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Current Neuropharmacology

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Systematic Review Article

Interferon-Beta Injection in Multiple Sclerosis Patients Related to the Induction of Headache and Flu-Like Pain Symptoms: A Systematic Review and Meta-Analysis of Randomised Controlled Trials

Author(s): Leonardo Gomes Pereira, Patrícia Rodrigues, Fernanda Tibolla Viero, Julia Maria Frare, Luís Guilherme Ramanzini and Gabriela Trevisan*

Volume 20, Issue 8, 2022

Published on: 11 April, 2022

Page: [1600 - 1612] Pages: 13

DOI: 10.2174/1570159X19666211101142115

Price: $65

Abstract

Multiple sclerosis (MS) is a chronic neurodegenerative, inflammatory, and autoimmune disease characterised by the demyelination of the central nervous system. One of the main approaches for treating MS is the use of disease-modifying therapies (DMTs). Among the DMTs are interferons (IFNs), which are cytokines responsible for controlling the activity of the immune system while exerting immunomodulatory, antiviral, and antiproliferative activities. IFN-beta (IFN-β) is the first-choice drug used to treat relapsing-remitting MS. However, the administration of IFN-β causes numerous painful adverse effects, resulting in lower adherence to the treatment. Therefore, this study aimed to investigate the headache and flu-like pain symptoms observed after IFNβ injection in MS patients using a systematic review and meta-analysis of randomised controlled trials. A total of 2370 articles were identified through research databases. Nine articles were included (three involving IFNβ-1b and six involving IFNβ-1a). All studies included in the meta-analysis had a low risk of bias. The odds ratio of headache and flu-like pain symptoms increased in MS patients treated with IFN-β. Thus, the adverse effects of headache and flu-like pain symptoms appear to be linked to IFN-β treatment in MS. The protocol of the study was registered in the Prospective International Registry of Systematic Reviews (registration number CRD42021227593).

Keywords: Adverse effects, disability, disease-modifying therapies, immunomodulatory, neuroinflammation, treatment.

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[1]
Dobson, R.; Giovannoni, G. Multiple sclerosis - a review. Eur. J. Neurol., 2019, 26(1), 27-40.
[http://dx.doi.org/10.1111/ene.13819] [PMID: 30300457]
[2]
Ogura, H.; Arima, Y.; Kamimura, D.; Murakami, M. The gateway theory: how regional neural activation creates a gateway for immune cells via an inflammation amplifier. Biomed. J., 2013, 36(6), 269-273.
[http://dx.doi.org/10.4103/2319-4170.113187] [PMID: 24385068]
[3]
Voskuhl, R.R.; Patel, K.; Paul, F.; Gold, S.M.; Scheel, M.; Kuchling, J.; Cooper, G.; Asseyer, S.; Chien, C.; Brandt, A.U.; Meyer, C.E.; MacKenzie-Graham, A. Sex differences in brain atrophy in multiple sclerosis. Biol. Sex Differ., 2020, 11(1), 49.
[http://dx.doi.org/10.1186/s13293-020-00326-3] [PMID: 32859258]
[4]
Ferraro, D.; Plantone, D.; Morselli, F.; Dallari, G.; Simone, A.M.; Vitetta, F.; Sola, P.; Primiano, G.; Nociti, V.; Pardini, M.; Mirabella, M.; Vollono, C. Systematic assessment and characterization of chronic pain in multiple sclerosis patients. Neurol. Sci., 2018, 39(3), 445-453.
[http://dx.doi.org/10.1007/s10072-017-3217-x] [PMID: 29224058]
[5]
Elmazny, A.; Hamdy, S.M.; Abdel-Naseer, M.; Shalaby, N.M.; Shehata, H.S.; Kishk, N.A.; Nada, M.A.; Mourad, H.S.; Hegazy, M.I.; Ab-delalim, A.; Ahmed, S.M.; Hatem, G.; Fouad, A.M.; Mahmoud, H.; Hassan, A. Interferon-beta-induced headache in patients with multiple sclerosis: frequency and characterization. J. Pain Res., 2020, 13(13), 537-545.
[http://dx.doi.org/10.2147/JPR.S230680] [PMID: 32210609]
[6]
Kalincik, T. Multiple sclerosis relapses: epidemiology, outcomes and management. A systematic review. Neuroepidemiology, 2015, 44(4), 199-214.
[http://dx.doi.org/10.1159/000382130] [PMID: 25997994]
[7]
Oh, J.; Vidal-Jordana, A.; Montalban, X. Multiple sclerosis: clinical aspects. Curr. Opin. Neurol., 2018, 31(6), 752-759.
[http://dx.doi.org/10.1097/WCO.0000000000000622] [PMID: 30300239]
[8]
Klineova, S.; Lublin, F.D. Clinical course of multiple sclerosis. Cold Spring Harb. Perspect. Med., 2018, 8(9), a028928.
[http://dx.doi.org/10.1101/cshperspect.a028928] [PMID: 29358317]
[9]
Zeydan, B.; Atkinson, E.J.; Weis, D.M.; Smith, C.Y.; Gazzuola Rocca, L.; Rocca, W.A.; Keegan, B.M.; Weinshenker, B.G.; Kantarci, K.; Kantarci, O.H. Reproductive history and progressive multiple sclerosis risk in women. Brain Commun., 2020, 2(2), fcaa185.
[http://dx.doi.org/10.1093/braincomms/fcaa185]
[10]
McGinley, M.P.; Goldschmidt, C.H.; Rae-Grant, A.D. Diagnosis and treatment of multiple sclerosis: a review. JAMA, 2021, 325(8), 765-779.
[http://dx.doi.org/10.1001/jama.2020.26858] [PMID: 33620411]
[11]
Chataway, J.; De Angelis, F.; Connick, P.; Parker, R.A.; Plantone, D.; Doshi, A.; John, N.; Stutters, J.; MacManus, D.; Prados Carrasco, F.; Barkhof, F.; Ourselin, S.; Braisher, M.; Ross, M.; Cranswick, G.; Pavitt, S.H.; Giovannoni, G.; Gandini Wheeler-Kingshott, C.A.; Hawkins, C.; Sharrack, B.; Bastow, R.; Weir, C.J.; Stallard, N.; Chandran, S. Efficacy of three neuroprotective drugs in secondary progressive multi-ple sclerosis (MS-SMART): a phase 2b, multiarm, double-blind, randomised placebo-controlled trial. Lancet Neurol., 2020, 19(3), 214-225.
[http://dx.doi.org/10.1016/S1474-4422(19)30485-5] [PMID: 31981516]
[12]
Thompson, A.J.; Baranzini, S.E.; Geurts, J.; Hemmer, B.; Ciccarelli, O. Multiple sclerosis. Lancet, 2018, 391(10130), 1622-1636.
[http://dx.doi.org/10.1016/S0140-6736(18)30481-1] [PMID: 29576504]
[13]
Hauser, S.L.; Cree, B.A.C. Treatment of multiple sclerosis: a review. Am. J. Med., 2020, 133(12), 1380-1390.e2.
[http://dx.doi.org/10.1016/j.amjmed.2020.05.049] [PMID: 32682869]
[14]
Hart, F.M.; Bainbridge, J. Current and emerging treatment of multiple sclerosis. Am. J. Manag. Care, 2016, 22(6)(Suppl.), s159-s170.
[PMID: 27356025]
[15]
Correale, J.; Gaitán, M.I.; Ysrraelit, M.C.; Fiol, M.P. Progressive multiple sclerosis: from pathogenic mechanisms to treatment. Brain, 2017, 140(3), 527-546.
[http://dx.doi.org/10.1093/brain/aww258] [PMID: 27794524]
[16]
Limmroth, V.; Putzki, N.; Kachuck, N.J. The interferon beta therapies for treatment of relapsing-remitting multiple sclerosis: are they equally efficacious? A comparative review of open-label studies evaluating the efficacy, safety, or dosing of different interferon beta for-mulations alone or in combination. Ther. Adv. Neurol. Disord., 2011, 4(5), 281-296.
[http://dx.doi.org/10.1177/1756285611413825] [PMID: 22010041]
[17]
Miller, A.E.; Rhoades, R.W. Treatment of relapsing-remitting multiple sclerosis: current approaches and unmet needs. Curr. Opin. Neurol., 2012, 25(Suppl.), S4-S10.
[http://dx.doi.org/10.1097/01.wco.0000413319.87092.19] [PMID: 22398662]
[18]
Filipi, M.L.; Beavin, J.; Brillante, R.T.; Costello, K.; Hartley, G.C.; Hartley, K.; Namey, M.; O’Leary, S.; Remington, G. Nurses’ perspec-tive on approaches to limit flu-like symptoms during interferon therapy for multiple sclerosis. Int. J. MS Care, 2014, 16(1), 55-60.
[http://dx.doi.org/10.7224/1537-2073.2013-006] [PMID: 24688355]
[19]
Filipi, M.; Jack, S. Interferons in the Treatment of Multiple Sclerosis: A Clinical Efficacy, Safety, and Tolerability Update. Int. J. MS Care, 2020, 22(4), 165-172.
[http://dx.doi.org/10.7224/1537-2073.2018-063] [PMID: 32863784]
[20]
McNab, F.; Mayer-Barber, K.; Sher, A.; Wack, A.; O’Garra, A. Type I interferons in infectious disease. Nat. Rev. Immunol., 2015, 15(2), 87-103.
[http://dx.doi.org/10.1038/nri3787] [PMID: 25614319]
[21]
Page, M.J.; McKenzie, J.E.; Bossuyt, P.M.; Boutron, I.; Hoffmann, T.C.; Mulrow, C.D.; Shamseer, L.; Tetzlaff, J.M.; Akl, E.A.; Brennan, S.E.; Chou, R.; Glanville, J.; Grimshaw, J.M.; Hróbjartsson, A.; Lalu, M.M.; Li, T.; Loder, E.W.; Mayo-Wilson, E.; McDonald, S.; McGuinness, L.A.; Stewart, L.A.; Thomas, J.; Tricco, A.C.; Welch, V.A.; Whiting, P.; Moher, D. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ, 2021, 29, 372.
[http://dx.doi.org/10.1136/bmj.n71]
[22]
Munnangi, S.; Boktor, S.W. Epidemiology of study design; StatPearls: Treasure Island, FL, 2021.
[23]
Schünemann, H.J.; Oxman, A.D.; Brozek, J.; Glasziou, P.; Jaeschke, R.; Vist, G.E.; Williams, J.W., Jr; Kunz, R.; Craig, J.; Montori, V.M.; Bossuyt, P.; Guyatt, G.H. Grading quality of evidence and strength of recommendations for diagnostic tests and strategies. BMJ, 2008, 336(7653), 1106-1110.
[http://dx.doi.org/10.1136/bmj.39500.677199.AE] [PMID: 18483053]
[24]
Higgins, J.P.; Altman, D.G.; Gøtzsche, P.C.; Jüni, P.; Moher, D.; Oxman, A.D. Savović, J.; Schulz, K.F.; Weeks, L.; Sterne, J.A Cochrane Bias Methods Group; Cochrane Statistical Methods Group. The Cochrane Collaboration’s tool for assessing risk of bias in randomised tri-als. BMJ, 2011, 343, d5928.
[http://dx.doi.org/10.1136/bmj.d5928]
[25]
Egger, M.; Davey Smith, G.; Schneider, M.; Minder, C. Bias in meta-analysis detected by a simple, graphical test. BMJ, 1997, 315(7109), 629-634.
[http://dx.doi.org/10.1136/bmj.315.7109.629] [PMID: 9310563]
[26]
Begg, C.B.; Mazumdar, M. Operating characteristics of a rank correlation test for publication bias. Biometrics, 1994, 50(4), 1088-1101.
[http://dx.doi.org/10.2307/2533446] [PMID: 7786990]
[27]
Rodrigues, P.; Bochi, G.V.; Trevisan, G. Advanced oxidative protein products role in multiple sclerosis: A systematic review and meta-analysis. Mol. Neurobiol., 2021, 58(11), 5724-5742.
[http://dx.doi.org/10.1007/s12035-021-02493-9] [PMID: 34392502]
[28]
DerSimonian, R.; Laird, N. Meta-analysis in clinical trials. Control. Clin. Trials, 1986, 7(3), 177-188.
[http://dx.doi.org/10.1016/0197-2456(86)90046-2] [PMID: 3802833]
[29]
Kappos, L.; Polman, C.H.; Freedman, M.S.; Edan, G.; Hartung, H.P.; Miller, D.H.; Montalban, X.; Barkhof, F.; Bauer, L.; Jakobs, P.; Pohl, C.; Sandbrink, R. Treatment with interferon beta-1b delays conversion to clinically definite and McDonald MS in patients with clinically isolated syndromes. Neurology, 2006, 67(7), 1242-1249.
[http://dx.doi.org/10.1212/01.wnl.0000237641.33768.8d] [PMID: 16914693]
[30]
Montalban, X.; Sastre-Garriga, J.; Tintoré, M.; Brieva, L.; Aymerich, F.X.; Río, J.; Porcel, J.; Borràs, C.; Nos, C.; Rovira, A. A single-center, randomized, double-blind, placebo-controlled study of interferon beta-1b on primary progressive and transitional multiple sclero-sis. Mult. Scler., 2009, 15(10), 1195-1205.
[http://dx.doi.org/10.1177/1352458509106937] [PMID: 19797261]
[31]
Wroe, S.J. Effects of dose titration on tolerability and efficacy of interferon beta-1b in people with multiple sclerosis. J. Int. Med. Res., 2005, 33(3), 309-318.
[http://dx.doi.org/10.1177/147323000503300306] [PMID: 15938592]
[32]
Calabresi, P.A.; Kieseier, B.C.; Arnold, D.L.; Balcer, L.J.; Boyko, A.; Pelletier, J.; Liu, S.; Zhu, Y.; Seddighzadeh, A.; Hung, S.; Deykin, A. Pegylated interferon β-1a for relapsing-remitting multiple sclerosis (ADVANCE): a randomised, phase 3, double-blind study. Lancet Neurol., 2014, 13(7), 657-665.
[http://dx.doi.org/10.1016/S1474-4422(14)70068-7] [PMID: 24794721]
[33]
Freedman, M.S.; Francis, G.S.; Sanders, E.A.C.M.; Rice, G.P.A.; O’Connor, P.; Comi, G.; Duquette, P.; Metz, L.; Murray, T.J.; Bouchard, J-P.; Abramsky, O.; Pelletier, J.; O’Brien, F. Randomized study of once-weekly interferon β-1la therapy in relapsing multiple sclerosis: three-year data from the OWIMS study. Mult. Scler., 2005, 11(1), 41-45.
[http://dx.doi.org/10.1191/1352458505ms1126oa] [PMID: 15732265]
[34]
Gold, R.; Rieckmann, P.; Chang, P.; Abdalla, J. The long-term safety and tolerability of high-dose interferon β-1a in relapsing-remitting multiple sclerosis: 4-year data from the PRISMS study. Eur. J. Neurol., 2005, 12(8), 649-656.
[http://dx.doi.org/10.1111/j.1468-1331.2005.01083.x] [PMID: 16053475]
[35]
Kappos, L.; Li, D.; Calabresi, P.A.; O’Connor, P.; Bar-Or, A.; Barkhof, F.; Yin, M.; Leppert, D.; Glanzman, R.; Tinbergen, J.; Hauser, S.L. Ocrelizumab in relapsing-remitting multiple sclerosis: a phase 2, randomised, placebo-controlled, multicentre trial. Lancet, 2011, 378(9805), 1779-1787.
[http://dx.doi.org/10.1016/S0140-6736(11)61649-8] [PMID: 22047971]
[36]
Comi, G.; De Stefano, N.; Freedman, M.S.; Barkhof, F.; Polman, C.H.; Uitdehaag, B.M.; Casset-Semanaz, F.; Hennessy, B.; Moraga, M.S.; Rocak, S.; Stubinski, B.; Kappos, L. Comparison of two dosing frequencies of subcutaneous interferon beta-1a in patients with a first clin-ical demyelinating event suggestive of multiple sclerosis (REFLEX): a phase 3 randomised controlled trial. Lancet Neurol., 2012, 11(1), 33-41.
[http://dx.doi.org/10.1016/S1474-4422(11)70262-9] [PMID: 22146409]
[37]
De Stefano, N.; Sormani, M.P.; Stubinski, B.; Blevins, G.; Drulovic, J.S.; Issard, D.; Shotekov, P.; Gasperini, C. Efficacy and safety of subcutaneous interferon β-1a in relapsing-remitting multiple sclerosis: further outcomes from the IMPROVE study. J. Neurol. Sci., 2012, 312(1-2), 97-101.
[http://dx.doi.org/10.1016/j.jns.2011.08.013] [PMID: 21880336]
[38]
Madsen, C. The innovative development in interferon beta treatments of relapsing-remitting multiple sclerosis. Brain Behav., 2017, 7(6), e00696.
[http://dx.doi.org/10.1002/brb3.696] [PMID: 28638705]
[39]
Bischof, A.; Sprenger, T. Interferon beta-associated recurrence of painful trigeminal neuropathy attributed to a multiple sclerosis plaque. J. Headache Pain, 2014, 15(1), 21.
[http://dx.doi.org/10.1186/1129-2377-15-21] [PMID: 24742132]
[40]
Hariton, E.; Locascio, J.J. Randomised controlled trials - the gold standard for effectiveness research: Study design: randomised controlled trials. BJOG, 2018, 125(13), 1716.
[http://dx.doi.org/10.1111/1471-0528.15199] [PMID: 29916205]
[41]
Freedman, M.S.; Comi, G.; De Stefano, N.; Barkhof, F.; Polman, C.H.; Uitdehaag, B.M.J.; Lehr, L.; Stubinski, B.; Kappos, L. Moving to-ward earlier treatment of multiple sclerosis: Findings from a decade of clinical trials and implications for clinical practice. Mult. Scler. Relat. Disord., 2014, 3(2), 147-155.
[http://dx.doi.org/10.1016/j.msard.2013.07.001] [PMID: 25878002]
[42]
Horn-Hofmann, C.; Büscher, P.; Lautenbacher, S.; Wolstein, J. The effect of nonrecurring alcohol administration on pain perception in humans: a systematic review. J. Pain Res., 2015, 8, 175-187.
[http://dx.doi.org/10.2147/JPR.S79618] [PMID: 25960674]
[43]
Dassieu, L.; Kaboré, J-L.; Choinière, M.; Arruda, N.; Roy, É. Painful lives: Chronic pain experience among people who use illicit drugs in Montreal (Canada). Soc. Sci. Med., 2020, 246, 112734.
[http://dx.doi.org/10.1016/j.socscimed.2019.112734] [PMID: 31864968]
[44]
Brownlee, W.J.; Hardy, T.A.; Fazekas, F.; Miller, D.H. Diagnosis of multiple sclerosis: progress and challenges. Lancet, 2017, 389(10076), 1336-1346.
[http://dx.doi.org/10.1016/S0140-6736(16)30959-X] [PMID: 27889190]
[45]
Polman, C.H.; Reingold, S.C.; Edan, G.; Filippi, M.; Hartung, H.P.; Kappos, L.; Lublin, F.D.; Metz, L.M.; McFarland, H.F.; O’Connor, P.W.; Sandberg-Wollheim, M.; Thompson, A.J.; Weinshenker, B.G.; Wolinsky, J.S. Diagnostic criteria for multiple sclerosis: 2005 revi-sions to the “McDonald Criteria”. Ann. Neurol., 2005, 58(6), 840-846.
[http://dx.doi.org/10.1002/ana.20703] [PMID: 16283615]
[46]
Schumacher, G.A.; Beebe, G.; Kibler, R.F.; Kurland, L.T.; Kurtzke, J.F.; McDowell, F.; Nagler, B.; Sibley, W.A.; Tourtellotte, W.W.; Willmon, T.L. Problems of experimental trials of therapy in multiple sclerosis: report by the panel on the evaluation of experimental trials of therapy in multiple sclerosis. Ann. N. Y. Acad. Sci., 1965, 122(1), 552-568.
[http://dx.doi.org/10.1111/j.1749-6632.1965.tb20235.x] [PMID: 14313512]
[47]
Poser, C.M.; Paty, D.W.; Scheinberg, L.; McDonald, W.I.; Davis, F.A.; Ebers, G.C.; Johnson, K.P.; Sibley, W.A.; Silberberg, D.H.; Tourtel-lotte, W.W. New diagnostic criteria for multiple sclerosis: guidelines for research protocols. Ann. Neurol., 1983, 13(3), 227-231.
[http://dx.doi.org/10.1002/ana.410130302] [PMID: 6847134]
[48]
Zettl, U.K.; Hecker, M.; Aktas, O.; Wagner, T.; Rommer, P.S. Interferon β-1a and β-1b for patients with multiple sclerosis: updates to current knowledge. Expert Rev. Clin. Immunol., 2018, 14(2), 137-153.
[http://dx.doi.org/10.1080/1744666X.2018.1426462] [PMID: 29318902]
[49]
Comini-Frota, E.R.; Vasconcelos, C.C.F.; Mendes, M.F. Guideline for multiple sclerosis treatment in Brazil: Consensus from the Neuro-immunology Scientific Department of the Brazilian Academy of Neurology. Neuro-Psiquiatr, 2017, 75, 57-65.
[50]
Carlsson, A.M. Assessment of chronic pain. I. Aspects of the reliability and validity of the visual analogue scale. Pain, 1983, 16(1), 87-101.
[http://dx.doi.org/10.1016/0304-3959(83)90088-X] [PMID: 6602967]
[51]
Fletcher, J. What is heterogeneity and is it important? BMJ, 2007, 334(7584), 94-96.
[http://dx.doi.org/10.1136/bmj.39057.406644.68] [PMID: 17218716]
[52]
Sabidó-Espin, M.; Munschauer, R. Reasons for discontinuation of subcutaneous interferon β-1a three times a week among patients with multiple sclerosis: a real-world cohort study. BMC Neurol., 2017, 17(1), 57.
[http://dx.doi.org/10.1186/s12883-017-0831-4] [PMID: 28335743]

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