A multicentric pharmacovigilance study: collection and analysis of adverse drug reactions in relapsing-remitting multiple sclerosis patients

Figures & data

Table 1 Details about the drugs considered in this study

Drug	Commercial name and manufacturer	Characteristics and mechanism of action	References
IFN β-1a-A	Avonex^®; Biogen, Cambridge, MA, USA	Avonex is glycosylated like natural IFN β and exerts its biological actions through the binding to specific receptors on cell surface that starts a cascade of intracellular events leading to the expression of numerous genes and markers, such as MHC Class I, Mx protein, 2″/5′-oligoadenylate synthetase, β2-microglobulin, and neopterin	^Citation14
IFN β-1a-R	Rebif^®; Merck Serono, Darmstadt, Germany	Rebif presents the same amino acid sequence of endogenous human IFN β. It is produced in mammalian cells (Chinese hamster ovary) and is glycosylated such as the natural protein	^Citation15
IFN β-1b-B IFN β-1b-E	Betaferon^®; Bayer, Leverkusen, Germany Extavia^®; Novartis, Basel, Switzerland	The biological actions of IFN β-1b are mediated by its binding to specific receptors on the cell surface that triggers the expression of gene products that mediates its biological actions. IFN β-1b both decreases the binding affinity and enhances the internalization and degradation of the IFN γ receptor. IFN β-1b also enhances the suppressor activity of peripheral blood mononuclear cells	^Citation16, ^Citation17
PEG IFN β-1a	Plegridy^®; Biogen, Cambridge, MA, USA	Plegridy is an IFN β-1a conjugated with a single, linear molecule of methoxy poly(ethyleneglycol)-O-2-methylpropionaldehyde. It binds to the type I IFN receptor on the cell surface inducing a cascade of intracellular events leading to the regulation of IFN-responsive gene expression. Biological effects may include upregulation of anti-inflammatory cytokines, downregulation of pro-inflammatory cytokines, and inhibition of activated T cells’ migration across the blood–brain barrier	^Citation18
GA	Copaxone^®; Teva Pharmaceutical Industries, Petach Tikva, Israel	GA is a pool of synthetic peptides that simulate sequences of myelin and then acts as a false target preventing the immune system attack against this protein	^Citation6, ^Citation19
NAT	Tysabri^®; Biogen, Cambridge, MA, USA	NAT is a recombinant humanized anti-α4-integrin antibody produced in a murine cell line by recombinant DNA technology. Its binding to the integrin blocks the interaction with its endothelial receptor, the VCAM-1, leading to the inhibition of leukocyte migration into the CNS and attenuating inflammation	^Citation5, ^Citation20
Teriflunomide	Aubagio^®; Sanofi, Paris, France	Teriflunomide has anti-inflammatory properties that reversibly inhibits the mitochondrial enzyme DHO-DH, required for the pyrimidine synthesis. The result is that teriflunomide reduces the proliferation of dividing cells that need the synthesis of pyrimidine. In this way, teriflunomide reduces the proliferation of T and B cells	^Citation7, ^Citation22
FTY720	Gilenya^®; Novartis, Basel, Switzerland	FTY720 is a S1P receptor modulator. After the action of sphingosine kinase, the active metabolite FTY720 phosphate binds to S1P receptor 1 located on lymphocytes and crosses the blood–brain barrier to bind to S1P receptor 1 located on neural cells in the CNS. Acting as an antagonist of S1P receptors on lymphocytes, FTY720 phosphate inhibits the exit of lymphocytes from lymph nodes, causing a redistribution. It reduces the infiltration of lymphocytes into the CNS	^Citation8, ^Citation21
DMF	Tecfidera^®; Biogen, Cambridge, MA, USA	DMF exerts a cytoprotective effect on neuronal cells by activating the Nrf2	^Citation9, ^Citation23

Abbreviations: CNS, central nervous system; DHO-DH, dihydroorotate dehydrogenase; DMF, dimethyl fumarate; FTY720, fingolimod; GA, glatiramer acetate; IFN, interferon; IFN β-1a-A, interferon β-1a Avonex^®; IFN β-1a-R, interferon β-1a Rebif^®; IFN β-1b-B, interferon β-1b Betaferon^®; IFN β-1b-E, interferon β-1b Extavia^®; NAT, natalizumab; Nrf2, nuclear factor erythroid 2-related factor 2; PEG IFN β-1a, peginterferon β-1a; S1P, sphingosine 1-phosphate; VCAM-1, vascular cell adhesion molecule-1.

Figure 1 (A–D) Distribution of RR-MS population reporting adverse reactions treated with interferons, in relation to age and sex.

Abbreviations: F, female; IFN β-1a-A, interferon β-1a Avonex^®; IFN β-1a-R, interferon β-1a Rebif^®; IFN β-1b-B, interferon β-1b Betaferon^®; M, male; RR-MS, relapsing-remitting multiple sclerosis.

Figure 2 (A–E) Distribution of RR-MS population reporting adverse reactions in relation to age and sex.

Abbreviations: F, female; M, male; RR-MS, relapsing-remitting multiple sclerosis.

Figure 3 Total expected and unexpected adverse events for each drug evaluated.

Notes: **P<0.01. ***P<0.001. ****P<0.0001.
Abbreviations: DMF, dimethyl fumarate; FTY720, fingolimod; GA, glatiramer acetate; IFN β-1a-A, interferon β-1a Avonex^®; IFN β-1a-R, interferon β-1a Rebif^®; IFN β-1b-B, interferon β-1b Betaferon^®; IFN β-1b-E, interferon β-1b Extavia^®; NAT, natalizumab; PEG IFN β-1a, peginterferon β-1a.

Table 2 Clinical data of RR-MS patients and adverse event characteristics for all the reported expected reactions

Drug	Medical history of the patient			Characteristics of the adverse event
	Concomitant diseases	Previous therapy	Number of doses	Adverse event	Severity	Action taken
IFN β-1a-A	No	No	192	Myalgia	Mild	Continuation
				Arthralgia	Mild
	No	Steroids	384	Flu-like symptoms	Mild	Continuation
				Mixed anxiety-depressive disorder	Mild
	Hashimoto thyroiditis	No	180	Leukopenia	Severe	Discontinuation
	No	No	104	Nephrotic syndrome	Severe	Discontinuation
	No	No	104	Flu-like symptoms	Mild	Continuation
				Pruritus	Mild
	Dyslipidemia, anxiety	Methylprednisolone	308	Injection site necrosis	Severe	Temporary
				Diarrhea	Severe	discontinuation
	No	No	886	Flu-like symptoms	Mild	Discontinuation
	No	No	260	Pain	Mild	Continuation
	Headache	No	17	Hepatic transaminases increased	Moderate	Discontinuation
	Thyroiditis, headache, mitral insufficiency	No	68	Flu-like symptoms	Moderate	Discontinuation
	Hypertension	No	NA	Injection site bruising	Moderate	Continuation
	No	No	NA	Flu-like symptoms	Mild	Continuation
	No	No	468	Flu-like symptoms	Mild	Continuation
	No	No	NA	Flu-like symptoms	Mild	Continuation
	No	No	52	Myalgia	Mild	Continuation
				Arthralgia	Mild
	Diabetes type 1	No	1	Vomiting	Mild	Continuation
	No	No	52	Malaise	Moderate	Discontinuation
				Tachycardia	Moderate
	No	No	NA	Pyrexia	Mild	Continuation
	No	No	4	Pyrexia	Mild	Continuation
	Diabetes	No	104	Flu-like symptoms	Mild	Continuation
	No	No	NA	Flu-like symptoms	Moderate	Continuation
	No	No	52	Flu-like symptoms	Mild	Discontinuation
IFN β-1a-R	Hashimoto thyroiditis	Steroids, Cyclophosphamide, Dexamethasone, Methotrexate, IFN β-1a-R, Methylprednisolone	2,016	Urticaria	Severe	Continuation
	No	IFN β-1a-A	2,000	Arthralgia	Moderate	Discontinuation
	Diabetes type 1, thyroiditis	No	234	Flu-like symptoms	Moderate	Continuation
	Osteoporosis	No	90	Flu-like symptoms	Mild	Continuation
	No	Azathioprine	1,407	Injection site abscess	Moderate	Continuation
	No	No	NA	Insomnia	Mild	Continuation
	No	No	780	Musculoskeletal stiffness	Moderate	Discontinuation
	Diabetes type 2, thyroiditis	IFN β-1b-B	312	Flu-like symptoms	Moderate	Discontinuation
	Depression	No	NA	Headache	Moderate	Discontinuation
	No	No	312	Pyrexia	Moderate	Continuation
	No	No	36	Injection site pain	Moderate	Continuation
	No	No	NA	Flu-like symptoms	Moderate	Continuation
	No	No	12	Pain in extremity	Mild	Continuation
	Asthma	No	24	Flu-like symptoms	Moderate	Discontinuation
	No	No	1,251	Hepatic transaminases increased	Moderate	Continuation
	Diabetes	No	468	Hepatic transaminases increased	Moderate	Continuation
	No	No	2,190	Hepatic transaminases increased	Moderate	Continuation
	No	No	75	Flu-like symptoms	Mild	Continuation
				Insomnia	Mild
	Hashimoto thyroiditis	No	312	Injection site redness	Mild	Continuation
	Glaucoma	No	936	Headache	Moderate	Continuation
	Neurofibromatosis type 1	No	36	Injection site necrosis	Moderate	Continuation
				Flu-like symptoms	Moderate
	Hashimoto thyroiditis	No	780	Headache	Mild	Continuation
	No	GA, NAT	468	Headache	Moderate	Discontinuation
				Asthenia	Moderate
	No	No	NA	Headache	Moderate	Discontinuation
				Asthenia	Moderate
	Raynaud syndrome	No	NA	Headache	Moderate	Continuation
	Hashimoto thyroiditis	No	NA	Headache	Mild	Continuation
	Diabetes type 1, thyroiditis	No	390	Flu-like symptoms	Moderate	Discontinuation
	No	No	468	Injection site erythema	Moderate	Continuation
IFN β-1b-B	No	IFN β-1a-A	1,900	Headache	Mild	Discontinuation
	No	No	1,800	Pyrexia	Mild	Discontinuation
				Injection site pain	Mild
	Bipolar disorder	GA, NAT, methylprednisolone	667	Injection site abscess	Severe	Discontinuation
	Depression	No	NA	Headache	Moderate	Discontinuation
				Paresthesia	Moderate
	No	No	1,460	Injection site mass	Mild	Discontinuation
	No	Cyclophosphamide	547	Gamma-glutamyl-transferase increased	Moderate	Discontinuation
	No	No	912	Asthenia	Moderate	Discontinuation
				Myasthenia	Moderate
	No	IFN β-1a-A	150	Pyrexia	Moderate	Continuation
				Injection site pain	Moderate
	Methylprednisolone and ketoprofen allergies	No	912	Malaise	Moderate	Continuation
				Injection site pain	Moderate
	Vertigo	No	273	Injection site pain	Moderate	Discontinuation
	No	No	273	Injection site mass	Moderate	Continuation
	No	No	912	Injection site skin reaction	Moderate	Discontinuation
	No	No	730	Injection site bruising	Moderate	Discontinuation
				Injection site pain	Moderate
	Hypertension	No	NA	Flu-like symptoms	Mild	Continuation
	Thyroiditis	IFN β-1a-A	105	Lymphopenia	Moderate	Discontinuation
IFN β-1b-E	No	IFN β-1a-A, IFN β-1a-R, GA	140	Abdominal pain	Moderate	Discontinuation
	Depression, disk herniation	No	135	Urticaria	Mild	Continuation
PEG IFN β-1a	No	Methylprednisolone	6	Flu-like symptoms	Severe	Continuation
	Dysthyroidism, hypertension	IFN β-1b-E, DMF, teriflunomide	10	Injection site rash	Mild	Discontinuation
	No	NA	8	Flu-like symptoms	Mild	Continuation
	No	NA	NA	Flu-like symptoms	NA	NA
	Anemia	IFN β-1a-A	NA	Lymphopenia	Mild	Discontinuation
	No	NA	12	Lymphopenia	Mild	Discontinuation
	No	DMF	2	Urticaria	Moderate	Discontinuation
	Depression	IFN β-1a-R, IFN β-1a-A	3	Injection site redness	Mild	Discontinuation
	Diabetes	IFN β-1a-A	2	Flu-like symptoms	Moderate	Continuation
				Injection site redness	Moderate
	Cardiopathy, capitellum fracture, duodeal ulcer, anxiety	IFN β-1b-B	2	Flu-like symptoms	Moderate	Continuation
				Injection site redness	Moderate
	Allergies	IFN β-1a-R	2	Flu-like symptoms	Moderate	Continuation
				Injection site rash	Moderate
	No	IFN β-1b-B	2	Flu-like symptoms	Moderate	Continuation
	Meningioma	IFN β-1b-B, Teriflunomide	4	Myalgia	Mild	Continuation
				Arthralgia	Mild
	Depression	IFN β-1b-B	4	Flu-like symptoms	Moderate	Continuation
				Injection site redness	Moderate
	No	IFN β-1b-B	1	Arthralgia	Moderate	Continuation
	No	IFN β-1a-A, IFN β-1a-R, mitoxantrone, GA, IFN β-1b-B, DMF	6	Lymphopenia	Severe	Discontinuation
	No	IFN β-1a-A, IFN β-1a-R	1	Flu-like symptoms	Moderate	Continuation
				Injection site rash	Moderate
	Pulmonary valve stenosis	IFN β-1a-R	2	Pyrexia	Moderate	Continuation
				Injection site rash	Moderate
	No	IFN β-1a-A	1	Injection site redness	Moderate	Continuation
	No	No	2	Injection site erythema	Moderate	Discontinuation
	Glucose-6-phosphate dehydrogenase deficiency	GA	4	Myalgia	Moderate	Continuation
				Asthenia	Moderate
	No	IFN β-1b-B, teriflunomide	4	Myalgia	Mild	Continuation
				Arthralgia	Mild
	No	No	6	Thrombocytopenia	Moderate	Discontinuation
	Thyroiditis	Mitoxantrone, IFN β-1a-R	10	Flu-like symptoms	Moderate	Continuation
	No	IFN β-1b-B	1	Injection site redness	Mild	Continuation
	No	IFN β-1a-A	6	Flu-like symptoms	Mild	Discontinuation
	Thyroiditis	IFN β-1a-A	NA	Injection site erythema	Mild	Continuation
	Diabetes	No	6	Flu-like symptoms	Moderate	Continuation
	Thyroiditis	IFN β-1a-A	6	Myalgia	Mild	Discontinuation
				Urticaria	Mild
	No	IFN β-1a-R	NA	Pyrexia	Mild	Continuation
				Injection site redness	Mild
	No	IFN β-1a-R, GA	10	Urticaria	Moderate	Discontinuation
	Anxiety	IFN β-1a-A, IFN β-1b-B	NA	Flu-like symptoms	Mild	Continuation
	Anxiety	IFN β-1b-B	1	Pyrexia	Moderate	Continuation
				Injection site necrosis	Moderate
	No	Azathioprine, IFN β-1a-R	1	Flu-like symptoms	Mild	Continuation
	No	IFN β-1a-R	26	Pyrexia	Mild	Continuation
	No	No	6	Flu-like symptoms	Mild	Continuation
	No	IFN β-1a-R, mitoxantrone, IFN β-1b-B, IFN β-1a-A	6	Flu-like symptoms	Moderate	Continuation
	No	IFN β-1a-R	NA	Injection site redness	Moderate	Continuation
	No	No	NA	Flu-like symptoms	Moderate	Continuation
				Hepatic transaminases increased	Moderate
	No	No	8	Pyrexia	Moderate	Continuation
	No	IFN β-1b-B	NA	Asthenia	Mild	Continuation
				Injection site redness	Mild
	No	No	1	Pyrexia	Mild	Continuation
				Injection site rash	Mild
GA	Hypercholesterolemia, anxiety	No	620	Mixed anxiety-depressive disorder	Moderate	Discontinuation
	No	Methylprednisolone	48	Rash	Moderate	Discontinuation
				Tachycardia	Moderate
				Depression	Moderate
	Allergic asthma	No	2,002	Dyspnea	Severe	Continuation
				Tachycardia	Severe
				Vomiting	Severe
	Hiatal hernia, contact dermatitis	Methylprednisolone, IFN β-1b-E, DMF	60	Injection site rash	Moderate	Continuation
	Hypercholesterolemia	Methylprednisolone	140	Rash	Severe	Discontinuation
				Flushing	Severe
				Choking sensation	Severe
	Anxiety	IFN β-1b-B, NAT, DMF, teriflunomide	90	Chest pain	Moderate	Discontinuation
				Flushing	Moderate
				Syncope	Moderate
	Gastroesophageal reflux disease, depression	No	51	Injection site rash	Mild	Continuation
	Anxiety	IFN β-1b-B	93	Choking sensation	Severe	Discontinuation
				Hypersensitivity	Severe
	No	IFN β-1b-B, NAT	NA	Urticaria	Moderate	Discontinuation
	No	IFN β-1a-A	NA	Urticaria	Moderate	Discontinuation
				Tachycardia	Moderate
				Anxiety	Moderate
	No	IFN β-1a-R	NA	Injection site mass	Mild	Continuation
	No	IFN β-1a-A	NA	Injection site pruritus	Mild	Continuation
	No	No	NA	Injection site pain	Moderate	Continuation
				Injection site mass	Moderate
				Dyspnea	Moderate
				Influenza	Moderate
				Palpitation	Moderate
	No	No	NA	Injection site redness	Moderate	Continuation
				Injection site mass	Moderate
	No	No	1,567	Skin disorder	Moderate	Discontinuation
	Pituitary microadenoma	IFN β-1a-A	6	Injection site rash	Moderate	Discontinuation
	No	IFN β-1a-A, IFN β-1a-R, IFN β-1b-B	36	Influenza	Moderate	Discontinuation
	Thyroiditis	IFN β-1a-R	238	Injection site mass	Mild	Continuation
	Pneumonia with autoimmune features	DMF, PEG IFN β-1a	16	Rash	Moderate	Discontinuation
	No	No	67	Injection site mass	Moderate	Continuation
	No	IFN β-1a-A	1	Anxiety	Moderate	Continuation
				Vomiting	Moderate
				Visual field defect	Moderate
				Dyspnea	Moderate
				Confusional state	Moderate
	No	Azathioprine, IFN β-1a-A, IFN β-1a-R	628	Pyrexia	Moderate	Discontinuation
				Nausea	Moderate
				Chest pain	Moderate
	Myoclonic epilepsy	IFN β-1a-R	63	Hypersensitivity	Moderate	Discontinuation
	Depression, diabetes type 2, glaucoma	No	160	Rash	Moderate	Discontinuation
				Dyspnea	Moderate
	No	IFN β-1b-B	2	Pyrexia	Moderate	Discontinuation
				Rash	Moderate
				Motor dysfunction	Moderate
	Thyroiditis	No	238	Hypersensitivity	Moderate	Discontinuation
NAT	No	No	52	Pyrexia	Mild	Continuation
	No	IFN β-1b-B, GA, IFN β-1a-A	104	Pyrexia	Mild	Continuation
	No	NA	3	Pyrexia	Moderate	Discontinuation
				Chest pain	Moderate
FTY720	Bronchial asthma, allergies	Methylprednisolone, IFN β-1a-A, GA, IFN β-1b-B	1,095	Headache	Moderate	Discontinuation
				Pruritus	Moderate
				Urinary tract infection	Moderate
	Hypercholesterolemia	Methylprednisolone, cyclophosphamide, azathioprine	240	Hepatic enzyme increased	Severe	Temporary
				Influenza	Severe	discontinuation
				Headache	Severe
				Peripheral edema	Severe
	Neurogenic bladder	Methylprednisolone, azathioprine, IFN β-1b-E, IFN β-1a-A	730	Alopecia	Moderate	Discontinuation
	Diabetes type 1, thyroiditis	Steroids, IFN β-1a-R, Methylprednisolone, NAT	120	Asthenia	Moderate	Continuation
	No	No	75	Headache	Mild	Continuation
	No	GA	270	Hepatic enzyme increased	Mild	NA
	No	IFN β-1a-A	120	Hepatic enzyme increased	Moderate	Temporary discontinuation
	Hashimoto thyroiditis	GA, Azathioprine	547	Lymphopenia	Moderate	Continuation
	Panic attacks, hyperandrogenism, retinal detachment	No	1,460	Candidiasis	Moderate	Continuation
	No	GA	365	Leukopenia	Severe	Temporary discontinuation
	No	IFN β-1b-B	365	Hepatic enzyme increased	Moderate	Discontinuation
	No	IFN β-1a-R, NAT, IFN β-1b-B	455	Basal cell carcinoma	Moderate	Discontinuation
Teriflunomide	Autoimmune thyroiditis	IFN β-1a-A, IFN β-1a-R	510	Musculoskeletal pain	Mild	Continuation
	No	Steroids	970	Alopecia	Mild	Continuation
				Respiratory tract infection	Mild
	Neurogenic bladder, gastroduodenal ulcer	Aminopyridine, IFN β-1a-A, methylprednisolone	365	Asthenia	Severe	Continuation
				Arthralgia	Severe
				Alopecia	Severe
	Aniridia	DMF	NA	Hepatic transaminases increased	Mild	Continuation
	No	IFN β-1a-R	89	Leukopenia	Mild	Continuation
	Mixed anxiety-depressive disorder	IFN β-1a-A	540	Hypertension	Moderate	Temporary discontinuation
	No	No	35	Hepatic transaminases increased	Mild	Continuation
	Ebstein anomaly	IFN β-1a-A, IFN β-1b-B, IFN β-1a-R, NAT	30	Musculoskeletal pain	Moderate	Discontinuation
	Osgood–Schlatter disease	IFN β-1a-R	7	Hypertension	Moderate	Discontinuation
	Panic attacks	GA	10	Gastroenteritis	Moderate	Discontinuation
				Headache	Moderate
				Pain	Moderate
	Panic attacks, thyroiditis	IFN β-1a-A, IFN β-1a-R	7	Abdominal pain upper	Moderate	Continuation
				Nausea	Moderate
	Asthma, gastroesophageal reflux disease	Azathioprine, IFN β-1a-A, mitoxantrone, GA, immunoglobulins, IFN β-1b-B, NAT, FTY720	365	Alopecia	Moderate	Discontinuation
				Diarrhea	Moderate
	Depression, neonatal asphyxia, intellectual disability	IFN β-1a-A	30	Diarrhea	Mild	Continuation
	Autoimmune thyroiditis	IFN β-1a-R, GA, azathioprine	30	Alopecia	Moderate	Discontinuation
				Diarrhea	Moderate
				Weight decrease	Moderate
	No	IFN β-1a-A, IFN β-1a-R	90	Alopecia	Moderate	Continuation
	No	IFN β-1a-R, mitoxantrone, IFN β-1b-E	547	Hypertension	Moderate	Temporary discontinuation
	Disk herniation	No	60	Hypertension	Moderate	Continuation
	Anxiety, pain in extremity	GA	NA	Gastroenteritis	Moderate	Continuation
				Headache	Moderate
				Pain	Moderate
	Gastroesophageal reflux disease	GA, IFN β-1b-B	182	Hepatic transaminases increased	Severe	Discontinuation
	Autoimmune thyroiditis	Azathioprine, IFN β-1a-R	90	Hypertension	Moderate	Continuation
	No	IFN β-1b-B	16	Rash	Moderate	Discontinuation
	Diabetes type 2, thyroiditis	IFN β-1a-A	365	Gastroenteritis	Moderate	Discontinuation
	No	IFN β-1a-R, IFN β-1a-A	60	Hypertension	Moderate	Discontinuation
	No	IFN β-1a-R, mitoxantrone, GA	60	Alopecia	Mild	Continuation
	No	IFN β-1a-R, GA	60	Pancreatitis	Moderate	Temporary discontinuation
	Depression	IFN β-1b-B	730	Hypertension	Moderate	Continuation
	No	IFN β-1a-A, IFN β-1a-R, GA, azathioprine	90	Neutropenia	Moderate	Discontinuation
	No	IFN β-1a-R	365	Diarrhea	Mild	Continuation
	Autoimmune thyroiditis	IFN β-1a-R	365	Alopecia	Moderate	Continuation
				Diarrhea	Moderate
	No	IFN β-1a-A	365	Alopecia	Mild	Continuation
				Pancreatitis	Mild
	No	IFN β-1a-A, IFN β-1a-R	240	Alopecia	Mild	Continuation
	Autoimmune thyroiditis	IFN β-1a-A, GA	30	Abdominal pain upper	Mild	Continuation
	Panic attacks, thyroiditis	IFN β-1a-A, IFN β-1a-R	547	Nausea	Moderate	Discontinuation
				Abdominal pain upper	Moderate
				Diarrhea	Moderate
	No	IFN β-1a-A, IFN β-1a-R	NA	Diarrhea	Mild	Continuation
	No	IFN β-1a-A, IFN β-1a-R, GA, DMF	NA	Abdominal pain upper	Moderate	Discontinuation
				Diarrhea	Moderate
				Hepatic transaminases increased	Moderate
	No	No	912	Abdominal pain upper	Mild	Discontinuation
				Nausea	Mild
DMF	No	Steroids, IFN β-1a-A, IFN β-1a-R, GA	410	Abdominal pain upper	Mild	Continuation
				Flushing	Mild
				Pruritus	Mild
	No	GA, IFN β-1a-A, teriflunomide	210	Abdominal pain upper	Mild	Continuation
				Flushing	Mild
				Burning sensation	Mild
	No	Steroids	720	Flushing	Moderate	Temporary
				Pruritus	Moderate	discontinuation
				Hepatic transaminases increased	Moderate
	No	Methylprednisolone, IFN β-1a-A, IFN β-1a-R	900	Flushing	Mild	Continuation
				Rash	Mild
	No	No	25	Abdominal pain	Moderate	Discontinuation
				Diarrhea	Moderate
	No	IFN β-1b-B, methotrexate	450	Gastrointestinal disorder	Mild	Continuation
	Neurogenic bladder	IFN β-1a-R	180	Rash	Severe	Discontinuation
	Myastenia, meningioma	IFN β-1a-R, GA	300	Lymphopenia	Moderate	Temporary discontinuation
	No	No	420	Drug-induced liver injury	Severe	Discontinuation
	Anxiety	IFN β-1a-R	180	Diarrhea	Severe	Discontinuation
				Abdominal pain	Severe
	No	No	30	Abdominal pain	Moderate	Discontinuation
	No	IFN β-1b-B, IFN β-1a-A	30	Gastrointestinal disorder	Mild	Continuation
	Hashimoto thyroiditis	IFN β-1a-R	14	Flushing	Mild	Continuation
	No	FTY720	2	Abdominal pain	Moderate	Discontinuation
				Flushing	Moderate
	Diabetes type 2, thyroiditis	IFN β-1b-B	180	Abdominal pain	Moderate	Discontinuation
				Flushing	Moderate
	Headache, primary fibromyalgia	IFN β-1a-R, GA	60	Asthenia	Moderate	Discontinuation
	No	No	NA	Pruritus	Mild	Continuation
				Flushing	Mild
	No	IFN β-1a-R	40	Rash	Moderate	Continuation
	No	No	960	Flushing	Moderate	Continuation
	Panic attacks, claustrophobia, thyroiditis	IFN β-1a-A, IFN β-1b-B, NAT	NA	Rash	Moderate	Discontinuation
	No	GA	1,094	Flushing	Moderate	Continuation
	Depression	IFN β-1a-A, NAT	60	Pruritus	Moderate	Discontinuation
	No	IFN β-1a-R, GA	365	Flushing	Moderate	Continuation
				Nausea	Moderate
	Autoimmune thyroiditis	IFN β-1a-A	30	Gastroenteritis	Severe	Discontinuation
	No	IFN β-1a-A	NA	Flushing	Mild	Continuation
				Diarrhea	Mild
	Hypertension, epilepsy	IFN β-1a-R	30	Diarrhea	Severe	Discontinuation
	No	No	NA	Abdominal pain upper	Moderate	Continuation
				Flushing	Moderate
	Autoimmune thyroiditis	IFN β-1b-B	730	Abdominal pain upper	Mild	Continuation
	No	IFN β-1b-B	60	Gastrointestinal disorder	Moderate	Discontinuation
	Multinodular goiter	IFN β-1a-R	NA	Flushing	Mild	Continuation
				Gastrointestinal disorder	Mild
	Autoimmune thyroiditis	IFN β-1b-E	NA	Flushing	Mild	Continuation
	Hepatitis B	IFN β-1a-A, NAT	NA	Flushing	Moderate	Continuation
	Hashimoto thyroiditis, psoriasis	IFN β-1b-B, GA	60	Gastrointestinal disorder	Moderate	Discontinuation
	No	IFN β-1b-B	900	Flushing	Mild	Continuation
	No	IFN β-1a-R	240	Flushing	Moderate	Continuation
				Pruritus	Moderate
	Psoriasis	No	730	Flushing	Moderate	Continuation
	No	GA	60	Gastrointestinal disorder	Mild	Discontinuation
	No	No	420	Flushing	Mild	Continuation
				Diarrhea	Mild
	No	IFN β-1a-A, IFN β-1b-B, mitoxantrone, GA	60	Flushing	Mild	Continuation
	No	IFN β-1a-R	NA	Flushing	Mild	Continuation
				Abdominal pain	Mild
	No	IFN β-1b-B	730	Flushing	Mild	Continuation
	Hashimoto thyroiditis	IFN β-1b-B	120	Flushing	Mild	Continuation
				Abdominal pain	Mild
	Anxiety, depression	IFN β-1b-B, IFN β-1a-R, GA, teriflunomide	240	Hepatic transaminases increased	Moderate	Discontinuation
	No	IFN β-1a-A	180	Flushing	Mild	Continuation
	Thyroiditis	IFN β-1b-B, FTY720	300	Flushing	Moderate	Discontinuation
				Lymphopenia	Moderate
	Hypertension	No	180	Flushing	Mild	Continuation
	No	GA, IFN β-1a-R	60	Flushing	Mild	Continuation
				Gastrointestinal disorder	Mild
	Hypertension	No	60	Flushing	Mild	Continuation
	No	IFN β-1a-A	480	Lymphopenia	Moderate	Discontinuation
	No	IFN β-1a-R	240	Flushing	Moderate	Continuation
				Pruritus	Moderate
	No	IFN β-1b-B	NA	Flushing	Mild	Continuation
	No	IFN β-1a-A	60	Nausea	Moderate	Discontinuation
				Gastrointestinal disorder	Moderate
				Abdominal pain	Moderate
	No	IFN β-1a-R	NA	Flushing	Moderate	Continuation
				Diarrhea	Moderate
	No	No	NA	Flushing	Mild	Continuation

Abbreviations: DMF, dimethyl fumarate; FTY720, fingolimod; GA, glatiramer acetate; IFN β-1a-A, interferon β-1a Avonex^®; IFN β-1a-R, interferon β-1a Rebif^®; IFN β-1b-B, interferon β-1b Betaferon^®; IFN β-1b-E, interferon β-1b Extavia^®; NAT, natalizumab; PEG IFN β-1a, peginterferon β-1a; RR-MS, relapsing-remitting multiple sclerosis; NA, not available.

Table 3 Clinical data of RR-MS patients and adverse event characteristics for all the reported unexpected reactions

Drug	Medical history of the patient			Characteristics of the adverse event
	Concomitant diseases	Previous therapy	Number of doses	Adverse event	Severity	Action taken
IFN β-1a-A	Dyslipidemia, anxiety	Methylprednisolone	308	Erectile dysfunction	Severe	Temporary discontinuation
	No	No	4	Irritable mood	Moderate	Discontinuation
IFN β-1a-R	Wolff-Parkinson-White syndrome	No	1,251	Erectile dysfunction	Mild	Discontinuation
	No	No	1,095	Panic attacks	Moderate	Discontinuation
				Tachycardia	Moderate
	No	No	NA	Nervousness	Moderate	Discontinuation
IFN β-1b-E	No	IFN β-1a-A, IFN β-1a-R, GA	140	Rachialgia	Moderate	Discontinuation
Peginterferon β-1a	Dysthyroidism, hypertension	IFN β-1b-E, DMF, Teriflunomide	10	Unmotivated anger	Mild	Discontinuation
	No	NA	NA	Localized erythema	NA	NA
	No	DMF	2	Eyelid edema	Moderate	Discontinuation
	No	IFN β-1b-B	1	Abdominal pain	Moderate	Continuation
				Diarrhea	Moderate
				Confusional state	Moderate
	No	No	1	Oral aphthae	Mild	Continuation
GA	No	No	2,555	Vertigo	Moderate	Continuation
				Postural instability	Moderate
				Right hemiparesis	Mild
	Allergic asthma	No	2,002	Tachypnea	Severe	Continuation
	Anxiety	No	67	Panic attacks	Moderate	Continuation
	No	IFN β-1a-A, IFN β-1a-R, IFN β-1b-B	36	Panic attacks	Moderate	Discontinuation
	No	IFN β-1a-A	1,099	Panic attacks	Mild	Continuation
	No	IFN β-1a-R	940	Irritable mood	Mild	Continuation
NAT	No	GA	36	Femoral fracture	Severe	Discontinuation
	Diabetes type 1	Methylprednisolone	29	Paresthesia	Mild	Continuation
				Hyposthenia	Mild
	Mixed anxiety-depressive disorder, conversion disorder	GA	34	Bronchopneumonia	Moderate	Continuation
	No	IFN β-1b-B, GA, IFN β-1a-A	104	Cough	Mild	Continuation
	No	IFN β-1b-B	109	Diarrhea	Moderate	Continuation
	No	NA	3	Cough	Moderate	Discontinuation
Fingolimod	Depression	IFN β-1a-A, IFN β-1b-E	560	Aortic dissection leading to death	Severe	NA
	No	IFN β-1a-A	605	Warts	Severe	Discontinuation
	Hypotyroidism	Cyclophosphamide, methotrexate, mitoxantrone	1,440	Insomnia	Severe	Continuation
				Behavioral disorder	Severe
	Bronchial asthma, allergies	Methylprednisolone, IFN β-1a-A, GA, IFN β-1b-B	1,095	Pain in extremity	Moderate	Discontinuation
				Muscle spasms	Moderate
	Neurogenic bladder	Methylprednisolone, azathioprine, IFN β-1b-E, IFN β-1a-A	730	Pain in extremity	Moderate	Discontinuation
	Diabetes type 1, thyroiditis	Steroids, IFN β-1a-R, methylprednisolone, NAT	120	Arthralgia	Moderate	Continuation
				Insomnia	Moderate
	Acne	DMF	52	Acne worsening	Moderate	Continuation
	Cervical spine trauma	No	70	Chest pain	Moderate	Continuation
	No	No	75	Anxiety	Mild	Continuation
	No	IFN β-1a-A, IFN β-1a-R	60	Hypotyroidism	Moderate	Continuation
	Depression	Azathioprine, IFN β-1a-R	1,825	Bilateral ovarian carcinoma	Severe	Discontinuation
Teriflunomide	No	No	390	Depression	Moderate	Discontinuation
	Neurogenic bladder, gastroduodenal ulcer	Aminopyridine, IFN β-1a-A, methylprednisolone	365	Chest pain	Severe	Continuation
				Herpes zoster	Severe
	Ebstein anomaly	IFN β-1a-A, IFN β-1b-B, IFN β-1a-R, NAT	30	Tachycardia	Moderate	Discontinuation
	Asthma, gastroesophageal reflux disease	Azathioprine, IFN β-1a-A, mitoxantrone, GA, immunoglobulins, IFN β-1b-B, NAT, FTY720	365	Pruritus	Moderate	Discontinuation
	No	IFN β-1a-R, mitoxantrone, IFN β-1b-E	547	Tachycardia	Moderate	Temporary discontinuation
	No	IFN β-1a-A, IFN β-1a-R, NAT	60	Progressive multifocal leukoencephalopathy	Severe	Discontinuation
DMF	No	IFN β-1a-A, IFN β-1a-R	160	Thrombocytosis	Mild	Continuation
	No	IFN β-1b-B, IFN β-1a-A	900	Insomnia	Mild	Continuation
	Neurogenic bladder	IFN β-1a-R	180	Headache	Severe	Discontinuation
	Petrous apex cholesterol granuloma	IFN β-1a-R	300	Omphalitis	Moderate	Discontinuation
	Headache, primary fibromyalgia	IFN β-1a-R, GA	60	Pain	Moderate	Discontinuation
	No	No	60	Headache	Moderate	Discontinuation
				Respiratory failure	Moderate
	No	GA	1,094	Vertigo	Moderate	Continuation
				Rhinitis	Moderate
	No	IFN β-1a-R, GA	365	Dyspnea	Moderate	Continuation
				Vaginal discharge	Moderate
	Autoimmune thyroiditis	IFN β-1a-A	30	Lymphadenopathy	Severe	Discontinuation
	Hepatitis B	IFN β-1a-A, NAT	NA	Weight decrease	Moderate	Continuation
				Chest pain	Moderate
	No	IFN β-1a-R	240	Vertigo	Moderate	Continuation

Abbreviations: DMF, dimethyl fumarate; GA, glatiramer acetate; IFN β-1a-A, interferon β-1a Avonex^®; IFN β-1a-R, interferon β-1a Rebif^®; IFN β-1b-B, interferon β-1b Betaferon^®; IFN β-1b-E, interferon β-1b Extavia^®; NAT, natalizumab; RR-MS, relapsing-remitting multiple sclerosis; NA, not available.

Figure 4 (A–C) Expected adverse events divided on the bases of the severity grade.

Notes: *P<0.05. **P<0.01. ***P<0.001. ****P<0.0001.
Abbreviations: DMF, dimethyl fumarate; FTY720, fingolimod; GA, glatiramer acetate; IFN β-1a-A, interferon β-1a Avonex^®; IFN β-1a-R, interferon β-1a Rebif^®; IFN β-1b-B, interferon β-1b Betaferon^®; IFN β-1b-E, interferon β-1b Extavia^®; NAT, natalizumab; PEG IFN β-1a, peginterferon β-1a.

Figure 5 (A–C) Unexpected adverse events divided on the bases of the severity grade.

Note: *P<0.05.
Abbreviations: DMF, dimethyl fumarate; FTY720, fingolimod; GA, glatiramer acetate; IFN β-1a-A, interferon β-1a Avonex^®; IFN β-1a-R, interferon β-1a Rebif^®; IFN β-1b-B, interferon β-1b Betaferon^®; IFN β-1b-E, interferon β-1b Extavia^®; NAT, natalizumab; PEG IFN β-1a, peginterferon β-1a.

EMA European Medicines AgencyInterferon β-1a (Avonex^®) Summary of Product Characteristics Available from: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000102/WC500029425.pdfAccessed September 5, 2018

 Google Scholar

EMA European Medicines AgencyInterferon β-1a (Rebif^®) Summary of Product Characteristics Available from: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000136/WC500048681.pdfAccessed September 5, 2018

 Google Scholar

EMA European Medicines AgencyInterferon β-1b (Betaferon^®) Summary of Product Characteristics Available from: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000081/WC500053225.pdfAccessed September 5, 2018

 Google Scholar

EMA European Medicines AgencyInterferon β-1b (Extavia^®) Summary of Product Characteristics Available from: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000933/WC500034701.pdfAccessed September 5, 2018

 Google Scholar

EMA European Medicines AgencyPeginterferon β-1a (Plegridy^®) Summary of Product Characteristics Available from: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002827/WC500170302.pdfAccessed September 5, 2018

 Google Scholar

ZiemssenTSchrempfWGlatiramer acetate: mechanisms of action in multiple sclerosisInt Rev Neurobiol20077953757017531858

 PubMed Web of Science ®Google Scholar

AIFA Italian Drug AgencyGlatiramer acetato (Copaxone^®) Rias-sunto delle caratteristiche del prodotto [Glatiramer Acetate Summary of Product Characteristics] Available from: https://farmaci.agenziafarmaco.gov.it/aifa/servlet/PdfDownloadServlet?pdfFileName=footer_002351_035418_RCP.pdf&retry=0&sys=m0b1l3Accessed September 5, 2018

 Google Scholar

HutchinsonMNatalizumab: A new treatment for relapsing remitting multiple sclerosisTher Clin Risk Manag20073225926818360634

 PubMedGoogle Scholar

EMA European Medicines AgencyNatalizumab (Tysabris^®) Summary of Product Characteristics Available from: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000603/WC500044686.pdfAccessed September 5, 2018

 Google Scholar

MillerAEOral teriflunomide in the treatment of relapsing forms of multiple sclerosis: clinical evidence and long-term experienceTher Adv Neurol Disord2017101238139629204190

 PubMed Web of Science ®Google Scholar

EMA European Medicines AgencyTeriflunomide (Aubagio^®) Summary of Product Characteristics Available from: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002514/WC500148682.pdfAccessed September 5, 2018

 Google Scholar

KapposLRadueEWO’ConnorPA placebo-controlled trial of oral fingolimod in relapsing multiple sclerosisN Engl J Med2010362538740120089952

 PubMed Web of Science ®Google Scholar

EMA European Medicines AgencyFingolimod (Gilenya^®) Summary of Product Characteristics Available from: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002202/WC500104528.pdfAccessed September 5, 2018

 Google Scholar

MillsEAOgrodnikMAPlaveAMao-DraayerYEmerging Understanding of the Mechanism of Action for Dimethyl Fumarate in the Treatment of Multiple SclerosisFront Neurol20189529410647

 PubMed Web of Science ®Google Scholar

EMA European Medicines AgencyDimethyl fumarate (Tecfidera^®) Summary of Product Characteristics Available from: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002601/WC500162069.pdfAccessed September 5, 2018

 Google Scholar