Pulsed immune reconstitution therapy in multiple sclerosis

Abstract

Whereas drugs used for maintenance/escalation therapy do not maintain their beneficial effect after cessation of therapy, some new highly effective therapies can show prolonged treatment effects after a short treatment course. Such therapies have been named pulsed immune reconstitution therapies or pulsed immunosuppressive therapies, and typical representatives are alemtuzumab and cladribine. Autologous haematopoietic stem cell transplantation could be considered as the strongest immune reconstitution therapy. Both alemtuzumab and cladribine induce depletion of lymphocytes, and a common mechanism of action is preferential depletion of class-switched and unswitched memory B-cells. Whereas CD-19+ B-lymphocytes repopulate within 6 months, CD4+ T-cells repopulate at a slower rate, taking 1–2 years to reach the lower level of normal. In general, the depletion of lymphocytes is more profound and the repletion of T-cells is slower after alemtuzumab than after cladribine treatment. Both drugs have a strong effect on relapses and magnetic resonance imaging (MRI) activity, and reduce disability worsening. The therapeutic effect is maintained beyond the period of active treatment in a large proportion of patients, which is best documented for alemtuzumab. Adverse effects include reactivation of latent infections such as tuberculosis and risk of herpes zoster. The main disadvantage in alemtuzumab-treated patients is the risk of secondary immune-mediated disorders. Pulsed immune reconstitution therapy is an option as initial therapy in relapsing-remitting multiple sclerosis patients with high disease activity and in patients on treatment with another disease-modifying therapy with significant relapse and/or MRI activity.

Immune Reconstitution Therapy or Continuous Immunosuppression for the Management of Active Relapsing–Remitting Multiple Sclerosis Patients? A Narrative Review

“…The effects of aHSCT on immune cell populations appear to be more profound than those with any pharmacologic DMD [18]. However, DMDs with the characteristics of an IRT may present a more practicable alternative for most patients requiring high-efficacy therapy for MS [19][20][21]. Key therapeutic properties of these DMDs are summarized below.…”

“…Ocrelizumab is effective in RMS, achieving reductions of 46-47% in relapse rates and reduced rates of disability progression, compared with interferon-beta [9]. However, it is not known whether the efficacy of ocrelizumab outlasts the period of its administration in the manner of other treatments hypothesized to act like an IRT [19]. Reviews in this area have described ocrelizumab as an agent which ''might be either called a chronic immunosuppressive or pulsed immune reconstitution therapy'' [19] or have placed this agent in a class of its own between maintenance therapy and IRT [20].…”

Expert consensus from the Arabian Gulf on selecting disease-modifying treatment for people with multiple sclerosis according to disease activity

“…Further treatment courses of alemtuzumab beyond the initial two courses may be given if required, but there is no requirement for further treatment with cladribine tablets beyond this 2-year period, according to its labeling (see Table 1). Ocrelizumab is an antibody directed against the CD20 antigen: this mechanism is also consistent with immune reconstitution, based on observations with rituximab, which shares this mechanism [41,42]. However, the pivotal trials that evaluated ocrelizumab involved continuing, 6-monthly administration of this DMD [25,32], so that the potential for ocrelizumab as an immune reconstitution therapy has yet to be demonstrated clinically [41,42].…”

Biomarkers and Disease Activity in Multiple Sclerosis : A cohort study on patients with clinically isolated syndrome and relapsing remitting multiple sclerosis

“…However, the risks and patient discomfort related to AHSCT can be deterring. Some view alemtuzumab and cladribine as pulsed immune reconstitution therapies, since they have profound effects on lymphocyte subpopulations and can have longstanding effects on disease activity after the two initial years of pulsed treatment administration [24]. Anti-CD20 therapy results in B cell depletion and is highly effective in RRMS [25].…”