One of the most prevalent and disabling signs of multiple sclerosis (MS) is fatigue, which has been linked to a lower quality of life ^[1][2][3][1,2,3]. Little is understood about the fundamental reason, despite its relevance. Numerous pharmacological and non-pharmacological modalities have been researched, but there are limited data to support their efficacy ^[4][5][4,5]. It was proposed that peripheral or central inflammation could be the root of fatigue [6].

Fatigue severity is self-reported. Over the years, several imaging biomarkers have been identified in an attempt to associate the subjective nature of fatigue with objective measures ^[7][8][9][7,8,9].

Fatigue remains a significant issue for most MS patients and along with depression is closely correlated with the quality of life in the MS patients [10]. Given that the pathophysiology of MS-related fatigue may involve neuroinflammation, it is reasonable to hypothesize that the DMTs with their well-known anti-inflammatory action may potentially ameliorate fatigue. However, it is unknown how these drugs affect fatigue because the duration of fatigue was not examined in randomized, prospective trials ^[7][8][9][7,8,9].

2. Fatigue and Rating Scales

Different scales have been used to measure fatigue severity. The modified fatigue impact scale (MFIS) is a modified version of the 40-item Fatigue Impact Scale (FIS), which was developed initially to evaluate how fatigue affects people with chronic diseases, notably MS, in terms of quality of life. A questionnaire containing 10 “physical” questions, 10 “cognitive” items, and 20 “social” items is used by FIS patients to score how much tiredness has interfered with their lives over the previous four weeks, with 0 denoting “no problem” and 4 denoting “severely affected”. Maximum score is 160 ^[1][11][1,11]. Nine “physical” items, ten “cognitive” items, and two “psycho-social” elements make up the MFIS. Higher ratings indicate a stronger influence on quality of life, with a maximum score of 84. Another scale is FSS, which was created by Krupp in 1989; it is a self-reported scale that assesses the level of fatigue. FSS contains nine items. The patient is asked to select a number between 1 and 7, where 1 denotes strong disagreement and 7 denotes strong agreement to represent how strongly the patient agrees or disagrees with each statement in each question. Severe fatigue is typically indicated by a score of 4 or higher [3]. The Fatigue Symptoms and Impacts Questionnaire–Relapsing Multiple Sclerosis (FSIQ-RMS-S) is another scale for MS fatigue severity measurement. Seven questions make up the FSIQ-RMS-S, which measures symptoms of fatigue during the preceding 24 h. Physical weakness, mental exhaustion, physical fatigue, energy, feeling worn out, feeling sleepy, and feeling worn out while at rest are the things listed. On an 11-point numerical rating scale (NRS), from 0 (no symptoms) to 10, respondents are asked to score each item (highest level of symptoms). Individual item scores are added together to produce an FSIQ-RMS-S score that ranges from 0 to 70 and is then rescaled to range from 0 to 100. More serious fatigue is indicated by a higher FSIQ-RMS-S score [12].

3. MS Therapies

The most typical technique to monitor MS disease progression is through routine clinical evaluations and MRI scans. It is crucial to keep track of these metrics in order to assess whether and how well a patient’s DMT is controlling their MS. For MS patients, a range of DMTs are currently available. The various administration methods, action and effect of different DMTs on fatigue are shown in Table 1 and Table 2.

4. Oral DMTs

4.1. Dimethyl Fumarate (Tecfidera)

Dimethyl fumarate (DMF) is an FDA-approved drug for relapsing forms of MS (RRMS, CIS and SPMS). DMF activates the erythroid-derived nuclear factor, a defense system against oxidative and inflammatory stress [59]. Several previous studies explore the effect of DMF on fatigue. A large prospective 12-month observational study (RESPOND) on 318 RRMS patients who switched from glatiramer acetate (GA) to DMF showed marked improvement in MFIS on DMF, from 10.7 (5.2) at baseline to 9.3 (5.2) after 12 months (mean change 0.83 [3.51]; p = 0.0002) [13]. A smaller prospective study of 24 month duration on 34 RRMS patients showed that at 3, 6, 12, and 24 months following DMF treatment, MFIS scores were considerably reduced (7.85 ± 12.20, p < 0.01; 7.75 ± 15.59, p < 0.01; 8.40 ± 15.55, p < 0.001; 10.25 ± 10.92, p = 0.0001) [16]. Amato et al. confirmed the previous results in reduction in MFIS score over 24 months among 165 RRM patients (least square mean (LSM) difference: −3.526, 95% CI: −4.782 to −2.271; p < 0.001) [15]. Additionally, the PROTEC study showed that 867 of 1105 RRMS patients treated with DMTs showed marked improvement in MFIS [14]. MFIS-5 remained stable over a 12-month period of DMF treatment in the ESTEEM trial involving 2025 RRMS patients [18]. In a retrospective small sample study by Pandey et al. failed to show any improvement in self-reported fatigue in DMT-treated patients especially when it co-exists with depression [19]. Comi and colleagues investigated the effect of DMF on sleep quality on 223 RRMS over 48 weeks (177 RRMS on DMF, 46 RRMS on interferon). The study explored fatigue as a secondary end point using the FSS. Despite the subjective self-reported improvement in fatigue due to significant positive effect on sleep quality, the study failed to demonstrate significant changes in fatigue, mobility or quality of life over the study duration [17].

4.2. Sphinosine-1—Phosphate Modulators

4.2.1. Fingolimod

Fingolimod is an FDA-approved DMT for CIS and RRMS also marketed as Gilenya. It has distinct immunoregulatory characteristics and affects sphingosine-1-phosphate receptors. Fingolimod stops immune cells from leaving lymphoid tissue and reaching the inflammatory tissue [60]. There are limited studies which evaluate the impact of fingolimod on fatigue. Masinque’s earlier prospective open label trial on 54 RRMS patients found no improvement in the MFIS-measured fatigue score and FSS at a 6-month interval [28]. In contrast, another study compared the effect of fingolimod with that of the injectable DMT among 1053 RRMS patients, which showed that marked improvement in FSS in the fingolimod group who received it at least 6 months after switch from injectable DMT ^[21][22][61][21,22,61]. This can be better explained by a lower mean of EDSS (2.5 versus 2.7) in Masingue’s study. The Hamburg Quality of Life Questionnaire in MS (HAQUAMS) was administered to 281 patients who were randomly assigned to take oral fingolimod (n = 188) or a placebo (n = 93). With fingolimod, the overall HAQUAMS score improved, while with placebo, it worsened. The mean score changed by 0.02 with fingolimod 1.25 mg (p < 0.05 against placebo), 0.01 with fingolimod 5.0 mg, and 0.12 with placebo from baseline to month six. Additionally, fingolimod 1.25 mg was superior to placebo in the HAQUAMS sub-domain for fatigue/thinking (p < 0.05 vs. placebo) [20]. As a side effect, all groups in FREEDOMS and TRANSFORMS experienced documented adverse events at a similar rate. Fatigue and headache were among the side effects that occurred in the fingolimod groups and affected approximately 10% of participants ^[26][27][26,27]. In another trial, 24 (19.7%) of the 122 patients receiving fingolimod had fatigue [25]. This was confirmed by another study conducted by Rojas [24] who reported that 16 patients of 145 (11%) of fingolimod-treated patients reported fatigue. The same percentage was also reported by Brown et al. [23]. More studies are needed for further exploration to identify patients whose fatigue will benefit from fingolimod versus those who will develop fatigue as a side effect.

4.2.2. Siponimod

Siponimod is also known as Mayzent, an FDA-approved medication for CIS, RRMS and SPMS. Its lipophilic nature makes it capable of crossing the blood–brain barrier and act on sphingosine-1-phosphate. There are limited data on the relation between it and fatigue. In prior research, the safety of Siponimod has been explored, namely in the EXPAND trial which included 1099 secondary progressive MS patients for more than 5 years. It showed that fatigue may be reported as a side effect of Siponimod use with an incidence rate of 6.3% compared to 6.6% in the placebo group [29]. Hoffman et al. reported that among 1500 patients treated by Siponimod, fatigue and quality of life remained stable after 12 months using MFSC and EQ-5D, respectively [30].

4.2.3. Ponesimod

Ponesimod is a highly selective modulator of sphingosine-1-phosphate receptor 1 (S1P1) with low potential for drug–drug interaction because it is an orally active drug [62]. It also has no active metabolites. Ponesimod prevents lymphocytes from leaving lymphoid organs, which causes a quick, dose-dependent, and reversible decrease in peripheral blood lymphocyte levels ^[63][64][63,64]. Ponesimod was compared with teriflunomide in phase three OPTIMUM study, which included 1133 patients with RRMS. Ponesimod was significantly superior to teriflunomide in reducing fatigue using FSIQ-RRM with a mean score of −3.57 (−0.01 vs. 3.56; p < 0.001) in the ponesimod group [31].

4.2.4. Ozanimod

Ozanimod received FDA- approval in March 2020 to treat RRMS, active SPMS, and CIS. Ozanimod is a sphingosine-1-phosphate receptor (S1PR) modulator and is marketed under the trade name ZEPOSIA. The only S1PR modulator currently approved by the US FDA that does not need genetic testing or first-dose monitoring is Ozanimod, in contrast to earlier medications in its class ^[65][66][65,66]. The first study examined ozanimod on fatigue is the OCEAN study, which is still ongoing in Germany. It aims to include 1300 RRMMS patients over 36 months. Their primary outcomes include patient satisfaction and effectiveness. As a secondary outcome, it also aims to study fatigue and quality of life using FSMC and MSQOL-54, respectively [67].

4.3. Teriflunomide (Aubagio)

The FDA has approved teriflunomide for CIS and RRMS patients. It works by inhibiting mitochondrial dihydro-orotate dehydrogenase (DHODH), which results in less pyrimidine being synthesized, which is essential for the proliferation of lymphocytes. Therefore, the absence of DHODH caused by teriflunomide limits the ability of lymphocytes to attack the neurological system. Previous studies explore its effect on fatigue. A total of 324 individuals were randomly assigned to receive IFN-1a, teriflunomide 7 mg, or teriflunomide 14 mg. FIS scores showed more prominent fatigue in the INF-1a group, though differences were only significant when compared with teriflunomide 7 mg [33]. Additionally, in Teri-Real observational study, which includes 212 patients, the overall FIS score as well as its cognitive and psychosocial components remained stable. After two years, compared to the baseline, the physical component of FIS did exhibit a statistically significant improvement (11.33 vs. 13.09) [32]. Despite having a favorable outcome, Teri-FAST, which was a 2-year, prospective, observational study over 210 patients, confirmed that fatigue remained stable with no significant improvement [35]. Data from TEMSO and TOWER showed that there is an increased fatigue rate especially with relapses leading to hospitalization [34].

4.4. Cladribine

A deoxyadenosine analogue called cladribine is phosphorylated to form human lymphocyte-specific cytotoxin 2-chlorodeoxyadenosine triphosphate ^[68][69][68,69]. A prior two-year study examined how cladribine affected quality of life using the Multiple Sclerosis Quality of Life-54 (MSQOL-54) and the EuroQol five-dimension three-level (EQ-D5-3L)18. Low-dose cladribine 3.5 mg administered to 5148 RRMS patients showed marked improvement using EQ-5D but failed to show any statistical improvement using MSQOL-54 [36]. Further research is needed to reach a definite conclusion.