Influence of personalized extended interval dosing on the natalizumab wearing-off effect - a sub-study of the NEXT-MS trial.

BACKGROUND AND OBJECTIVES: Wearing-off symptoms during natalizumab treatment in multiple sclerosis are characterized by an increase of MS-related symptoms prior to natalizumab administration. The influence of extended interval dosing (EID) on wearing-off symptoms are important to consider, as this might cause hesitancy in initiating or continuing EID. METHODS: Participants of the NEXT-MS trial, in which treatment intervals are adjusted based on drug concentrations, were divided into two groups: an extended group containing participants with at least one week of additional interval extension, and a group with a fixed interval during the trial (range 4-7 weeks). Changes in the occurrence, frequency, onset, and severity of wearing-off symptoms were evaluated. RESULTS: 255 participants were included (extended group n = 171, fixed group n = 84). The odds on occurrence of wearing-off symptoms in the extended group did not increase after extending the treatment interval. Additional analyses for frequency, onset, and severity of wearing-off symptoms showed no changes over time. Mean decrease in natalizumab drug concentration did not influence the frequency of wearing-off symptoms. DISCUSSION: Wearing-off symptoms were not reinforced by further extending the natalizumab interval. Wearing-off symptoms might increase in a minority of patients after EID, although our data support the view that wearing-off symptoms appear to be unrelated to the decrease in natalizumab trough drug concentrations.

Decrease of natalizumab drug levels after switching from intravenous to subcutaneous administration in patients with multiple sclerosis.

BACKGROUND: Natalizumab is effective in the treatment of multiple sclerosis (MS). In 2021, the European Medicines Agency approved the subcutaneous (SC) variant of natalizumab which can be used instead of intravenous administration. However, the course of drug levels varies between administration routes, and the Food and Drug Administration rejected the request for approval of natalizumab SC for reasons that were not disclosed. Our objective was to evaluate the course of natalizumab trough drug levels in patients who switched from natalizumab intravenous to SC on various treatment intervals. METHODS: The NEXT-MS trial (N=382) investigates personalised treatment of natalizumab, in which infusion intervals are prolonged based on individual natalizumab trough drug levels. In 2021, an amendment was approved allowing participants to switch from intravenous to SC administration with frequent measurements of natalizumab drug levels and antidrug antibodies (ADAs). Results were compared with linear mixed model analyses. RESULTS: Until December 2022, 15 participants switched to SC natalizumab. Natalizumab drug levels with SC administration were on average 55% lower compared with intravenous administration (Exp (estimate) 0.45, 95% CI 0.39 to 0.53, p<0.001), leading to very low trough drug levels in three patients on extended treatment intervals. No natalizumab ADAs were detected during intravenous or SC treatment. None of the participants on natalizumab SC showed evidence of MS disease activity. CONCLUSIONS: Natalizumab trough drug levels can decrease after switching from natalizumab intravenous to SC administration. We advise to monitor trough drug levels in patients with low natalizumab drug levels during intravenous treatment, patients with higher body mass index or patients on extended treatment intervals who switch to SC administration of natalizumab.

Regional specific changes of cerebral metabolism in systemic lupus erythematosus identified by positron emission tomography.

In order to test the hypothesis whether the pathogenesis of cerebral systemic lupus erythematosus (SLE) may include an immune-mediated deficit in specific vulnerable brain regions, the regional cerebral metabolism in 9 patients with diffuse as well as focal cerebral symptoms was compared with that of 10 age-matched control subjects. The cerebral distribution of 2-[18F]fluoro-2-deoxy-D-glucose (FDG) uptake was measured by means of positron emission tomography. Subsequently performed statistical parametric mapping showed (i) a relative increase in metabolism in the striatum and (ii) regional decreases in the premotor cortex as a common feature in the patient group. Region of interest measurements of absolute FDG uptake confirmed these findings. The increased striatal activity may support the presence of a direct immune response against neuronal tissue in SLE, similar to the cross-reaction against inhibitory components in striatal tissue provoked by streptococcal antigens.

An unusual cause of neonatal seizures in a newborn infant.

Neonatal seizures in the neonatal period are symptoms of numerous underlying disorders of the neonate. We present a case in which neonatal seizures due to cerebral infarction led to a diagnosis in the mother. Neonatal convulsions caused by cerebral artery thrombosis is relatively rare in the neonatal period and is often secondary to indwelling intravascular catheters that cause thromboembolism, but may be associated with many conditions.1 Cerebral artery thrombosis in newborns, in which antiphospholipid antibodies (APA) were found in the mother, has been described in three case reports. Two of these premature infants were born with other risk factors for thrombosis. APA could not be identified in any of these three infants. In the two cases reported by Silver et al the diagnosis was made several months after birth. This case is unique in the fact that no other risk factors for thrombosis could be identified to explain the infarction, and that APA were found in the offspring of an apparently healthy mother. Whether the prior fetal death was caused by APA remains unclear. The finding of lupus anticoagulant in her child led to the diagnosis of antiphospholipid antibody syndrome in her. We believe that in case of cerebral artery thrombosis in a neonate, with no trivial cause such as an indwelling catheter or sepsis, both mother and infant should be tested for presence of APA, even when the mother seems healthy.

Tuberculous meningitis in native Dutch children: a report of four cases.

Although it is believed that in the western countries tuberculosis is a disease confined to high-risk groups such as immigrants, we describe four cases of tuberculous meningitis (TBM) in native Dutch children. The inverse relation between the delay in starting therapy and the clinical outcome makes early diagnosis of TBM essential. The often non-specific presenting symptoms and laboratory results, the time-consuming character of cultures and the unfamiliarity of western medical staff with the disease all may contribute to a delay in diagnosis of TBM. We believe that especially gadolinium-enhanced MRI or contrast-enhanced CT can be very helpful in the early diagnosis. Although not specific, hydrocephalus and basal meningeal enhancement on MRI or CT, together with the clinical suspicion can suggest the diagnosis to such an extent that there is enough reason to start antituberculous treatment.

Cobalt-55 positron emission tomography in relapsing-progressive multiple sclerosis.

Multiple sclerosis (MS) is an immune-mediated disease of the white matter in the brain that can have a progressive course. However, the progression of relapsing-remitting (RR) MS into relapsing-progressive (RP) MS might represent a more fundamental change in disease activity, i.e. decay of vulnerable neurons and oligodendrocytes. In RP-MS, this may imply that the major loss of brain tissue structure is caused by a combination of demyelination and cellular loss, both of which are likely to cause disability in MS. We used the PET isotope cobalt-55 (Co) as a calcium (Ca) tracer to visualize brain tissue damage, based on the fact that Ca influx is essential in both cell death and T-lymphocyte activation in MS. The aim of this study was to determine whether Co-PET detects any RP-MS lesions and, if so, to assess any correlation with the progression rate (PR) of the disease and with MS lesions as detected by MRI. Seven RP-MS patients (Poser) with EDSS > 4.0 (Kurtzke) and 7 healthy controls underwent MRI (Miller, Barkhof) and Co-PET. Comparison of both image modalities was made by merging. Co-PET lesion frequency was assessed and correlated with the PR of the disease. Co-PET demonstrated significantly more lesions in the MS brain than in the healthy brain, both periventricular and cortical. Every single MRI lesion could be retrieved as a Co-PET lesion. The Co-PET lesion frequency correlated significantly with PR. Our pilot study possibly suggests Co-PET as a tool in estimating disease activity in RP-MS.(ABSTRACT TRUNCATED AT 250 WORDS)

Correlation between magnetic resonance imaging and clinical parameters in multiple sclerosis.

In this study, the course of 60 consecutive multiple sclerosis patients (relapsing-remitting (RR), relapsing-progressive (RP), primary-progressive (PP)) was compared with the number and mean size of the lesions as well as the total load of the lesions as shown on magnetic resonance imaging (MRI). Significant differences were found between RR and RP patients in total load and number of lesions. Between RR and PP patients statistical significant differences were found in total load, number and size of the lesions when correlated with EDSS. Between RP and PP patients statistical differences were found in total load and size of the lesions on MRI. Patients with a relapsing course of the MS (RR or RP) had a higher total load and size of the lesions than PP patients. The total load, number and size of the lesions corrected for EDSS were also lower compared to relapsing patients. Factor analysis showed a correlation between clinical progression rate and progression rate of MRI abnormalities. No correlation between EDSS and total load of MRI lesions could be found. In conclusion, this study confirms the results of previous studies of differences between MRI scans of patients with a different course of MS.

Marrow donor immunity to herpes simplex virus: association with acute graft-versus-host disease.

The interactions between humoral and cellular immunity to herpes simplex virus (HSV) in bone marrow donors, the occurrence of active HSV infections, and the development of grades II-IV acute graft-versus-host disease (GVHD) in their HLA-A,B,C,DR-identical sibling recipients were studied. The absence of IgG-class HSV antibodies in the marrow donors was associated with a low incidence of GVHD: 38 of 53 recipients (72%) of marrow from HSV-seropositive donors developed GVHD versus only two of 15 recipients (13%) with HSV-seronegative donors (p = 0.0004). The cellular immunity to HSV was studied in vitro by evaluating the degree of lymphocyte proliferative responses to that virus and was also significantly associated with GVHD: 30 of 43 recipients (70%) of marrow from donors with a positive test developed GVHD versus 10 of 25 recipients (40%) of marrow from donors with a negative test (p = 0.03). The previously reported risk for GVHD attributed to donor CMV antibodies increased the risk of GVHD due to donor HSV antibodies. Of 31 recipients of marrow from donors who were both HSV- and CMV-seropositive, 27 (85%) developed GVHD versus 11 of 22 recipients (50%) of marrow from HSV-seropositive but CMV-seronegative donors (p = 0.008).

Is aciclovir prophylaxis necessary after bone marrow transplantation?

To assess the cost-effect relationship of aciclovir prophylaxis versus early treatment, we performed a retrospective study in 44 allogeneic bone marrow transplant recipients, who had only received aciclovir for therapeutic purposes. After bone marrow transplantation 18 herpes simplex infections occurred in 15 of the 33 patients who were seropositive for herpes simplex virus. In ten patients without clinical signs, routine viral cultures yielded herpes simplex virus. Aciclovir was given intravenously to the patients with mucocutaneous herpes infection. All infections responded rapidly. It can be calculated that restricting the drug to therapeutic use reduced the amount of aciclovir used, which in turn diminished the cost of treatment and the risk of aciclovir resistance.

Cytomegalovirus immunity in allogeneic marrow grafting.

IgM and IgG class antibodies to cytomegalovirus (CMV) late antigen were studied in 58 bone marrow transplant (BMT) recipients and their donors using a sensitive enzyme-linked immunosorbent assay (ELISA) and with standard virological and histomorphological techniques. Patients who were CMV-seropositive before BMT had a significantly higher risk for active CMV infection after BMT than seronegative ones (23 of 29 vs. 3 of 26 patients; P less than 1 X 10(-6)). Transplantation of marrow from CMV-seropositive donors was associated with a higher incidence of active CMV infection after BMT than transplantation of marrow from seronegative donors (17 of 28 vs. 9 of 27 patients). Such transplantations also had a significantly higher incidence of grades II-IV acute graft-versus-host disease (23 of 29 vs. 11 of 27 patients; P = 0.007). Following BMT, the evolution of the IgG class CMV antibody response was influenced by the serological status of the marrow donor. First, a fall in IgG class CMV antibody titers during the first month after BMT was seen less often after transplantation of marrow from seropositive donors than after transplantation of marrow from seronegative donors. Second, recipients of marrow from CMV-seropositive donors who developed active CMV infection had an earlier IgG antibody response than those with seronegative marrow donors. These results suggest that the transfer of memory B and T cells occurs with the graft. Failure to mount a sustained IgM or IgG antibody response upon active CMV infection was associated with a fatal outcome.