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Biologic Response Modifiers (BRMs)
Indications
Biologic response modifiers (BRMs), also known as immunomodulators or cytokine inhibitors, are naturally occurring substances in our body that can also be manufactured in the laboratory. Autoimmune diseases incur a substantial economic burden to the patients and society. BRMs target the disease-causing mechanism and have now become revolutionary in the treatment of many autoimmune phenomena. Unsatisfactory response or evidence of disease progression despite treatment with conventional therapy mandates the use of BRM alone or in combination with traditional treatment.[1] For example, tumor necrosis factor (TNF) inhibitors, in conjunction with methotrexate, were superior to either methotrexate or a TNF inhibitor alone in patients with rheumatoid arthritis (RA) resistant to initial therapy.[2] A combination of a biologic agent and an immunomodulator is commonly used to induce and maintain remission in patients with moderate to severe Crohn disease.[3] BRMs are also recommended first-line therapy for severe psoriatic arthritis who already have erosive changes, and axial involvement in the form of sacroilitis or spondylitis. Patients with axial ankylosing spondylitis (AS) who have very high disease activity, defined as a Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) more than or equal to four and patients with peripheral AS with concomitant moderate to severe psoriasis, inflammatory bowel disease or flares of anterior uveitis also benefit from BRMs.[4] Anakinra used as initial therapy in patients with systemic juvenile idiopathic arthritis (JIA) resulted in rapid symptom relief and also prevented chronic arthritis.[5]
Knowing the fact that TNF-alpha, interleukin (IL)-17, IL-1 are vital mediators of graft versus host disease,[6] BRMs have been used to prevent and treat GVHD.[7] BRMs are also therapeutic in various cancers of the lung, head, neck, skin, kidneys, bladder, and hematologic malignancies. Biologics targeting programmed cell death protein (PD-1), e.g., pembrolizumab and nivolumab, have been emerging as a newer treatment modality for melanoma, renal cell cancer, non-squamous lung cancer, lymphoma, and gastrointestinal cancers.[8] BRMs are also found to be effective in secondary amyloidosis in patients with RA and AS.[9] Biologics targeting IL-5 have been emerging in the treatment of severe hypereosinophilic asthma.[10]
TNF inhibitors, e.g., infliximab, etanercept, adalimumab, certolizumab, and golimumab has been FDA approved for use in RA, ulcerative colitis (UC), Crohn disease (CD), AS, JIA, plaque psoriasis and, psoriatic arthritis. Adalimumab also has approval for hidradenitis suppurativa and uveitis. Non-FDA-approved indications include pyoderma gangrenosum, pustular psoriasis, and GVHD(etanercept). Interleukin-1 inhibitor, e.g., anakinra, is FDA approved for RA and neonatal-onset multisystem inflammatory disease. IL-2 inhibitor, e.g., aldesleukin, is used in metastatic renal cell carcinoma and melanoma. Tocilizumab is an interleukin-6 inhibitor used in giant cell arteritis, JIA, and RA. Secukinumab that targets interleukin-17 is FDA approved for psoriasis (plaque and arthritis), and AS. Ustekinumab blocks interleukin 12/23 and has been FDA-approved for plaque psoriasis, psoriatic arthritis, and CD. Abatacept (T-cell co-stimulation blocker) has approval for use in RA, JIA, and Psoriatic arthritis. Rituximab is FDA approved for chronic lymphocytic leukemia, non-Hodgkins lymphoma, RA, granulomatous polyangiitis, and pemphigus vulgaris. Off label uses include Burkitt lymphoma, CNS lymphoma, GVHD, lupus nephritis, and Hodgkin lymphoma. Tofacitinib is Janus kinase (JAK) inhibitors indicated for psoriatic arthritis, RA, and UC.[11]
Mechanism of Action
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Mechanism of Action
CD4-T cells can differentiate into T helper cells Th1 and Th2. Th1 cells participate in cell-mediated inflammation by producing interferon-gamma, TNF, and IL 2 that target intracellular pathogens. Th2 cells participate in humoral immunity that stimulates antibody production by B cells to produce IL-4, IL-5, IL-10, and IL-13 that target extracellular pathogens. These cytokines are involved in the mediation of inflammatory response, infection, autoimmunity, transplant rejection, and GVHD.[12] Biologic response modifiers modulate the immune response by either interfering with the effect of these cytokines,[13] inhibiting the costimulation of T cell activation,[14] depleting/inhibiting B cells.[15] JAK inhibitors target at the intracellular level by blocking the cellular signaling pathway.
Administration
Biologic response modifier therapy is administered either by intravenous (IV) or subcutaneous (SC) route. IV is usually done in the hospital or outpatient setting, while SC is generally self-administered by patients or by health care professionals.[16] The administration could be weekly, biweekly, monthly, or bimonthly depending on the indication and half-life of the medication. Infliximab, sarilumab, tocilizumab, secukinumab, rituximab, and abatacept administration is intravenous. Adalimumab, golimumab, etanercept, certolizumab, anakinra, and ustekinumab administration is subcutaneous. Administration of batacept, tocilizumab, and golimumab can be either SC or IV, and tofacitinib dosing is oral.[17]
Adverse Effects
The adverse effects of biologic response modifier therapy could be secondary to stimulation, suppression, or disruption of immune homeostasis.[18] Immune stimulation causing activation of various immune cells including macrophages, monocytes, lymphocytes and natural killer cells leads to massive release of cytokines including IL1, TNF alfa, INF gamma, IL 6 and IL 8 that often cause symptoms such as fever, chills, muscle aches, weakness, loss of appetite, nausea, vomiting, diarrhea and skin rash.[19]
Since T cell-mediated response is involved in the destruction of pathogens, inhibition of immune response by BRM increases the risk of asymptomatic to life-threatening infection due to the virus, bacteria, mycobacteria, fungi, and protozoa.[20][21] Infection risk is increased, notably in patients with advanced diseases and those who already have received treatment with other immunosuppressants. Infections include reactivation of hepatitis B, hepatitis C, Mycobacterium tuberculosis (TB), non-mycobacterial TB, Histoplasma, Cryptococcus, Coccidioides, Blastomyces, Pulmonary actinomycosis,[22] Pneumocystis carinii,[23] and CMV. There are reports of infections due to the West Nile virus, parvovirus B19, influenza, herpes simplex, VZV, Aspergillus, Candida, Listeria, Streptococcus pneumoniae.[24][25] Though severe infection often leads to discontinuation of the drug, the rate of serious infections has been declining recently, likely due to increased vigilance and surveillance associated with the use of these medications.[26][27] The frequency of adverse events with each of these medications has been observed to be disease-specific. For example, researchers noted that the treatment of AS with TNF inhibitors was associated with a lower rate of serious adverse events compared to the treatment of RA. It could be explainable by the fact that RA in itself causes immunosuppression, and treatment is often in combination with other DMARD or steroids.[28]
Several biologics also increase the risk of malignancies, such as Hodgkin and non-Hodgkin lymphoma, leukemia, non-melanoma skin cancer.[29]
Disruption of immune homeostasis causes a paradoxical effect in various tissues leading to autoimmunity. Various BRM has associations with a lupus-like syndrome, antiphospholipid syndrome, vasculitis, dermatomyositis, polymyositis, peripheral neuropathy, multiple sclerosis, autoimmune hepatitis, optic neuritis, uveitis, and interstitial lung disease.[30] TNF inhibitors used to treat certain autoimmune diseases was found to exacerbate inflammatory bowel disease,[31] sarcoidosis-like lesions and psoriasis.[32][33] Adalimumab was found to be associated with multiple sclerosis.[34] BRM molecules can also act as an antigen for preformed antibodies in the body, causing anaphylactic reactions.[18] Additionally, infusion reaction can manifest as fever, urticaria, hypotension, and angioedema due to acute hypersensitivity reaction or polyarthritis, and rash due to a delayed hypersensitivity reaction.[35] Injection site reactions manifest as redness, pain, swelling, cutaneous infection, bruising, and itching.[36]
Contraindications
Biologic response modifiers should not be taken by patients who have active infections, demyelinating diseases, e.g., (multiple sclerosis, optic neuritis), and immunodeficiency syndromes. The use of TNF alfa blockers in chronic granulomatous disease-associated colitis was found to increase rates of severe infections and even mortality.[37]
BRM should also be avoided in patients with chronic recurrent infections and untreated latent TB. TNF inhibitors should be avoided or used with caution in a patient with CHF.[38] Evidence is limited for safety during pregnancy and breastfeeding. It is advised to avoid pregnancy or breastfeeding while taking BRMs.[39]
Monitoring
Before starting biologic response modifier therapy, patients should undergo evaluation for latent TB with the past medical history of TB, tuberculin skin test, chest X-ray, and TB interferon. Latent TB should have treatment for nine months, and treatment with BRM can be started one month after the treatment initiation. This approach has demonstrated to decrease the rate of reactivation of TB.[40] For active TB infection, treatment with BRM should be started only often completion of treatment for TB. Hepatitis B surface Antigen test, liver function test (LFT), complete blood count (CBC), age-appropriate screening for cancer, pregnancy test, monitoring for contraindications and drug interactions should be done. Age-appropriate vaccine status should be updated, e.g., pneumococcal, influenza, and hepatitis B vaccinations.[41] The live vaccine should be given at least four weeks before BRM treatment.
All patients taking BRM should have monitoring for both treatment-related efficacy and safety. The patient's symptom relief, physical exam, erythrocyte sedimentation rate, C-reactive protein, autoimmune markers, radiography, CBC, and LFT can be used to monitor efficacy and safety.[42] Treatment should stop if there is no evidence of effectiveness within 3 to 6 months of therapy or any evidence of severe side effects or pregnancy. Due to concern for risks of infection, many experts recommend stopping BRMs at least two half-life of particular medication before surgery and resume once wound healing, and no evidence of infection is ensured usually after 1 to 2 weeks.[43]
Toxicity
Biologic response modifiers can often cause bone marrow suppression, hepatotoxicity, cardiopulmonary and renal dysfunction, disseminated intravascular coagulation, and often death. Toxicity is usually due to immune system activation and is manageable by premedication or adjusting dose.[44]
Enhancing Healthcare Team Outcomes
Early treatment with a biologic response modifier improves outcomes and prevents disability related to autoimmune diseases; however, currently, no clinical predictors or biomarkers are available to guide physicians to select BRM for an individual patient. Not all patients with the same illness respond to particular BRM. Genetic polymorphism in the genes encoding the receptors that the BRM targets affect the efficacy of BRM. Performing genetic tests before starting the treatment may help in choosing a specific BRM for a particular patient.
It is crucial to consider patient-related factors, e.g., patient convenience, local availability, patient's understanding of risks of medication, route, the frequency of administration, and cost-effectiveness while choosing BRM. The patient should be actively involved while choosing and making a treatment decision, and they should be aware of the adverse effects of the medication under consideration.
Nursing can help the patient with administration instructions and a discussion about possible side effects. The pharmacist must verify the dosing of the agent, check for drug-drug interactions, and also counsel the patient on signs of potential adverse effects. Nursing and pharmacy both need to have an open line of communication with the prescriber to adjust treatment if necessary.
BRM therapy requires an interprofessional team approach, including physicians, specialists, specialty-trained nurses, and pharmacists, all collaborating across disciplines to achieve optimal patient results. [Level V]
References
Singh JA, Hossain A, Tanjong Ghogomu E, Mudano AS, Tugwell P, Wells GA. Biologic or tofacitinib monotherapy for rheumatoid arthritis in people with traditional disease-modifying anti-rheumatic drug (DMARD) failure: a Cochrane Systematic Review and network meta-analysis (NMA). The Cochrane database of systematic reviews. 2016 Nov 17:11(11):CD012437 [PubMed PMID: 27855242]
Level 1 (high-level) evidenceFerraccioli G. [Biologic therapy with anti-TNFα in rheumathoid arthritis]. Reumatismo. 2005:57(4 Suppl):17-21 [PubMed PMID: 16385351]
D'Haens G, Baert F, van Assche G, Caenepeel P, Vergauwe P, Tuynman H, De Vos M, van Deventer S, Stitt L, Donner A, Vermeire S, Van De Mierop FJ, Coche JR, van der Woude J, Ochsenkühn T, van Bodegraven AA, Van Hootegem PP, Lambrecht GL, Mana F, Rutgeerts P, Feagan BG, Hommes D, Belgian Inflammatory Bowel Disease Research Group, North-Holland Gut Club. Early combined immunosuppression or conventional management in patients with newly diagnosed Crohn's disease: an open randomised trial. Lancet (London, England). 2008 Feb 23:371(9613):660-667. doi: 10.1016/S0140-6736(08)60304-9. Epub [PubMed PMID: 18295023]
Level 1 (high-level) evidenceWard MM, Deodhar A, Akl EA, Lui A, Ermann J, Gensler LS, Smith JA, Borenstein D, Hiratzka J, Weiss PF, Inman RD, Majithia V, Haroon N, Maksymowych WP, Joyce J, Clark BM, Colbert RA, Figgie MP, Hallegua DS, Prete PE, Rosenbaum JT, Stebulis JA, van den Bosch F, Yu DT, Miller AS, Reveille JD, Caplan L. American College of Rheumatology/Spondylitis Association of America/Spondyloarthritis Research and Treatment Network 2015 Recommendations for the Treatment of Ankylosing Spondylitis and Nonradiographic Axial Spondyloarthritis. Arthritis & rheumatology (Hoboken, N.J.). 2016 Feb:68(2):282-98. doi: 10.1002/art.39298. Epub 2015 Sep 24 [PubMed PMID: 26401991]
Nigrovic PA, Mannion M, Prince FH, Zeft A, Rabinovich CE, van Rossum MA, Cortis E, Pardeo M, Miettunen PM, Janow G, Birmingham J, Eggebeen A, Janssen E, Shulman AI, Son MB, Hong S, Jones K, Ilowite NT, Cron RQ, Higgins GC. Anakinra as first-line disease-modifying therapy in systemic juvenile idiopathic arthritis: report of forty-six patients from an international multicenter series. Arthritis and rheumatism. 2011 Feb:63(2):545-55. doi: 10.1002/art.30128. Epub [PubMed PMID: 21280009]
Hülsdünker J, Zeiser R. Insights into the pathogenesis of GvHD: what mice can teach us about man. Tissue antigens. 2015 Jan:85(1):2-9. doi: 10.1111/tan.12497. Epub 2014 Dec 23 [PubMed PMID: 25532439]
Level 3 (low-level) evidenceCutler C, Antin JH. Novel drugs for the prevention and treatment of acute GVHD. Current pharmaceutical design. 2008:14(20):1962-73 [PubMed PMID: 18691107]
Level 3 (low-level) evidenceVoena C, Chiarle R. Advances in cancer immunology and cancer immunotherapy. Discovery medicine. 2016 Feb:21(114):125-33 [PubMed PMID: 27011048]
Level 3 (low-level) evidencePamuk ÖN, Kalyoncu U, Aksu K, Omma A, Pehlivan Y, Çağatay Y, Küçükşahin O, Dönmez S, Çetin GY, Mercan R, Bayındır Ö, Çefle A, Yıldız F, Balkarlı A, Kılıç L, Çakır N, Kısacık B, Öksüz MF, Çobankara V, Onat AM, Sayarlıoğlu M, Öztürk MA, Pamuk GE, Akkoç N. A multicenter report of biologic agents for the treatment of secondary amyloidosis in Turkish rheumatoid arthritis and ankylosing spondylitis patients. Rheumatology international. 2016 Jul:36(7):945-53. doi: 10.1007/s00296-016-3500-9. Epub 2016 May 24 [PubMed PMID: 27221456]
Mukherjee M, Sehmi R, Nair P. Anti-IL5 therapy for asthma and beyond. The World Allergy Organization journal. 2014:7(1):32. doi: 10.1186/1939-4551-7-32. Epub 2014 Dec 4 [PubMed PMID: 25709744]
Davis BP, Ballas ZK. Biologic response modifiers: Indications, implications, and insights. The Journal of allergy and clinical immunology. 2017 May:139(5):1445-1456. doi: 10.1016/j.jaci.2017.02.013. Epub 2017 Mar 2 [PubMed PMID: 28263774]
Mosmann TR, Moore KW. The role of IL-10 in crossregulation of TH1 and TH2 responses. Immunology today. 1991 Mar:12(3):A49-53 [PubMed PMID: 1648926]
Level 3 (low-level) evidenceBendtzen K, Hansen MB, Ross C, Poulsen LK, Svenson M. Cytokines and autoantibodies to cytokines. Stem cells (Dayton, Ohio). 1995 May:13(3):206-22 [PubMed PMID: 7613489]
Dilek N, Poirier N, Hulin P, Coulon F, Mary C, Ville S, Vie H, Clémenceau B, Blancho G, Vanhove B. Targeting CD28, CTLA-4 and PD-L1 costimulation differentially controls immune synapses and function of human regulatory and conventional T-cells. PloS one. 2013:8(12):e83139. doi: 10.1371/journal.pone.0083139. Epub 2013 Dec 23 [PubMed PMID: 24376655]
Rein P, Mueller RB. Treatment with Biologicals in Rheumatoid Arthritis: An Overview. Rheumatology and therapy. 2017 Dec:4(2):247-261. doi: 10.1007/s40744-017-0073-3. Epub 2017 Aug 22 [PubMed PMID: 28831712]
Level 3 (low-level) evidenceAnselmo AC, Gokarn Y, Mitragotri S. Non-invasive delivery strategies for biologics. Nature reviews. Drug discovery. 2019 Jan:18(1):19-40. doi: 10.1038/nrd.2018.183. Epub 2018 Nov 30 [PubMed PMID: 30498202]
Dowty ME, Lin J, Ryder TF, Wang W, Walker GS, Vaz A, Chan GL, Krishnaswami S, Prakash C. The pharmacokinetics, metabolism, and clearance mechanisms of tofacitinib, a janus kinase inhibitor, in humans. Drug metabolism and disposition: the biological fate of chemicals. 2014 Apr:42(4):759-73. doi: 10.1124/dmd.113.054940. Epub 2014 Jan 24 [PubMed PMID: 24464803]
Descotes J. Immunotoxicity of monoclonal antibodies. mAbs. 2009 Mar-Apr:1(2):104-11 [PubMed PMID: 20061816]
Level 3 (low-level) evidenceWing M, Monoclonal antibody first dose cytokine release syndromes-mechanisms and prediction. Journal of immunotoxicology. 2008 Jan; [PubMed PMID: 18382853]
Level 3 (low-level) evidenceBrowne SK, Holland SM. Immunodeficiency secondary to anticytokine autoantibodies. Current opinion in allergy and clinical immunology. 2010 Dec:10(6):534-41. doi: 10.1097/ACI.0b013e3283402b41. Epub [PubMed PMID: 20966748]
Level 3 (low-level) evidenceWallis RS. Infectious complications of tumor necrosis factor blockade. Current opinion in infectious diseases. 2009 Aug:22(4):403-9. doi: 10.1097/QCO.0b013e32832dda55. Epub [PubMed PMID: 19491672]
Level 3 (low-level) evidenceCohen R, Bowie W, Enns R, Flint J, Fitzgerald M. Pulmonary actinomycosis complicating infliximab therapy for Crohn disease. BMJ case reports. 2009:2009():. pii: bcr11.2008.1262. doi: 10.1136/bcr.11.2008.1262. Epub 2009 May 10 [PubMed PMID: 21686384]
Level 3 (low-level) evidenceKaur N, Mahl TC. Pneumocystis jiroveci (carinii) pneumonia after infliximab therapy: a review of 84 cases. Digestive diseases and sciences. 2007 Jun:52(6):1481-4 [PubMed PMID: 17429728]
Level 2 (mid-level) evidenceKelesidis T, Salhotra A, Fleisher J, Uslan DZ. Listeria endocarditis in a patient with psoriatic arthritis on infliximab: are biologic agents as treatment for inflammatory arthritis increasing the incidence of Listeria infections? The Journal of infection. 2010 May:60(5):386-96. doi: 10.1016/j.jinf.2010.02.009. Epub 2010 Feb 20 [PubMed PMID: 20176052]
Level 3 (low-level) evidenceLe Saux N, Canadian Paediatric Society, Infectious Diseases and Immunization Committee. Biologic response modifiers to decrease inflammation: Focus on infection risks. Paediatrics & child health. 2012 Mar:17(3):147-54 [PubMed PMID: 23449972]
Singh JA, Wells GA, Christensen R, Tanjong Ghogomu E, Maxwell L, Macdonald JK, Filippini G, Skoetz N, Francis D, Lopes LC, Guyatt GH, Schmitt J, La Mantia L, Weberschock T, Roos JF, Siebert H, Hershan S, Lunn MP, Tugwell P, Buchbinder R. Adverse effects of biologics: a network meta-analysis and Cochrane overview. The Cochrane database of systematic reviews. 2011 Feb 16:2011(2):CD008794. doi: 10.1002/14651858.CD008794.pub2. Epub 2011 Feb 16 [PubMed PMID: 21328309]
Level 1 (high-level) evidenceSakai R, Cho SK, Nanki T, Koike R, Watanabe K, Yamazaki H, Nagasawa H, Amano K, Tanaka Y, Sumida T, Ihata A, Yasuda S, Nakajima A, Sugihara T, Tamura N, Fujii T, Dobashi H, Miura Y, Miyasaka N, Harigai M, REAL study group. The risk of serious infection in patients with rheumatoid arthritis treated with tumor necrosis factor inhibitors decreased over time: a report from the registry of Japanese rheumatoid arthritis patients on biologics for long-term safety (REAL) database. Rheumatology international. 2014 Dec:34(12):1729-36. doi: 10.1007/s00296-014-3045-8. Epub 2014 May 23 [PubMed PMID: 24852650]
Fouque-Aubert A, Jette-Paulin L, Combescure C, Basch A, Tebib J, Gossec L. Serious infections in patients with ankylosing spondylitis with and without TNF blockers: a systematic review and meta-analysis of randomised placebo-controlled trials. Annals of the rheumatic diseases. 2010 Oct:69(10):1756-61. doi: 10.1136/ard.2008.098822. Epub 2009 Jul 28 [PubMed PMID: 19640854]
Level 1 (high-level) evidenceLebrec H, Ponce R, Preston BD, Iles J, Born TL, Hooper M. Tumor necrosis factor, tumor necrosis factor inhibition, and cancer risk. Current medical research and opinion. 2015 Mar:31(3):557-74. doi: 10.1185/03007995.2015.1011778. Epub 2015 Feb 16 [PubMed PMID: 25651481]
Level 3 (low-level) evidencePerez-Alvarez R,Pérez-de-Lis M,Ramos-Casals M, Biologics-induced autoimmune diseases. Current opinion in rheumatology. 2013 Jan; [PubMed PMID: 23114587]
Level 3 (low-level) evidenceToussirot É, Houvenagel É, Goëb V, Fouache D, Martin A, Le Dantec P, Dernis E, Wendling D, Ansemant T, Berthelot JM, Bader-Meunier B, Kantelip B, Le CRI. Development of inflammatory bowel disease during anti-TNF-α therapy for inflammatory rheumatic disease: a nationwide series. Joint bone spine. 2012 Oct:79(5):457-63. doi: 10.1016/j.jbspin.2011.10.001. Epub 2011 Nov 15 [PubMed PMID: 22088934]
Level 2 (mid-level) evidenceNagy G, Lukács K, Sziray A, Fazekas K, Florián A, Tamási L, Károlyi Z. [Adverse events during biological therapy -- focusing on dermatological side-effects]. Orvosi hetilap. 2011 Feb 6:152(6):212-20. doi: 10.1556/OH.2011.28987. Epub [PubMed PMID: 21278026]
Level 2 (mid-level) evidenceJoyau C, Veyrac G, Dixneuf V, Jolliet P. Anti-tumour necrosis factor alpha therapy and increased risk of de novo psoriasis: is it really a paradoxical side effect? Clinical and experimental rheumatology. 2012 Sep-Oct:30(5):700-6 [PubMed PMID: 22935567]
Matsumoto T, Nakamura I, Miura A, Momoyama G, Ito K. New-onset multiple sclerosis associated with adalimumab treatment in rheumatoid arthritis: a case report and literature review. Clinical rheumatology. 2013 Feb:32(2):271-5. doi: 10.1007/s10067-012-2113-2. Epub 2012 Nov 14 [PubMed PMID: 23149905]
Level 3 (low-level) evidenceKerbleski JF, Gottlieb AB. Dermatological complications and safety of anti-TNF treatments. Gut. 2009 Aug:58(8):1033-9. doi: 10.1136/gut.2008.163683. Epub [PubMed PMID: 19592682]
Otani IM, Levin AS, Banerji A. Cutaneous Manifestations of Reactions to Biologics. Current allergy and asthma reports. 2018 Feb 21:18(2):12. doi: 10.1007/s11882-018-0764-z. Epub 2018 Feb 21 [PubMed PMID: 29464437]
Uzel G, Orange JS, Poliak N, Marciano BE, Heller T, Holland SM. Complications of tumor necrosis factor-α blockade in chronic granulomatous disease-related colitis. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2010 Dec 15:51(12):1429-34. doi: 10.1086/657308. Epub 2010 Nov 8 [PubMed PMID: 21058909]
Level 3 (low-level) evidenceKwon HJ, Coté TR, Cuffe MS, Kramer JM, Braun MM. Case reports of heart failure after therapy with a tumor necrosis factor antagonist. Annals of internal medicine. 2003 May 20:138(10):807-11 [PubMed PMID: 12755552]
Level 3 (low-level) evidencePham-Huy A, Sadarangani M, Huang V, Ostensen M, Castillo E, Troster SM, Vaudry W, Nguyen GC, Top KA. From mother to baby: antenatal exposure to monoclonal antibody biologics. Expert review of clinical immunology. 2019 Mar:15(3):221-229. doi: 10.1080/1744666X.2019.1561282. Epub 2019 Jan 24 [PubMed PMID: 30570400]
Carmona L, Gómez-Reino JJ, Rodríguez-Valverde V, Montero D, Pascual-Gómez E, Mola EM, Carreño L, Figueroa M, BIOBADASER Group. Effectiveness of recommendations to prevent reactivation of latent tuberculosis infection in patients treated with tumor necrosis factor antagonists. Arthritis and rheumatism. 2005 Jun:52(6):1766-72 [PubMed PMID: 15934089]
Hanson RL, Gannon MJ, Khamo N, Sodhi M, Orr AM, Stubbings J. Improvement in safety monitoring of biologic response modifiers after the implementation of clinical care guidelines by a specialty. Journal of managed care pharmacy : JMCP. 2013 Jan-Feb:19(1):49-67 [PubMed PMID: 23383700]
Level 2 (mid-level) evidenceCush JJ. Biological drug use: US perspectives on indications and monitoring. Annals of the rheumatic diseases. 2005 Nov:64 Suppl 4(Suppl 4):iv18-23 [PubMed PMID: 16239379]
Level 3 (low-level) evidenceDel Olmo L, Hernández B, Galindo-Izquierdo M, Tébar D, Balsa A, Carmona L. [Peri-operative management of disease modifying anti-rheumatic drugs: recommendations based on a meta-analysis]. Revista espanola de cirugia ortopedica y traumatologia. 2012 Sep-Oct:56(5):393-412. doi: 10.1016/j.recot.2012.05.001. Epub 2012 Jun 28 [PubMed PMID: 23594897]
Level 1 (high-level) evidenceGribble EJ, Sivakumar PV, Ponce RA, Hughes SD. Toxicity as a result of immunostimulation by biologics. Expert opinion on drug metabolism & toxicology. 2007 Apr:3(2):209-34 [PubMed PMID: 17428152]
Level 3 (low-level) evidence