Key Summary Points
Until alternative scientific evidence becomes available, consensus from neurology experts is needed to guide clinicians on the administration and monitoring requirements of high-efficacy disease-modifying therapies for multiple sclerosis (MS) in Saudi Arabia. The study required experts to evaluate the administration and monitoring properties of disease-modifying therapies through the modified Delphi method. In the majority of cases, experts voted cladribine as the least burdensome therapy and alemtuzumab as the most burdensome. Despite the insights offered by the experts, real-world data with long-term follow-up of patients is critically needed.
| Until alternative scientific evidence becomes available, consensus from neurology experts is needed to guide clinicians on the administration and monitoring requirements of high-efficacy disease-modifying therapies for multiple sclerosis (MS) in Saudi Arabia. |
| The study required experts to evaluate the administration and monitoring properties of disease-modifying therapies through the modified Delphi method. |
| In the majority of cases, experts voted cladribine as the least burdensome therapy and alemtuzumab as the most burdensome. |
| Despite the insights offered by the experts, real-world data with long-term follow-up of patients is critically needed. |
Introduction
Clinical management of multiple sclerosis (MS), an inflammatory demyelinating and neurodegenerative disease, is highly challenging as a result of its long-term course and uncertain prognosis [ 1 , 2 ]. Therefore, periodic review of the literature is important to develop guidance on the appropriate use of various disease-modifying treatments [ 3 ]. Fortunately, the increasing number of available high-efficacy disease-modifying therapies (HE DMTs) has contributed to a reduction in the number of MS-associated relapses [ 4 , 5 ]. Consequently, neurological disability and radiological activity are found to be lower owing to available HE DMTs [ 6 – 8 ]. According to the efficacy of an individual, DMTs are typically grouped into moderate-efficacy (ME) DMTs and HE DMTs. Many authors classify ozanimod, siponimod, ofatumumab, cladribine, alemtuzumab, natalizumab, ocrelizumab, and fingolimod as HE DMTs [ 5 , 8 – 12 ]. Although in recent decades the treatment landscape for MS has changed with a rise in the number of HE DMTs, this also poses a challenge with varied administration and monitoring requirements [ 8 , 13 , 14 ]. While DMTs have been reported to improve the outcomes of patients with MS [ 10 , 15 ], the administration and monitoring burden of DMTs used for MS cannot be overlooked [ 16 ]. Healthcare professionals face the challenge of available HE DMTs with numerous administration and monitoring requirements, thus stretching their capacity [ 4 , 17 ]. Thus, to make evidence-based decisions for patients, awareness of different administration routes and modes of action along with the risk profile of each patient is needed [ 18 ]. The benefit–risk profile of each patient with MS influences the choice of their initial and follow-up therapies [ 18 ].
In addition, some of the challenges that may complicate the decision-making process include the dearth of predictive markers of therapeutic response to make decisions regarding DMT selection. Besides, current recommendations and treatment guidelines lack sufficient information regarding the best practice for switching between DMTs [ 9 – 11 , 19 – 21 ]. In addition, given the high variability in MS management approaches, evidence-based medicine may not always be sufficient to address the day-to-day management issues. Also, lack of high-quality evidence concerning certain aspects of the administration and monitoring burden of HE DMTs has led to variability in practice among neurologists treating MS. Given these challenges in the therapeutic management of MS, we carried out a consensus project to address two important aims in this field. The first was to establish consensus regarding the administration and monitoring burden of HE DMTs used for MS in Saudi Arabia. The second was to gather expert advice on the current clinical practice regarding the early use of cladribine tablets. Cladribine was selected for further discussion because, following its recent registration with the Saudi Food and Drug Administration in 2021, there remains a clinical practice gap among neurologists in Saudi Arabia regarding its use as a result of the scarcity of real-world evidence. We also assessed the relevance of the available data on early treatment with cladribine tablets and how these data resonate with the update of the Saudi consensus and ECTRIMS-EAN guidelines on the early use of HE treatments for MS [ 10 , 22 ]. This paper highlights the significance of considering the monitoring and administration burden associated with treatment as part of the clinical decision-making process. However, it is important to emphasize that these factors should not take precedence over the medication’s safety and efficacy profiles when selecting the best treatment for patients with MS.
Methods
A Two-Round Modified Delphi Technique
Between January and March 2023, we utilized the Delphi technique, an iterative process of repeated voting rounds, to establish a consensus between experts in treating and managing MS. The Delphi method is a reliable method for determining consensus between experts for an important clinical problem for which there is a dearth of evidence, to facilitate decision-making for healthcare professionals on the basis of the opinions of experienced clinicians [ 23 ]. For the current consensus project, we employed a two-round modified Delphi technique. During the first step, we used published literature to develop a questionnaire (details are below) that was distributed to a group of eight experts with clinical expertise in treating and managing MS. The experts were asked to evaluate a list of 17 properties related to the administration and monitoring burden of six individual HE DMTs on the basis of their clinical experience.
The experts were required to rank each property on a scale of 1–5, with 1 being the lowest burden and 5 being the highest burden. The panelists, who are all authors of this manuscript, ranked each property independently without any influence from other members of the group. This was followed by the first agreement voting round where the experts were asked to rate their agreement on the average scores presented for every individual DMT against each property. During the first agreement voting round, advisors were asked to rate their agreement on each generated score using a questionnaire. They selected a score on a continuous scale from 0 to 100, with 0 expressing complete disagreement and 100 expressing complete agreement. Accordingly, items of non-consensus were identified and discussed by the experts. This was followed by a second round of scoring using the same questionnaire and a comparison of the results of round 1 and round 2. Finally, the panel of experts discussed and voted by a show of hands to reach a final consensus. Attending advisors also commented on their experiences with the early use of cladribine tablets in practice in terms of monitoring burden for both the physician and the patient as well as observed clinical outcomes.
The panelists were healthcare providers from Saudi Arabia who are very experienced in the management of MS in various healthcare settings. They were recruited from different regions of Saudi Arabia and were identified on the basis of their clinical expertise in the treatment and management of MS.
This study did not involve human participants, human data, or human material; thus, ethics committee approval was not required.
Before the meeting, a questionnaire was developed using published literature and shared with all eight advisors selected as experts for the board meeting. The questionnaire included questions about the following properties of six selected MS DMTs: 1. administration burden; 2. monitoring burden; and 3. overall burden (Table 1 ). The average scores per property per DMT were discussed for each of the six HE DMTs including ofatumumab, cladribine, alemtuzumab, natalizumab, ocrelizumab, and fingolimod. The last of these was selected among other sphingosine-1-phosphate (S1P) modulators because it was the first oral medication approved for the treatment of relapsing–remitting MS, and consultants in Saudi Arabia are more familiar with it in clinical practice. The properties for each of the therapies mentioned above that were scored are shown in Table 1 . Advisors were asked to score each DMT property on a scale from 1 to 5 on the basis of their clinical experience and scientific knowledge. Consensus was defined as having at least 75% agreement among the advisors on the scores generated for each DMT property. The questionnaire was completed by eight out of the nine physicians in the task force of selected experts. Table 1 Administration and monitoring burden properties Administration burden 1 Precautions required during administration 2 Hospital visit time and facility use during administration 3 Time required for administration 4 Monitoring time required following administration 5 Route of administration 6 Medication preparation (mixing) Monitoring burden 7 Monitoring for specific side effects 8 Time required for monitoring 9 Frequency of follow-up visits required over the course of treatment 10 Number of laboratory tests required at baseline 11 Frequency of laboratory tests required at follow-up 12 Washout period for switching DMTs 13 Extensiveness of patient education 14 Frequency of communication with patients 15 Frequency of dosage/administration Overall, burden 16 Total time required for both administration and monitoring 17 Overall monitoring burden
Table 1
Administration and monitoring burden properties
| Administration burden | 1 Precautions required during administration |
| 2 Hospital visit time and facility use during administration | |
| 3 Time required for administration | |
| 4 Monitoring time required following administration | |
| 5 Route of administration | |
| 6 Medication preparation (mixing) | |
| Monitoring burden | 7 Monitoring for specific side effects |
| 8 Time required for monitoring | |
| 9 Frequency of follow-up visits required over the course of treatment | |
| 10 Number of laboratory tests required at baseline | |
| 11 Frequency of laboratory tests required at follow-up | |
| 12 Washout period for switching DMTs | |
| 13 Extensiveness of patient education | |
| 14 Frequency of communication with patients | |
| 15 Frequency of dosage/administration | |
| Overall, burden | 16 Total time required for both administration and monitoring |
| 17 Overall monitoring burden |
Analytic Plan
The answers were collected and the average score per property per DMT was calculated. For each question, a consensus threshold of at least 75% was specified a priori among experts at the board meeting. The results from the two voting rounds were consolidated into a single consensus document.
Results
Ranking of Six DMTs Based on Burden Score
Table 2 demonstrates the ranking of the six DMTs for each of the properties. The results of the average scores per DMT per property and the respective rankings of the DMTs for each of the properties from least burdensome to most burdensome are shown. Table 2 Ranking of DMTs based on burden score from lowest to highest burden (1–6)
Table 2
Ranking of DMTs based on burden score from lowest to highest burden (1–6)
Properties and DMTs with Non-consensus
In this section, we present the points discussed by experts concerning the ratings of DMT properties that failed to achieve 75% agreement during the first round of voting.
Consensus on Administration Burden Properties of DMTs
There was general agreement among the advisors on the scores of the administration burden properties for the DMTs, except for hospital visit time and facility use during administration (property 2) for ofatumumab, and the route of administration (property 5) for fingolimod. The details on these two properties are given below.
Property 2: Hospital Visit Time and Facility Use During Administration
Concerning the hospital visit time and facility use during administration, there was general agreement between advisors on the burden related to the frequency of laboratory tests required at follow-up for ofatumumab, which is higher than expected (2.5); hence there was disagreement on the score. Experts agreed that ofatumumab’s burden should be lower than that of fingolimod, whose visit time is 6 h in 1 year. There was agreement that ofatumumab’s score should be comparable to that of cladribine. Similar to cladribine, one of the experts believed the first dose of ofatumumab can be given at home or the hospital, but education is typically required, which should significantly lower its administration burden.
Property 5: Route of Administration
There was disagreement on fingolimod’s oral route of administration’s score being 3. According to one expert, some advisors considered other components such as safety concerns related to the risk of infection and malignancy while scoring during the first round.
Consensus on Monitoring Burden Properties of DMTs
There was general agreement among the experts on the scores of the monitoring burden properties for the DMTs, except for the monitoring of specific side effects (property 7), frequency of lab tests required at follow-up (property 11), and the washout period (property 12) for switching DMTs for natalizumab. Details of the disagreement on these three properties are given below.
Property 7: Monitoring of Specific Side Effects
There was no consensus on natalizumab’s score being 2.87. Experts discussed the burden of monitoring side effects associated with natalizumab. More precisely, two experts considered monitoring John Cunningham virus (JCV) to be of high burden since it requires much effort to do so because of logistic difficulties in Saudi Arabia. They found monitoring JCV to be burdensome in the private sector and believed disagreement stems from variations in practice among the advisors. On the contrary, three experts from the panel pointed out that JCV is the only biomarker for safety required in the monitoring of side effects for natalizumab. Hence, they considered JCV monitoring as an advantage rather than a burden, especially in comparison with other drugs that require regular follow-up of lymphocytes and immunoglobulins. JCV was considered a simple test, which is usually handled by the nurses, but the difficulty remains in the setup. Panelists who believed that JCV testing is burdensome acknowledged that although it is done only twice yearly, logistic issues are significant enough to make these two testing occasions quite cumbersome. In contrast, lab tests for patients on ocrelizumab—such as complete blood count (CBC) and liver function tests (LFTs)—are more frequent but easier to order.
Property 11: Frequency of Lab Tests Required at Follow-up
There was disagreement on the score of 2.75 for natalizumab. One expert drew the advisors’ attention to the fact that there are variations in clinical practice in terms of frequency of monitoring. For instance, he mentioned testing patients for natalizumab every 3 months (CBC and LFTs) because there are few case reports of hepatitis in patients treated with natalizumab until a few years following treatment [ 24 ]. In contrast, some of the expert’s colleagues order tests for follow-up much less frequently, and he believed this is due to varied practices among different clinical centers. Another expert pointed out that if tests are done every 6 months, the burden of natalizumab should not be much higher than that of ocrelizumab. A different expert commented that the risk of monitoring JCV is not the same as with B cell therapies; scores of ofatumumab and ocrelizumab should be almost equal (as they are) and this demonstrates a consensus among advisors about B cell therapies in general. As for the testing in natalizumab, it was brought to light that it may not be about the availability of testing but rather about the risk of monitoring JCV.
Property 12: Washout Period for Switching DMTs
There was no consensus on natalizumab’s burden being scored as 3.12. One expert highlighted that the degree of burden may differ depending on the motivation for switching DMTs; One expert thought it was burdensome to switch a patient from fingolimod or natalizumab regardless of the reason, because of the high risk of rebound. Another opinion was that it would be an issue to switch to higher DMTs whether for efficacy or side effects for both fingolimod and natalizumab. Fingolimod may have the highest burden because its washout period rebound is faster than that of other DMTs and the rebound may occur within 1–2 months. It was also discussed that natalizumab could have a slightly higher burden than reflected in the votes because of its higher risk of rebound. However, it would still be lower than fingolimod in its burden given that it may take around 3–4 months to rebound, so there would be more time for the clinician to switch therapies. Moreover, there was no burden of monitoring the lymphocyte count, as in the case of fingolimod, and this meant clinicians could switch DMTs faster. If the clinician managed to switch therapies within 1 month, it should be reasonable.
One expert expressed concern regarding “anti-trafficking medications”, fingolimod and natalizumab; One must monitor the cell count and if the patient on fingolimod develops failure, waiting may not be necessary despite a low cell count as it is usually benign. In contrast, with dimethyl fumarate, lymphopenia may last months or years and may also cause complications [ 25 ]. Another expert believed that the issue with fingolimod is not the low cell count but rather the risk of rebound and the timeline [ 26 ]. Moreover, in the case of natalizumab, there is the issue of positive JCV prompting the clinician to stop therapy and carry out an MRI and possibly a lumbar puncture to exclude asymptomatic progressive multifocal leukoencephalopathy (PML). There are studies suggesting carrying out periodic MRIs every 3 months, and this also contributes to a significant burden, even in comparison to alemtuzumab and B cell therapies [ 27 ]. According to one expert, the difference in burden between alemtuzumab and natalizumab is not very clear. The lack of clear guidelines regarding this issue may explain the limitations related to decision-making for switching.
Consensus on the Overall Burden of DMTs
There was general agreement among the advisors on the scores of the monitoring burden for the DMTs, except for the overall monitoring burden of natalizumab. With no consensus on natalizumab obtaining a score of 3.07 regarding the overall monitoring burden, a decision was made to present all burden-related information for the DMTs discussed throughout the session. This included showing the advisors the process of extracting the properties and characteristics related to the burden of each of the DMTs. The indications of each DMT were extracted from the European Medicines Agency or the US Food and Drug Administration. This also applied to other information such as the route of administration, the dosing, the screenings required before administration, and the monitoring requirements for the DMT once treatment starts.
Early Treatment of MS with High-Efficacy Therapies
The long-term benefits of early treatment initiation are increasingly evident in the literature [ 28 ]. In the BENEFIT study, EDSS progression was found to take a significantly longer time in patients on early treatment with interferon beta-1b than those on delayed treatment with a reduced risk of progression of 40% [ 29 ]. Additionally, the rate of progression to clinically definite MS was significantly lower in the early treatment initiation group at 5 years of follow-up [ 30 ].
Similarly, He et al. [ 31 ] highlighted that when a HE DMT was started early (0–2 years), the risk of disability progression was lower than if it was started later (4–6 years). Patients who received early treatment with HE DMTs had lower EDSS scores than those who received late treatment [ 31 ]. According to the study by De Stefano et al. [ 32 ], treatment with cladribine tablets significantly reduced T2 lesions and enhancing lesions on MRI starting in month 2 and continuing through all subsequent follow-up visits (months 2, 3, 4, 5, 6, 12, 15, 18, and 24). Likewise, in another study by Signori et al. [ 33 ], those who are using cladribine tablets early in the disease course showed higher improvement in their disabilities.
Disease-Modifying Therapies and MS
Major Reasons for Treatment Discontinuation
The experts highlighted that data from five major MS registries including the Danish MS registry, Italian MS registry, OFSEP (French) registry, Swedish MS registry, and MSBase (international) database suggest that lack of efficacy, safety, and tolerability issues with treatment are reported to be major reasons to discontinue the treatment.
Maintenance and Immune Reconstitution Therapies
Regarding maintenance therapies, our experts recommended continuing therapy to retain clinical efficacy. For immune reconstitution therapies, it was suggested that patients should take short courses of therapy followed by an extended period where further treatment is not necessary. The experts highlighted risks associated with maintenance therapies such as immunosuppression followed by risk of infection. In addition, some DMTs influence the ability of patients with MS to trigger an adequate antibody response following immunization [ 34 ]. Besides, age-related comorbidities might worsen the patient’s prognosis with subsequent treatment challenges.
Clinical Experience with Early Use of Cladribine Tablets: Expert Opinions
Cladribine tablets are linked to a very mild decline in T and B cells, and their progressive repopulation. Theoretically, immune reconstitution therapy such as cladribine does not permanently suppress the immune system and may avoid some dangers related to permanent immune cell suppression [ 35 ]. Although safety concerns, such as an elevated risk of infection, may still be present during the reduction phase of immune reconstitution therapy, one would anticipate that these issues would diminish as immune cells repopulate. Our experts suggested that cladribine can be given on the basis of patient-related factors such as busy lifestyle, poor access, bad track record of compliance, switching medications, patients who want an exit from therapy such as those in their 50s, male patients, and those who do not require DMT for a few years. One expert highlighted that after following patients on cladribine for the past 16 years, depression became less severe; most of the patients relapsed after 5 years, and some relapsed after 10 years. The ease of administration and the number of follow-up appointments are two main reasons to select cladribine. When compared to current issues with follow-up, dosing, planning, and renewal, cladribine will make a difference especially when a clinician treats many patients. Prescribing cladribine will reduce the timing burden on clinics and hospitals while maintaining or improving efficacy. Another expert shared his experience with 30 patients who received cladribine in Canada and were monitored for 1–2 years. Excellent outcomes in terms of compliance and illness control were observed. Another expert observed changes in EDSS, quality of life, spasticity, lesion size, and infections with cladribine. It was also suggested not to limit cladribine to patients with highly aggressive MS and to rather recommend it as a first-line DMT for early MS.
Switching to Cladribine Therapy: Expert Opinions
One expert mentioned that switching to cladribine from fingolimod can be considered because cladribine is an effective medication. It was also stated that it may be simpler to switch to cladribine than to any other drug, especially for people who failed fingolimod and those who are JCV positive. Another expert endorsed the same and mentioned that GLIMPSE (MSBase registry) data suggests that cladribine is superior to fingolimod [ 36 ]. Switching to cladribine for progressive rather than relapsing conditions may be preferable because many patients dislike discussing the unpredictability of monitoring and follow-up. Another expert also considered cladribine to possess a higher efficacy as compared to fingolimod. However, one should exercise caution regarding prescribing cladribine for young patients and those with a high disease burden as they may require further therapies; young patients will likely need more than two cycles, which may compromise their immune system with multiple DMTs. Two patients aged less than 28 years and treated by that expert were switched to cladribine (one from fingolimod and another from teriflunomide) and yet continued to experience disease activity. One expert stated the limitation with GLIMPSE (MSBase registry); although the findings are encouraging, treatment comparisons only included cladribine, fingolimod, teriflunomide, and dimethyl fumarate and did not include other important drugs such as natalizumab.
Challenges with the Use of Cladribine: Expert Opinions
Our experts discussed issues encountered when using cladribine. Some outbreaks of zoster virus (shingles) have been reported following cladribine, which warrants vaccination against shingles [ 37 ]. In addition, patients taking cladribine with mild transient lymphopenia have a low risk of infection, but those with severe lymphopenia have a higher risk of infection (less than 1% of patients experience grade 4 lymphopenia) [ 38 ]. It is expected that in most cases, the lymphocyte count will return to normal or to grade 1 lymphopenia [ 38 ]. Side effects most commonly encountered include fever, flu-like symptoms, or fatigue, but the patient usually recovers quickly, and skin reaction, which improves with time but leaves some scarring (self-limited itchiness and redness not requiring treatment). One study showed that 32% of patients have variable skin lesions and warrant thorough monitoring [ 39 ]. One expert’s patient experienced significant weakness during the early stages of the disease (just after the second month of therapy), but then she recovered. In month 8, another patient experienced a relapse (optic neuritis which may be a pseudo relapse but then she had decreased vision). Also, a patient who was transitioning from natalizumab (due to frequent pricking and infusions) had three severe relapses and eventually became wheelchair-bound because of dose delay. One expert mentioned that it is preferable to give B cell therapy or natalizumab to a patient with a highly aggressive disease. One important challenge regarding prescribing such therapies in the private sector is the elevated cost, which increases the risk of having claims being denied by insurance companies. Additionally, caution should be exercised with female patients of child-bearing age planning to conceive.
Round 1 vs Round 2 Results for Non-consensus Items
After discussion about the non-consensus items, experts voted during the second round. The scores from rounds 1 and 2 are shown in Table 3 . The results of round 2 reveal that following the discussion between experts based on the results of round 1, a consensus was reached between experts on all properties of HE DMTs during round 2. Table 3 Round 1 vs round 2 results for non-consensus items Property DMT Score Round 1 (%) Round 2 (%) Hospital visit time and facility use during administration Ofatumumab 2.5 74 100 Route of administration Fingolimod 3 70 75 Monitoring of specific side effects Natalizumab 2.87 74.5 75 Frequency of lab tests required at follow-up Natalizumab 2.75 69.4 100 Washout period for switching DMTs Natalizumab 3.12 70.5 75 Overall monitoring burden Natalizumab 3.07 73.88 87.5 DMTs disease-modifying therapies
Table 3
Round 1 vs round 2 results for non-consensus items
DMTs disease-modifying therapies
| Property | DMT | Score | Round 1 (%) | Round 2 (%) |
| Hospital visit time and facility use during administration | Ofatumumab | 2.5 | 74 | 100 |
| Route of administration | Fingolimod | 3 | 70 | 75 |
| Monitoring of specific side effects | Natalizumab | 2.87 | 74.5 | 75 |
| Frequency of lab tests required at follow-up | Natalizumab | 2.75 | 69.4 | 100 |
| Washout period for switching DMTs | Natalizumab | 3.12 | 70.5 | 75 |
| Overall monitoring burden | Natalizumab | 3.07 | 73.88 | 87.5 |
Discussion
The increase in HE DMTs brings challenges for clinicians in making complicated decisions regarding the management of MS, especially with administration and monitoring burden. Eight clinical specialists’ comments on the administration and monitoring burden of HE DMT are compiled here, with a particular focus on cladribine. Cladribine, immune reconstitution therapy, was deemed by the experts to have the least amount of monitoring required overall, followed by ofatumumab and ocrelizumab. Both fingolimod and natalizumab were assigned the same rating of fourth lowest burden. Alemtuzumab, on the other hand, was thought to carry the greatest burden.
The experts’ discussion regarding cladribine having the lowest monitoring and administration burden is supported by a group of experts from France and existing published literature. For instance, a group of neurology experts from France in 2024 reported that the use of cladribine beyond its initial courses of treatment will maximize the advantages of cladribine, mainly during the initial course of MS when the clinical priority is to suppress focal inflammation in the central nervous system to limit the progression of MS [ 40 ]. Similarly, a study by Butzkueven et al. [ 41 ], comparing treatment patterns and clinical outcomes in patients with MS newly treated with cladribine tablets versus other drugs—dimethyl fumarate, fingolimod, and teriflunomide—in the real world, showed that patients who receive cladribine tablets have significantly lower relapse rates and a delayed time for their first relapse. Also, the treatment of patients on cladribine lasted longer than patients on other oral DMTs that are typically provided early in the course of the illness [ 41 ]. In addition, findings from a clinical review by Giovannoni and Mathews [ 42 ] suggest that a lower monitoring burden of cladribine over other DMTs is attributed to two weekly treatment courses, with each course consisting of two treatment weeks in years 1 and 2.
The post hoc analyses of important clinical trials have also provided additional insights into the benefits of cladribine for MS. For instance, findings from the CLARITY Extension trial suggest that after 2 years of placebo following 2 years of treatment, 75% of the patients remained relapse-free in the absence of treatment after years 1 and 2 [ 43 ]. Besides, the results suggest that patients on cladribine versus placebo had a significantly lower risk of all types of relapses [ 43 ]. These results endorse the notion that the effect of cladribine in decreasing the frequency and severity of relapses is sustained without any additional management [ 32 ]. Given the high importance of real-world data from varying clinical settings on the safety and effectiveness of cladribine for MS, a myriad of studies are being conducted across the globe. The data from existing real-world studies, albeit mainly in European countries and the USA, have shown consistent results in terms of safety and efficacy outcomes compared with the earlier randomized controlled trials [ 44 – 51 ]. Yet, there is a lack of data from larger populations and longer follow-up periods to confirm the long-term benefits of cladribine.
However, one expert highlighted the cost of the medication as the main challenge with cladribine because patients’ claims are denied by insurance. While the cost associated with cladribine may be a challenge, the literature suggests that compared to other DMTs such as natalizumab, cladribine yielded higher quality of life years and lower costs [ 52 ]. For example, a 5-year cohort-based cost-effectiveness Markov model reported by Ayati et al. in 2021 suggests that compared to natalizumab, cladribine appears to save US $6607 with a gain on 0.003 additional quality of life year per patient [ 52 ]. Another challenge highlighted by the experts is the side effects of cladribine such as infections, fatigue, skin-related lesions, and lymphopenia. A retrospective observational multicenter study by Adamec et al. [ 45 ] from five European countries also reported the aforementioned side effects in their population. The authors found lymphopenia in 54.7% and 35% of the patients at 2 and 6 months, respectively [ 45 ]. The findings are further supported by a monocentric observational real-world study in Italy by Zanetta et al., where authors found grade 1 lymphopenia at 3 and 15 months [ 46 ]. Another safety and effectiveness single-center cohort study by Aerts et al. suggests that about 65% of the patients on cladribine reported to have fatigue and 38.6% were found to have skin-related problems [ 44 ].
Strengths and Limitations
The recommendations made in the consensus project provide useful insights into the challenges associated with monitoring and administration of HE DMTs. These recommendations can offer a framework or pathway to consider while prescribing HE DMTs to patients with MS. These recommendations may be useful, especially in the absence of available published literature related to administration and monitoring challenges with HE DMTs. However, they should be considered in the light of some limitations. First, the recommendations are based on expert opinions rather than established evidence from robust epidemiological studies. Besides, the recommendations reflect the clinical experience of expert clinicians in Saudi Arabia that is not endorsed by scientific societies or published data. Hence, they do not take into account individual patients’ characteristics such as age, gender, comorbidities, and clinical profile. Also, the content of this article is based on clinical experience from a group of experts based only in Saudi Arabia. Hence, it would be important to have opinions from experts from diverse countries to have an unbiased view related to the administration and monitoring burden of HE DMTs. While we acknowledge the limitations of the current consensus project, the agreement of the experts on many properties may address several difficulties faced by clinicians related to the administration and monitoring burden of HE DMTs used to treat MS.
Conclusion
Expert consensus in the context of the lack of alternative scientific data offer valuable insights into the administration and monitoring burden of highly effective disease-modifying therapies used for MS. While in most cases experts considered cladribine to be the least burdensome and alemtuzumab to be the most burdensome, more evidence-based real-world data with long-term follow-up of patients is required to assess sustainable beneficial effects of cladribine for patients with MS.
Acknowledgements
We wish to express our gratitude to Merck for their logistical support in facilitating the in-person meeting.
Medical Writing and Editorial Assistance
The authors would like to extend their thanks to Itkan Health Consulting Group for providing support in medical writing, funded by Merck Serono Middle East FZ-Ltd, an affiliate of Merck KGaA, Darmstadt, Germany. During the preparation of this work, the authors also used ChatGPT to improve word choice. After using this tool, the authors reviewed and edited the content as needed and take full responsibility for the content of the published article.
Author Contributions
Conceptualization: Seraj Makkawi, Mohammed Al Jumah, Ahmed Elboghdady, Lynn AlHajjar, Sahar Shami; methodology: Seraj Makkawi, Mohammed Al Jumah, Sahar Shami, Ahmed Elboghdady, Lynn AlHajjar; generation of expert recommendations: Seraj Makkawi, Ahmad Abulaban, Yaser Al Malik, Ibtisam Al Shehri, Ahmed Althobaiti, Salman Aljarallah, Saeed Bohlega, Mohammed Al Jumah; writing—original draft preparation: Seraj Makkawi, Lynn AlHajjar, Sahar Shami, Mohammed Al Jumah; writing—review and editing: Seraj Makkawi, Ahmad Abulaban, Yaser Al Malik, Ibtisam Al Shehri, Ahmed Althobaiti, Salman Aljarallah, Saeed Bohlega, Lynn AlHajjar, Sahar Shami, Mohammed Al Jumah; funding acquisition: Mohammed Al Jumah, Ahmed Elboghdady; supervision: Seraj Makkawi, Mohammed Al Jumah, Ahmed Elboghdady.
Funding
All authors participated in the closed meeting that gave rise to this article, organized and supported by Merck Serono Middle East FZ-Ltd, an affiliate of Merck KGaA, Darmstadt, Germany. The Rapid Service Fee was funded by the authors and Merck Sorono Middle East FZ-Ltd funded the workshop logistics.
Data Availability
Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.
Declarations
Conflict of Interest
Seraj Makkawi received an honorarium for attending the advisory board meeting on which this article is based. Also, he reports personal fees from Roche, Merck, Novartis, Sanofi Genzyme, Biogen, Janssen, Biologix, AstraZeneca, and Horizon Therapeutics outside the submitted work. Salman Aljarallah received an honorarium for attending the advisory board meeting on which this article is based. Also, he reports receiving speaker and consultation fees from Roche, Merck, Novartis, Sanofi Genzyme, Biogen, Janssen, Biologix, AstraZeneca, and Horizon Therapeutics outside the submitted work. All authors participated in the closed meeting that gave rise to this article, which was organized and supported by Merck Serono Middle East FZ-Ltd.
Ethical Approval
The study did not involve human participants, human data, or human material; thus, ethics committee approval was not required. The panelists were all authors of this paper.
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