Bhupendra O. Khatri

Double‐blind study of true vs. sham plasma exchange in patients treated with immunosuppression for acute attacks of multiple sclerosis

We enrolled 116 patients in a multicenter, randomized, double-blind controlled trial of an 8-week course of 11 plasma exchange (PE) treatments in exacerbations of MS. The control group received sham PE, and both groups received identical treatment with IM ACTH and oral cyclophosphamide. Serum IgG decreased in the PE and sham treatment groups by 76% versus 22% by treatment 5, and by 64% versus 14% by treatment 11. PE also produced significant reductions in IgA, IgM, C3, and fibrinogen. PE patients had moderately enhanced improvement at 2 weeks relative to the sham group. PE patients with relapsing/remitting disease had significantly enhanced improvement at 4 weeks and there was also an increased improvement at 12 months, although this latter effect disappeared when we analyzed relapsing/remitting patients as a separate subgroup. Life table analysis showed the median time to recover preattack disability status was shorter in PE- than in sham-treated relapsing/remitting patients (4 vs. 13 weeks), a result confirmed by raw disability status scores in which there was recovery to their average preattack disability score by 3 months. PE given with ACTH plus cyclophosphamide enhances recovery from an exacerbation of disease in relapsing/remitting patients, although we observed no clear long-term benefits.

Chronic progressive multiple sclerosis: double-blind controlled study of plasmapheresis in patients taking immunosuppressive drugs.

Fifty-four patients with chronic progressive multiple sclerosis received prednisone plus oral low-dose cyclophosphamide and either true plasmapheresis (PP) or “sham” PP weekly for 20 weeks in a double-blind controlled study. Immunosuppressive drug therapy alone (sham PP group, n = 29) was associated with improvement (≤ one step in Kurtzke Disability Status Scale [DSS]; mean change of 1.5) in 8 and stabilization of MS in 18 patients, with this status sustained in 23 patients at follow-up, 11 months after entry. In contrast, 14 of 26 patients who received “true” PP improved (≤ one step in DSS; mean change of 2.6), and 11 more were stable, with these changes sustained in 23 of 26 patients at follow-up. These differences, overall, between the PP and sham PP groups were significant at p < 0.007.

Plasma exchange in chronic progressive multiple sclerosis: a long-term study.

Plasma exchange (PE) was shown in a previous double-blind randomized controlled study to confer significant additional benefit at 1 year upon patients with chronic progressive multiple sclerosis (CPMS) treated with immuno- suppressive drug therapy (ISDT). Efficacy over an extended term, indications for retreatment, and long-term toxicity are dealt with in this analysis of a larger number of patients. During the past 7 years, 200 patients with CPMS have been treated with PE and low-dose ISDT at this center. Improvement on the Kurtzke Disability Status Scale by one or more steps post-therapy and at 3-year follow-up is significant by comparison with pre-PE disability status. Clinical improvement was maintained in the majority of patients, reaching as far as a 6-year follow-up. Major life-threatening complications attributable to this combined therapy were not observed.

Plasmapheresis with acute inflammatory polyneuropathy

Eleven children with acute inflammatory polyneuropathy were treated with a short course of intensive plasmapheresis. The 5 males and 6 females ranged in aged from 19 months to 16 years (mean: 7.8 years). The interval from disease onset to the initiation of plasmapheresis therapy was less than 7 days in 5 patients and less than 2 weeks in the others. At the time of the first plasmapheresis, 3 patients were on respirators (Grade 5 on the Guillain-Barré syndrome scale 0-6); 7 were bedridden (Grade 4); and 1 required assisted ambulation (Grade 3). One week after the last plasmapheresis, all but 1 patient had improved by 1 or more grades on the Guillain-Barré syndrome scale. At subsequent examination 6 months later, all patients were ambulatory and 9 of 11 had no significant neurologic findings. Electrophysiologic studies performed shortly before treatment initiation revealed predominant demyelinating neuropathy in 9 and axonal changes in 2. During the 76 plasmapheresis procedures, no severe complications were encountered. Although the number of patients treated is small, the clinical response observed would indicate plasmapheresis to be a safe and effective therapy in children with acute inflammatory polyneuropathy.

Maintenance plasma exchange therapy for steroid‐refractory neuromyelitis optica

Neuromyelitis optica (NMO) is a severe inflammatory demyelinating disease of the central nervous system with exacerbations involving the optic nerves, spinal cord, or both. This study explores the utility of maintenance plasma exchange (mTPE) as a therapy in patients with relapsing, corticosteroid‐refractory, NMO. This retrospective case series presents data on patients who were diagnosed with NMO using currently accepted criteria. These patients were refractory to high‐dose corticosteroids and received mTPE. Seven patients met the criteria for NMO diagnosis and all were positive for antibodies against aquaporin‐4. Over a mean of 7.1 years (range, 2–16), these patients received between 21 and 154 TPE treatments (mean, 76). Although treated with mTPE, five out of the seven patients improved by more than one point on the Expanded Disability Status Scale. Interruption in mTPE in five patients resulted in clinical worsening. When mTPE was restarted in three out of the five patients who experienced a cessation of mTPE, these patients either stabilized or improved. The two patients who did not restart the mTPE protocol died. Patients treated with mTPE also experienced a reduction in the number of NMO exacerbations. Finally, stabilization of the retinal nerve fiber layer thickness was observed while on mTPE. In this preliminary study, mTPE appeared safe and may bring about improvement in disability and sustained stabilization of the clinical course in patients with steroid‐refractory relapsing forms of NMO. J. Clin. Apheresis, 2012.

Immune Reactivity Against Membranes Containing Ganglioside GM1 in Chronic-Progressive Multiple Sclerosis: Observation by Spin-Membrane Immunoassay

A spin-membrane immunoassay has been employed to examine the immune reactivity of whole serum from patients with chronic-progressive multiple sclerosis (CPMS) against liposomes containing ganglioside GM1. Exposure to serum resulted in complement-mediated lysis of the GM1-liposomes. No lysis occurred with liposomes devoid of ganglioside. The mean (+/- S.E.M.) lysis values were 52.6 (+/- 9.8)% for fifteen CPMS patients and 32.9 (+/- 7.2)% for nine controls. The difference between the means was highly significant (students t-test, P less than 0.0001), indicating increased anti-ganglioside immunity in patients with CPMS.

Plasmapheresis and combined immunosuppressive drug therapy in chronic progressive multiple sclerosis. Choosing the patient who should respond.

Based on the assumptions that multiple sclerosis (MS) is an autoimmune disorder.’.’ and that plasmapheresis (PP) is an effective means of removing antibodies and other proteins from the circulation,” several pilot studies have been undertaken to ascertain the role of PP in patients with MS.”-’4 Encouraging results from these uncontrolled studies and lack of any effective treatment for MS” led to a double-blind, randomized, controlled study of immunosuppressive drug therapy with and without plasmapheresis in chronic progressive MS (CPMS). This studyI6 demonstrated statistically significant improvement in the Kurtzke Disability Status Scale (DSS)” in patients who received PP and immunosuppressive drug therapy, confirming our pilot study observations.” A retrospective analysis of this total experience was undertaken first to identify certain clinical and laboratory characteristics of the responders and nonresponders in both the pilot and double-blind study, and second, to determine the statistical significance of each of the characteristics in order eventually to predict those who should respond to this therapy.

Plasma Exchange in Secondary Progressive Multiple Sclerosis: Twenty-Five Year Follow-Up Study

Secondary Progressive multiple sclerosis (SPMS) is a common form of MS with few approved and effective therapies. Previous studies of therapeutic plasma exchange (PLEX) in SPMS have reported mixed results. The purpose of this study was to evaluate long-term efficacy and safety of PLEX in SPMS. We retrospectively analyzed 25 years of PLEX therapy in SPMS to identify improvements in disease progression and disability as well as potential predictors of therapeutic success. Using 271 patients, we show a significant improvement in Expanded Disability Status Scale (EDSS) lasting for at least three years following a course of PLEX. Furthermore, disability remained significantly improved or stabilized for seven years post-PLEX. Patients with continued and measureable disability worsening in the previous three years are more apt to improve with PLEX. A small number of patients (N=42) for whom PLEX was considered but denied by their insurance carriers, and who therefore received other treatments, were also followed over the 25 year period. Progression of disability in this group was significantly worse when compared with PLEX group. No major problems occurred during 8709 PLEX procedures. Peripheral vascular access (venous or arterial) was utilized to avoid complications related to central line placement. Because of the paucity of beneficial therapeutic interventions in SPMS and the relative safety and efficacy of long-term PLEX, this therapy should be considered in this form of MS.

The TRUST (EvaluaTion of Bladder Function in Relapsing-Remitting MUltiple Sclerosis Patients Treated with Natalizumab) observational study

BACKGROUND Bladder dysfunction is a common symptom of multiple sclerosis (MS). This study was designed to evaluate effects of natalizumab on bladder function in patients with relapsing-remitting MS. METHODS The TRUST (EvaluaTion of Bladder Function in Relapsing-Remitting MUltiple Sclerosis Patients Treated with Natalizumab) study was an open-label, single-arm, two-center study. Natalizumab-naive MS patients with disabling bladder dysfunction and initiating natalizumab were enrolled and followed for 6 months. The primary endpoint was change in the Urogenital Distress Inventory short form (UDI-6) score from baseline. Change in Incontinence Impact Questionnaire short form (IIQ-7) score from baseline was a secondary endpoint. RESULTS Thirty patients were enrolled. Mean baseline characteristics were age 49.9 years, Expanded Disability Status Scale score 4.6, number of relapses in previous year 2.4, UDI-6 score 10.4, and IIQ-7 score 12.3. Mean changes in UDI-6 and IIQ-7 scores were significantly improved from baseline beginning at week 4 and up to week 24; mean improvements at 24 weeks were 4.4 (P < .0001) and 4.9 (P = .0005) points, respectively. At week 24, 85.7% and 78.6% of patients demonstrated improvements from baseline in UDI-6 and IIQ-7 scores, respectively. CONCLUSIONS Incontinence-related quality of life as measured by UDI-6 and IIQ-7 scores improved significantly during natalizumab treatment.

PO114 Neda achievement by time interval with daclizumab

Background Significantly more DECIDE patients receiving subcutaneous daclizumab HYP (daclizumab) 150 mg achieved no evidence of disease activity (NEDA) vs intramuscular interferon beta-1a (IFNβ1a) 30 µg over 96 weeks. Early residual disease activity (from pretreatment epoch) present while a new therapy reaches full efficacy may impact NEDA evaluation. We examined NEDA-achieving patients in DECIDE post hoc, from baseline to week 24 (6 months) and at weeks 24–96 (18 months) of treatment. Methods NEDA was defined as the composite of no relapses, no 12 week confirmed disability progression (CDP), and no new/enlarging T2 (NET2) lesions (vs time interval start) and/or no gadolinium-enhancing (Gd+) lesions (on MRI performed after time interval start). Results From baseline to week 24, significantly more daclizumab vs IFNβ1a patients achieved overall, clinical (no relapses, no 12 week CDP), and MRI (no NET2, no Gd +lesions) NEDA (p<0.0001). Similar results were observed for weeks 24–96, with notably higher ORs for most measures. Conclusion The superiority of daclizumab over IFNβ1a on NEDA status was observed during the first 6 treatment months in DECIDE, becoming more prominent during the following 18 months when therapies reached full efficacy and effects were less diluted by pretreatment disease activity. Support Biogen, Abbvie; Author disclosures will be presented