Optimal use of platelet glycoprotein IIb/IIIa receptor antagonists in patients undergoing percutaneous coronary interventions. Drugs 2011; 71: 2009–30. 70 Tamhane UU, Gurm HS. The chimeric monoclonal antibody abciximab: a systematic review of its safety in contemporary practice. Expert Opin Drug Saf 2008; 7: 809–19. 71 Zhu X, Wu S, Dahut WL, Parikh CR. Risks of proteinuria and hypertension with bevacizumab, an antibody against vascular endothelial growth factor: systematic review and meta-analysis. Am J Kidney Dis 2007; 49: 186–93. 72 Modjtahedi H, Essapen S. Epidermal growth factor receptor inhibitors in cancer treatment: advances, challenges and opportunities. Anticancer Drugs 2009; 20: 851–5. 73 Argiles G, Dienstmann R, Elez E, Tabernero J. Panitumumab: a summary of clinical development in colorectal cancer and future directions. Future Oncol 2012; 8: 373–89. 74 den Hollander P, Savage MI, Brown PH. Targeted therapy for breast cancer prevention. Front Oncol 2013; 3: 250. 75 Criscitiello C, Metzger-Filho O, Saini KS et al. Targeted therapies in breast cancer: are heart and vessels also being targeted? Breast Cancer Res 2012; 14: 209. 76 Gampenrieder SP, Rinnerthaler G, Greil R. Neoadjuvant chemotherapy and targeted therapy in breast cancer: past, present, and future. J Oncol 2013; 2013: 732047. 77 Gianni L, Pienkowski T, Im YH et al. Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomised multicentre, open-label, phase 2 trial. Lancet Oncol 2012; 13: 25–32. 78 Cummings SR, San Martin J, McClung MR et al. Denosumab for
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prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med 2009; 361: 756–65. Anastasilakis AD, Toulis KA, Polyzos SA, Anastasilakis CD, Makras P. Long-term treatment of osteoporosis: safety and efficacy appraisal of denosumab. Ther Clin Risk Manag 2012; 8: 295–306. Shepherd J, Brodin H, Cave C, Waugh N, Price A, Gabbay J. Pegylated interferon alpha-2a and-2b in combination with ribavirin in the treatment of chronic hepatitis C: a systematic review and economic evaluation. Health Technol Assess 2004; 8: 39. Roth MS, Foon KA. Alpha interferon in the treatment of hematologic malignancies. Am J Med 1986; 81: 871–82. Group TIMSS. Interferon beta-1b is effective in relapsing-remitting multiple sclerosis I. Clinical results of a multicenter, randomized, double-blind, placebo-controlled trial. Neurology 1993; 43: 655– 61. Condino-Neto A, Newburger PE. Interferon-gamma improves splicing efficiency of CYBB gene transcripts in an interferon-responsive variant of chronic granulomatous disease due to a splice site consensus region mutation. Blood 2000; 95: 3548–54. Motzer RJ, Russo P. Systemic therapy for renal cell carcinoma. J Urol 2000; 163: 408–17.
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85 Dusheiko G. Side effects of a interferon in chronic hepatitis C. Hepatology 1997; 26: 112S–21S. 86 Walther E, Hohlfeld R. Multiple sclerosis side effects of interferon beta therapy and their management. Neurology 1999; 53: 1622. 87 Chamarthy MR, Williams SC, Moadel RM. Radioimmunotherapy of non-Hodgkin’s lymphoma: from the ‘magic bullets’ to ‘radioactive magic bullets’. Yale J Biol Med 2011; 84: 391–407. 88 Plosker GL, Figgitt DP. Rituximab: a review of its use in non-Hodgkin’s lymphoma and chronic lymphocytic leukaemia. Drugs 2003; 63: 803–43. 89 Berm udez A, Marco F, Conde E, Mazo E, Recio M, Zubizarreta A. Fatal visceral varicella-zoster infection following rituximab and chemotherapy treatment in a patient with follicular lymphoma. Haematologica 2000; 85: 894–5. 90 Quartier P, Tournilhac O, Archimbaud C et al. Enteroviral meningoencephalitis after anti-CD20 (rituximab) treatment. Clin Infect Dis 2003; 36: e47–9. 91 Schmidt E, Hennig K, Mengede C, Zillikens D, Kromminga A. Immunogenicity of rituximab in patients with severe pemphigus. Clin Immunol 2009; 132: 334–41. 92 Bross PF, Beitz J, Chen G et al. Approval summary: gemtuzumab ozogamicin in relapsed acute myeloid leukemia. Clin Cancer Res 2001; 7: 1490–6.
93 Jurcic JG. What happened to antiCD33 therapy for acute myeloid leukemia? Curr Hematol Malig Rep 2012; 7: 65–73. 94 Oldham RK, Dillman RO. Monoclonal antibodies in cancer therapy: 25 years of progress. J Clin Oncol 2008; 26: 1774–7. 95 Kalluri HV, Hardinger KL, Akoh JA et al. Current state of renal transplant immunosuppression: present and future. World J Transplant 2012; 24: 51–68. 96 EMEA-LEMTRADA. Cited 1 Feb 2014. Available from: http://www. ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/003718/ WC500150521.pdf. 97 Talamonti M, Spallone G, Di Stefani A, Costanzo A, Chimenti S. Efalizumab. Expert Opin Drug Saf 2011; 10: 239–51. 98 Solomon GE. T-cell agents in the treatment of rheumatoid arthritis. Bull NYU Hosp Jt Dis 2010; 68: 162–5. 99 Santoro FA, Rothe MJ, Strober BE. Ethical considerations when prescribing biologics in dermatology. Clin Dermatol 2012; 30: 492– 5. 100 IPILIMUMAB FDA. YERVOY (ipilimumab). Cited 1 Feb 2014. Available from http:// www.accessdata.fda.gov/ drugsatfda_docs/label/2011/ 125377s0000lbl.pdf
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REVIEW ARTICLE Oral Medicine
Orofacial adverse effects of biological agents Eleni A. Georgakopoulou1 & Crispian Scully2 1 Department of Histology and Embryology, National and Kapodistrian University of Athens, Athens, Greece 2 UCL Eastman Dental Institute, London, UK
Keywords autoimmune, biological agent, drug, infection, ulcer. Correspondence Dr E. A. Georgakopoulou, Laboratory of Histology–Embryology, Molecular Carcinogenesis Group, Medical School, National and Kapodistrian University of Athens, 75 Mikras Asias Street, Goudi, Athens 11527, Greece. Tel: +30-210-7462346 Email: [email protected] Received 3 February 2014; accepted 20 March 2014.
Abstract Biological agents (BA) are increasingly used effectively in the treatment of a range of disorders, but to date, their application in diseases affecting the orofacial region has been fairly limited. Several orofacial adverse effects related to BA have been recently reported. However, the evidence for such adverse reactions is not always strong, and some of the adverse effects of BA have only been reported in case reports or case series. Most reactions to BA reported thus far have been in association with antitumor necrosis factor-a agents, which is not surprising, as these are the most widely-used BA. In the present study, the orofacial adverse effects are reported with various BA in order to sensitize clinicians to the possibilities. In addition, we briefly summarize the mode of action and indications of these BA. As the use and range of BA increases, the number and diversity of adverse effects might well increase. Despite the adverse effects of biological agents, these may often be less serious than the adverse effects of the more traditional immunosuppressive agents.
doi: 10.1111/jicd.12102
Introduction Generated by recombinant biotechnology, biological agents (BA) target immunocytes or their products. BA comprise a number of human (suffix “mab”), humanized (suffix “zumab”), or chimeric (mouse–human) (suffix “ximab”) monoclonal antibodies (mAb) or variant fusion proteins (suffix “cept”) that target immunocytes or specific steps in pro-inflammatory pathways. Biological agents often bind directly to T- or B-lymphocytes, granulocytes, antigen-presenting cells (dendritic cells, macrophages), or other immunocytes and mediators (cytokines, chemokines, growth factors, complement components) in order to deplete them, suppress their function, prevent their homing to lymphoid organs and inflammatory sites, or to induce anergy. The three main classes of BA are tumor necrosis factor (TNF)-a inhibitors (e.g. infliximab, etanercept, and adalimumab), inhibitors or mimickers of other cytokines or key proteins in cellular reactions (e.g. interleukin [IL] inhibitor ustekinumab, which inhibits IL-12 and IL-23), and lymphocyte modulators (T-lymphocyte modulators, 252
e.g. alefacept and efalizumab; or B-lymphocyte modulators, e.g. rituximab). Biological agents are currently licensed for use in rheumatological, gastrointestinal, dermatological, and other systemic diseases, some of which can have orofacial lesions.1–4 Several dozen therapeutic mAb are now marketed for a variety of indications, and as their number increases exponentially, reports of adverse effects are also increasing. Immunomodulatory mAb (and Fc-fusion proteins) are indicated predominantly for the treatment of inflammatory and autoimmune diseases, or used to prevent organ transplant rejection. Immunomodulatory mAb have an inherent risk for producing adverse immune-mediated drug reactions, such as infusion reactions, cytokine storms, immunosuppression, autoimmunity, and other disorders.5 Most reactions have been reported to be associated with anti-TNF-a agents, the most widely used BA, but as the use of BA increases, the number and diversity of adverse effects might well increase. Some of these adverse effects affect the orofacial region. Few oral medicine specialists are very familiar with the use of BA, but they are the specialists ª 2014 Wiley Publishing Asia Pty Ltd
Orofacial effects of biological agents
E. A. Georgakopoulou and C. Scully
who will be called to recognize and possibly treat the orofacial adverse effects of BA. In the present study, we summarize the orofacial adverse effects of BA reported; these have been mainly reported in case reports and case series (published in peer-reviewed journals). We also refer to the orofacial side-effects officially recorded in the US Food and Drug Administration (FDA) and European Medicines Agency factsheets (classified by drug category in Tables 1–3), and include a brief section that refers to the mode of actions and the therapeutic applications (official and off label) of BA that so far have proved to have relevant orofacial adverse effects.
Orofacial adverse effects of BA Oral ulceration A Caucasian patient with a 13-year history of Crohn’s disease (CD), and who had been treated with infliximab infusions, suffered severe recurrent oral and esophageal ulceration, as well as loss of efficacy of the agent with undetectable levels of infliximab due to the appearance of antibodies to infliximab.6 Adalimumab and dapsone were used to control oral, esophageal, and enteric lesions.
Twelve patients on efalizumab, after pancreatic islet transplantation for type 1 diabetes, developed mouth ulcers, anemia, leukopenia, diarrhea, and hypertransaminasemia.7 Six females with type 1 diabetes, transplanted with allogenic islets and treated with daclizumab, sirolimus, and tacrolimus, frequently developed transient mouth ulcers, diarrhea, edema, hypercholesterolemia, weight loss, and myelosuppression, but the effects of agents other than BA that might induce mouth ulceration could not be excluded in either Turgeon et al.’s7 study or Hirshberg et al.’s8 study. Oral ulceration is among the possible adverse effects of the IL-2R antibodies basiliximab and daclizumab;9,10 rituximab;11 and alemtuzumab, which are used for rheumatoid arthritis.12 Oral ulceration has been reported to be a common adverse effect of abatacept.13,14 Mucositis Mucositis (also referred to in drug factsheets as “stomatitis”) is a severe adverse effect of several antineoplastic treatments. It has been reported to be a common adverse effects of mAb cetuximab, panitumumab, pertuzumab and trastuzumab, which are used in the treatment of various epithelial malignancies.15 Mucositis is also an adverse effect of combined chemotherapy and iodine-131–tositumomab.16
Table 1. Reported oral adverse effects of anti-TNF Monoclonal antibody/ fusion protein
Targets
Applications
Adalimumab (Humira)
TNF-a
CD, RA, psoriasis
Etanercept (Enbrel)
TNF-a
CD, RA, psoriasis, sarcoidosis
Infliximab (Remicade)
TNF-a
CD, RA, psoriasis, sarcoidosis
Oral adverse effects TB Carcinoma? (Lichenoid reaction) Candidosis Erythema multiforme Candidosis Carcinoma? Sarcoid nodules (on face) Erythema multiforme Histoplasmosis Infections Lichen planus Mandibular osteomyelitis (following surgical extraction) Parotid swelling Ulceration Erythema multiforme
CD, Crohn’s disease; RA, rheumatoid arthritis; TB, tuberculosis; TNF, tumor necrosis factor.
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Erythema multiforme Cutaneous eruptions, which are seen in approximately 20% of patients treated with anti-TNF-a agents,17 can include vesiculobullous reactions, such as erythema multiforme (EM),17–19 pemphigoid, or pemphigus;20–22 such reactions might include oral involvement. EM can be a consequence of a class effect with TNF-a inhibitors; for example, a patient treated with adalimumab and etanercept for psoriasis developed EM with both agents.23 Adalimumab has been reported to cause EM reactions in patients with CD.17 For example, a 29-year-old male with colonic and perianal CD developed severe oral mucositis, peripheral rash and desquamation, fevers, and respiratory symptoms concomitant with a second dose of adalimumab after a 2-month break from adalimumab therapy. The patient responded to hydrocortisone, and therapy was changed to infliximab without any recurrence of the Stevens–Johnson syndrome.17 EM major has also been reported following treatment with infliximab.24 Ibritumomab tiuxetan also has a box-FDA warning for serious mucocutaneous adverse reactions, including major EM.25 Nevertheless, BA, such as TNF-a antagonists, are also emerging as treatments for toxic epidermal necrolysis (TEN).26 253
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E. A. Georgakopoulou and C. Scully
Targets
Applications
Abciximab (ReoPro)
Glycoprotein II/IIIa
Coronary interventions
Basiliximab (Simulect)
IL-2R
Transplant rejection
Bevacizumab
VEGF
Cancers (various)
Cetuximab (Erbitux)
EGFR
Head and neck cancer
Daclizumab (Zenapax) Denosumab (Prolia) Interferons
IL-2R RANKL –
Panitumumab (Vectibix) Pertuzumab (Perjeta) Trastuzumab (Herceptin)
EGFR HER-2 ErbB2 (Her-2)
Transplant rejection Osteoporosis Viral hepatitis, Malignancies, Kaposi sarcoma, Multiple sclerosis, Chronic granulomatous disease, Chronic myeloid leukaemia, Renal cell carcinoma Cancers Breast cancer Breast cancer
Oral adverse effects
Table 2. Oral adverse effects of biological agents targeting or mimicking key proteins (cytokines, receptors, ligands)
Gingival bleeding Petechiae, Xerostomia Gingival swelling Ulcers Geographic tongue (?) Gingival bleeding Stomatitis Xerostomia Dysphagia mucositis (stomatitis) Pharyngitis Taste alterations Xerostomia Ulcers Osteonecrosis Dysgeusia Lichen planus Trigeminal neuropathy Xerostomia
Mucositis Stomatitis Dysgeusia Mucositis
EGFR, Epidermal growth factor receptor; HER, human epidermal growth factor receptor; IL, interleukin; RANKL, receptor activator of nuclear factor-KB ligand; VEGF, vascular endothelial growth factor.
Lichen planus and lichenoid reactions In their study, Worsnop et al. reported on a 32-year-old woman whose TEN was secondary to sulfasalazine was treated with infliximab. The patient then developed erosive lichen planus affecting the mouth and vulva.27 A similar reaction has been reported following adalimumab administration.28 Interferon has also been reported to trigger lichenoid reaction in patients with hepatitis C.29,30 Bacterial odontogenic infections The treatment of rheumatoid arthritis (RA) with an antiTNF-a agent plus methotrexate might predispose to Staphylococcus aureus carriage, although treatment with anti-TNF-a agents alone has not been associated with an increased S. aureus carriage rate.31 Anti-TNF-a therapy was not found to correlate with increased oral counts of
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microorganisms other than Candida.32 Patients with RA who are on anti-TNF-a medication appear to have lower indices of periodontal disease.33 Infliximab can have adverse effects, which could include diabetes mellitus, as well as a liability to infection. One report detailed the development of mandibular osteomyelitis after a surgical tooth extraction in a patient on infliximab.34 Two further cases of osteomyelitis of the jaw have been reported in patients on infliximab.35,36 Adalimumab given for the management of orofacial granulomatosis (OFG) was believed to be responsible for the development of perioral cellulitis in one report.37 The subsequent use of TNF-a blockade in OFG involves screening for labial S. aureus with antimicrobial treatment during therapy, as required.38 In Favero et al.’s39 study, etanercept given to a patient with RA was believed to be responsible for the development of septic arthritis related to Rothia dentocariosa.
ª 2014 Wiley Publishing Asia Pty Ltd
Orofacial effects of biological agents
E. A. Georgakopoulou and C. Scully
Table 3. Oral adverse effects of biological agents targeting B or T lymphocytes Monoclonal antibody/ fusion protein
Targets
Applications
Abatacept (Orencia) Gemtuzumab (Mylotarg)
CD80 & CD86 CD33
Rheumatoid arthritis, transplant rejection Acute myeloid leukemia
Ibritumomab (Zevalin)
CD20
Non-Hodgkin lymphoma
Rituximab (Mabthera)
CD20
Tositumomab (Bexxar)
CD20
Efalizumab (withdrawn)
CD11a
Non-Hodgkin lymphoma, rheumatoid arthritis Non-Hodgkin lymphoma Psoriasis
Oral adverse effects Ulcers Gingival Acute myeloid leukemia recurrence (not truly an adverse effect) Candidosis Dermatitis herpetiformis Desquamation Erythema multiforme Candidosis Ulcers
Mucositis (in combined chemotherapy) Ulcers
Tuberculosis Anti-TNF therapy has resulted in the reactivation of mycobacterial infections with orofacial manifestations.40– 42 In one report, Mycobacterium bovis was implicated.42
Fungal Candidosis Candidosis can be a complication of anti-TNF agents; two of 17 patients receiving TNF-a blocking agent infusions for the treatment of RA developed oral candidosis during treatment over the course of 1 year.43 There have also been reports of oropharyngeal candidosis.44 Oral candidosis has also been reported in some patients receiving ibritumomab and rituximab.25,45
Histoplasmosis Tumor necrosis factor-a antagonists, used in the management of RA and CD, have been implicated in the reactivation of histoplasmosis. In one study, oral histoplasmosis was reported in a 75-year-old-woman patient on infliximab.46
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Malignant disease A small number of cases of oral cancer have been reported in patients recently or actively receiving antiTNF-a agents,47,48 and another of severe oral epithelial dysplasia.49 Oral cancer has also been reported to coexist with rituximab therapy.50 Lymphomas have only rarely been reported. In their study, Deneau et al. reported on a child with active inflammatory bowel disease with oral ulceration, which resolved with infliximab therapy. However, the patient subsequently developed a fatal Epstein–Barr virus-associated natural killer⁄T-cell lymphoma.51 Uncommon orofacial adverse effects Allergic reactions are most likely to underlie the urticaria and angioedema seen with adalimumab. A rare salivary swelling reaction to infliximab has been reported,52 as has a granulomatous reaction after etanercept.53 The report of geographic tongue following therapy with bevacizumab, an mAb targeting a vascular endothelial growth factor protein, should probably be treated with skepticism, as erythema migrans is such a common genetic condition.54 Bad taste (dysgeusia) is a reported adverse effect of trastuzumab, cetuximab, and interferon,55 and xerostomia has been reportedly associated with abciximab, bevacizumab, cetuximab, and interferon.55–58 Gingival swelling can be an adverse effect of basiliximab,10 and gingival bleeding has been reported in patients on abciximab58 and bevacizumab.59 Osteonecrosis of the jaw is a well-documented adverse effect of denosumab.60 Trigeminal neuropathy has been reported following interferon treatment.61 The persistence of leukemic deposits on the gingival was also considered a failure of gemtuzumad in controlling a case of relapsed acute myeloid leukemia (AML).62 Anti-TNF BA Tumor necrosis factor, and more specifically, TNF-a inhibitors, are a relatively new class of injectable drugs, available for the treatment of RA and other chronic inflammatory conditions, including juvenile idiopathic arthritis, CD, psoriasis, and psoriatic arthritis. TNF inhibitors could have a strong anti-inflammatory effect, and show promise as a second-line treatment option where conventional disease-modifying drugs, such as diseasemodifying antirheumatic drugs, have failed.63 TNF inhibitors have also been used in oral medicine, as previously reported.64 These drugs might also be associated with a wide range of systemic adverse effects, such as infections and malignancies.65–67
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Orofacial effects of biological agents
BA targeting or mimicking key proteins (cytokines, receptors, ligands) Basiliximab is a chimeric anti-IL-2 receptor mAb used to prevent acute renal transplantation rejection. It attaches to the alpha chain of IL-2 receptors (IL-2R-a) on the surface of activated T lymphocytes, and blocks their function. The most usual undesirable effects of basiliximab in adult patients are constipation, infections, pain, nausea, peripheral edema, hypertension, anemia, headache, hyperkalemia, hypercholesterolemia, raised serum creatinine, and hypophosphatemia.10 Daclizumab is another anti-IL-2 receptor antibody used to prevent acute transplant rejection, and appears to share a similar safety profile with basiliximab.68. Abciximab is the Fab section of the chimeric human– murine mAb 7E3.69 Abciximab binds to the platelet receptor glycoprotein IIb/IIIa, and inhibits blood clot formation. The drug has been used in angioplasty since the mid-1990s. The main adverse effects are bleeding and thrombocytopenia.70 Bevacizumab (Avastin; Genetech/Roche, San Francisco, CA, USA) is a VEGF inhibitor that blocks angiogenesis, and is approved for the treatment of metastatic colorectal cancer; non-squamous, non-small cell lung cancer; metastatic breast cancer; glioblastoma; and metastatic renal cell carcinoma.59 Bevacizumab has an FDA warning for arterial thromboembolic events, hypertension, reversible posterior leukoencephalopathy syndrome, proteinuria, infusion reactions, and ovarian failure.71 The most common adverse reactions, however, are epistaxis, headache, hypertension, rhinitis, proteinuria, taste alterations, dry skin, rectal hemorrhage, lacrimation disorders, back pain, and exfoliative dermatitis.59 Cetuximab is an anti-epidermal growth factor receptor (EGFR) used in the treatment of metastatic epithelial cancers (namely head and neck, colorectal, non-small cell lung cancer).72 Cetuximab’s common adverse effect is a severe, generalized acneiform eruption. Panitumumab is another EGFR competitor approved for the treatment of metastatic colorectal carcinoma, but has an FDA warning for severe dermatological toxicities.73 Trastuzumab is a humanized mAb targeting the extracellular domain of the human epidermal growth factor receptor (HER)-2/neu protein.74 It is approved for the treatment of HER-2 overexpressing breast cancer and HER-2-overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma. Severe adverse effects include congestive heart failure and cardiac dysfunction, and there are cases of patients who have developed leukemia.75 Pertuzumab is also a recombinant humanized mAb that is directed at the extracellular dimerization domain (subdomain II) of HER-2, and in so doing hinders the 256
E. A. Georgakopoulou and C. Scully
ligand-dependent heterodimerization of HER-2 with further HER family members, including EGFR, HER-3, and HER-4.76 Pertuzumab is approved for metastatic breast cancer in combination with trastuzumab and conventional chemotherapy, but has an FDA warning for fetal toxicity. Common adverse effects are febrile neutropenia and leukopenia.77 Denosumab is a human mAb that targets the receptor activator of nuclear factor-KB (RANK) ligand (RANKL). It is approved for the treatment of osteoporosis (patients at high risk of fracture), bone mass augmentation in men receiving androgen-deprivation therapy, non-metastatic prostate cancer, and for women receiving adjuvant aromatase inhibitor therapy for breast cancer.78 Denosumab blocks RANKL binding to RANK, inhibiting osteoclast growth and action, reducing bone resorption, and enhancing bone density. Denosumab’s severe adverse events include skin exanthemas and infections, decreased physiological bone turnover, and osteonecrosis of the jaw.60,79 Interferons are cytokines produced by immune cells and fibroblasts, part of the non-specific immune response. Interferon-recombinant products are used for various therapeutic purposes. Interferon-a is used in the treatment of viral hepatitis, certain types of hematological malignancies, and Kaposi’s sarcoma.80,81 Interferon-b is used in the treatment of multiple sclerosis.82 Interferon-c is used in chronic granulomatous disease, chronic myeloid leukemia, and renal cell carcinoma.83,84 Common adverse effects of interferons are flu-like symptoms and psychiatric disorders, and they could also trigger immunological phenomena.85,86 BA targeting B or T lymphocytes Zevalin (ibritumomab tiuxetan) is a CD20-directed radiotherapeutic antibody used for treating patients with indolent B-cell non-Hodgkin lymphomas.87 Zevalin has an FDA warning for serious mucocutaneous adverse reactions. Another radiolabeled monoclonal anti-B-cell antibody is iodine-131 tositumomab.16 Rituximab is an anti-CD20 mAb successfully used to treat patients with various lymphoid malignancies,88 and in RA. Rituximab’s serious adverse effects include infections (some fatal), cutaneous eruptions, multifocal leukoencephalopathy (PML), and tumor lysis syndrome.89–91 Rituximab is emerging as a reliable alternative treatment choice in pemphigus patients who do not respond to conventional treatment,91 but patients could develop antibodies against rituximab and become resistant to its therapeutic effect.91 Gemtuzumab ozogamicin is a semisynthetic end-product of calicheamicin, a cytotoxic antibiotic connected to a recombinant mAb directed against the CD33 antigen on ª 2014 Wiley Publishing Asia Pty Ltd
Journal of Investigative and Clinical Dentistry (2015), 6, 252–260
REVIEW ARTICLE Oral Medicine
Orofacial adverse effects of biological agents Eleni A. Georgakopoulou1 & Crispian Scully2 1 Department of Histology and Embryology, National and Kapodistrian University of Athens, Athens, Greece 2 UCL Eastman Dental Institute, London, UK
Keywords autoimmune, biological agent, drug, infection, ulcer. Correspondence Dr E. A. Georgakopoulou, Laboratory of Histology–Embryology, Molecular Carcinogenesis Group, Medical School, National and Kapodistrian University of Athens, 75 Mikras Asias Street, Goudi, Athens 11527, Greece. Tel: +30-210-7462346 Email: [email protected] Received 3 February 2014; accepted 20 March 2014.
Abstract Biological agents (BA) are increasingly used effectively in the treatment of a range of disorders, but to date, their application in diseases affecting the orofacial region has been fairly limited. Several orofacial adverse effects related to BA have been recently reported. However, the evidence for such adverse reactions is not always strong, and some of the adverse effects of BA have only been reported in case reports or case series. Most reactions to BA reported thus far have been in association with antitumor necrosis factor-a agents, which is not surprising, as these are the most widely-used BA. In the present study, the orofacial adverse effects are reported with various BA in order to sensitize clinicians to the possibilities. In addition, we briefly summarize the mode of action and indications of these BA. As the use and range of BA increases, the number and diversity of adverse effects might well increase. Despite the adverse effects of biological agents, these may often be less serious than the adverse effects of the more traditional immunosuppressive agents.
doi: 10.1111/jicd.12102
Introduction Generated by recombinant biotechnology, biological agents (BA) target immunocytes or their products. BA comprise a number of human (suffix “mab”), humanized (suffix “zumab”), or chimeric (mouse–human) (suffix “ximab”) monoclonal antibodies (mAb) or variant fusion proteins (suffix “cept”) that target immunocytes or specific steps in pro-inflammatory pathways. Biological agents often bind directly to T- or B-lymphocytes, granulocytes, antigen-presenting cells (dendritic cells, macrophages), or other immunocytes and mediators (cytokines, chemokines, growth factors, complement components) in order to deplete them, suppress their function, prevent their homing to lymphoid organs and inflammatory sites, or to induce anergy. The three main classes of BA are tumor necrosis factor (TNF)-a inhibitors (e.g. infliximab, etanercept, and adalimumab), inhibitors or mimickers of other cytokines or key proteins in cellular reactions (e.g. interleukin [IL] inhibitor ustekinumab, which inhibits IL-12 and IL-23), and lymphocyte modulators (T-lymphocyte modulators, 252
e.g. alefacept and efalizumab; or B-lymphocyte modulators, e.g. rituximab). Biological agents are currently licensed for use in rheumatological, gastrointestinal, dermatological, and other systemic diseases, some of which can have orofacial lesions.1–4 Several dozen therapeutic mAb are now marketed for a variety of indications, and as their number increases exponentially, reports of adverse effects are also increasing. Immunomodulatory mAb (and Fc-fusion proteins) are indicated predominantly for the treatment of inflammatory and autoimmune diseases, or used to prevent organ transplant rejection. Immunomodulatory mAb have an inherent risk for producing adverse immune-mediated drug reactions, such as infusion reactions, cytokine storms, immunosuppression, autoimmunity, and other disorders.5 Most reactions have been reported to be associated with anti-TNF-a agents, the most widely used BA, but as the use of BA increases, the number and diversity of adverse effects might well increase. Some of these adverse effects affect the orofacial region. Few oral medicine specialists are very familiar with the use of BA, but they are the specialists ª 2014 Wiley Publishing Asia Pty Ltd
Orofacial effects of biological agents
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