***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: Background Natalizumab ( NTZ ) discontinuation leads to multiple sclerosis reactivation . The objective of this study is to compare disease activity in MS patients who continued on NTZ treatment to those who were switched to subcutaneous interferon 1b ( IFNB ) treatment . Methods 1-year r and omized , rater-blinded , parallel-group , pilot study ( Clinical Trial.gov ID : NCT01144052 ) . Relapsing remitting MS patients on NTZ for ≥12 months who had been free of disease activity on this therapy ( no relapses and disability progression for ≥6 months , no gadolinium-enhancing lesions on baseline MRI ) were r and omized  to NTZ or IFNB . Primary endpoint was time to first on- study relapse . Additional clinical , MRI and safety parameters were assessed . Analysis was based on intention to treat . Results 19 patients ( NTZ n=10 ; IFNB n=9 ) with similar baseline characteristics were included . 78 % of IFNB treated patients remained relapse free ( NTZ group : 100 % ) , and 25 % remained free of new T2 lesions ( NTZ group : 62.5 % ) . While time to first on- study relapse was not significantly different between groups ( p=0.125 ) , many secondary clinical and radiological endpoints ( number of relapses , proportion of relapse free patients , number of new T2 lesions ) showed a trend , or were significant ( new T2 lesions at month 6 ) in favoring NTZ . Conclusions De-escalation therapy from NTZ to IFNB over 1 year was associated with some clinical and radiological disease recurrence . Overall no major safety concerns were observed OBJECTIVE To assess clinical consequences of temporary natalizumab dosage suspension . DESIGN Prospect i ve cohort study . SETTING Multiple sclerosis ( MS ) center at an academic medical center in the United States . PATIENTS Thirty-two patients with MS who had received at least 12 consecutive natalizumab infusions .  MAIN OUTCOMES MEASURES Recurrent MS disease activity , defined as a clinical ly documented exacerbation with objective findings and /or the development of 1 or more new gadolinium-enhancing lesions on magnetic resonance imaging . RESULTS Thirty-eight percent of patients with relapsing-remitting and secondary progressive MS experienced relapses during therapy interruption or shortly after restarting natalizumab therapy ( 9 of 24 and 3 of 8 , respectively ) , but relapses were severe with unusually widespread evidence of inflammatory activity on magnetic resonance imaging in several patients with secondary progressive MS with greater inflammatory disease activity prior to starting natalizumab therapy . Imaging and cerebrospinal fluid findings in these cases were suggestive of an immune reconstitution inflammatory syndrome . Overall , relapses occurred more often in younger patients with fewer natalizumab infusions prior to therapy interruption . The number of gadolinium-enhancing lesions at the time of relapse after therapy interruption was modestly correlated with the number of gadolinium-enhancing lesions prior to starting natalizumab therapy ( r = 0.51 ; P = .45 ) . Prior disease control resumed after reinstitution of natalizumab therapy in all patients . CONCLUSIONS In this cohort of patients with MS who had disease refractive to multiple therapeutics before starting natalizumab treatment , magnetic resonance imaging and clinical disease activity returned , often aggressively , following discontinuation of natalizumab therapy . These findings suggest we should consider strategies to minimize the risk of immune reconstitution inflammatory syndrome after natalizumab discontinuation Objective : To characterize the reversibility of natalizumab-mediated changes in pharmacokinetics/pharmacodynamics in patients with multiple sclerosis ( MS ) following therapy interruption . Methods : Pharmacokinetic/pharmacodynamic data were collected in the Safety and Efficacy of Natalizumab in the Treatment of Multiple Sclerosis ( AFFIRM ) ( every 12 weeks for 116 weeks ) and R and omized Treatment Interruption of Natalizumab ( RESTORE ) ( every 4 weeks for 28 weeks ) studies . Serum natalizumab and soluble vascular cell adhesion molecule–1 ( sVCAM-1 ) were measured using immunoassays . Lymphocyte subsets , α4-integrin expression/saturation , and vascular cell adhesion molecule–1 ( VCAM-1 ) binding were assessed using flow cytometry . Results : Blood lymphocyte counts ( cells/L ) in  natalizumab-treated patients increased from 2.1 × 109 to 3.5 × 109 . Starting 8 weeks post last natalizumab dose , lymphocyte counts became significantly lower in patients interrupting treatment than in those continuing treatment ( 3.1 × 109 vs 3.5 × 109 ; p = 0.031 ) , plateauing at prenatalizumab levels from week 16 onward . All measured cell sub population , α4-integrin expression/saturation , and sVCAM changes demonstrated similar reversibility . Lymphocyte counts remained within the normal range . Ex vivo VCAM-1 binding to lymphocytes increased until ≈16 weeks after the last natalizumab dose , then plateaued , suggesting reversibility of immune cell functionality . The temporal appearance of gadolinium-enhancing lesions was consistent with pharmacodynamic marker reversal . Conclusions : Natalizumab 's effects on peripheral immune cells and pharmacodynamic markers were reversible , with changes starting 8 weeks post last natalizumab dose ; levels returned to those observed/expected in untreated patients ≈16 weeks post last dose . This reversibility differentiates natalizumab from MS treatments that require longer reconstitution times . Characterization of the time course of natalizumab 's biological effects may help clinicians make treatment sequencing decisions . Classification of evidence : This study provides Class III evidence that the pharmacodynamic markers of natalizumab are reversed ≈16 weeks after stopping natalizumab IMPORTANCE The appropriate sequencing of agents with strong immune system effects has become increasingly important . Transitions require careful balance between safety and protection against relapse . The cases presented herein highlight that rebound events after ceasing fingolimod treatment may happen even with short washout periods ( 4 weeks ) and may perpetuate despite steroid treatment or the immediate use of fast-acting immune therapies , such as rituximab . OBJECTIVE To describe rebound syndrome in patients with multiple sclerosis ( MS ) after cessation of fingolimod treatment . DESIGN , SETTING , AND PARTICIPANTS Clinical and demographic data were extracted from electronic medical records from the University of California , San Francisco , Multiple Sclerosis Center from January 2014 to December 2015 . Magnetic resonance images were review ed by MS neurologists ( J.S.G. , E.W. , B.N. , and E.C.H. ) . Rebound syndrome was defined as new severe neurological symptoms after ceasing fingolimod treatment , with the development of multiple new or enhancing lesions exceeding baseline activity . We review ed the PubMed data base from January 2010 to December 2015 for similar cases of severe disease reactivation after ceasing fingolimod treatment using search terms fingolimod and either rebound or reactivation . Participants were included if they stopped receiving fingolimod between January 2014 and December 2015 . Five patients were identified who experienced rebound  after ceasing fingolimod treatment . EXPOSURES Each patient received treatment with oral fingolimod for various duration s. MAIN OUTCOMES AND MEASURES Occurrence of rebound after ceasing fingolimod treatment . RESULTS The mean ( SD ) age of the 5 female patients presented in this case series was 35.2 ( 6.4 ) years . Of the 46 patients that stopped fingolimod treatment within the 2-year period , 5 ( 10.9 % ) experienced severe relapse 4 to 16 weeks after ceasing fingolimod treatment . Despite varying prior severity of relapsing-remitting course , all participants experienced unexpectedly severe clinical relapses accompanied by drastic increases in new or enhancing lesions seen on magnetic resonance imaging evidence d by a median ( range ) increase of 9 ( 0->30 ) new gadolinium-enhancing lesions and a median ( range ) of 9 ( 0->30 ) new T2 lesions . New lesion development persisted for 3 to 6 months despite treatment with corticosteroids ( n = 3 ) and initiation of B-cell depleting therapy ( n = 2 ) . In addition , 11 patients were identified through literature review reported as having severe relapses consistent with a rebound syndrome and similar features to our 5 cases . CONCLUSIONS AND RELEVANCE These cases provide evidence for a fingolimod rebound syndrome at a clinical ly relevant frequency , highlighting the need to determine the best methods for sequencing or discontinuing MS therapies . A large prospect i ve registry or population -based study would be helpful to confirm this rebound phenomenon and to determine contributing factors , including immune biomarkers , that increase risk for this syndrome In this study , the tolerability and safety of treatment with pulsed steroids and glatiramer acetate and the occurrence of clinical and radiological activity after  natalizumab ( NTZ ) cessation in multiple sclerosis ( MS ) patients were assessed . MS patients with NTZ were discontinued after 2 years of treatment , or if adverse events or disease progressed during NTZ . They were offered as alternative treatment 1 g methylprednisolone per month during 3 months followed by daily 20 mcg glatiramer acetate and were prospect ively studied . Adverse events , occurrence of immune reconstitution inflammatory syndrome , clinical exacerbations , and gadolinium-enhancing lesions in MRI performed at 3 and 6 months after NTZ cessation were recorded . EDSS change during follow-up was also recorded . A total of 18 MS patients entered the study and were followed up for a mean of 10 months ( range 6–18 months ) . There were no significant adverse events . At month 3 , no patient had clinical or radiological disease activity . At month 6 , 16.6 % of patients had had a relapse and 55.5 % of patients showed gadolinium-enhancing lesions in the MRI . After 6 months , 33.3 % of patients had a further relapse . There was no IRIS , severe relapses , or significant difference between EDSS at NTZ discontinuation and after follow-up . The alternative treatment with monthly prednisolone followed by GA prevents the development of IRIS , but not the return to previous inflammatory activity , which occurs between 5 and 6 months after NTZ withdrawal Objective : Natalizumab is a humanized recombinant monoclonal antibody against very late activation antigen-4 approved for the treatment of patients with multiple sclerosis ( MS ) . A phase II study failed to demonstrate a difference between natalizumab treatment groups and the placebo group with regard to gadolinium enhancing lesions on MRI 3 months after discontinuation of therapy . The objective of this study was to assess clinical MS disease activity , surrogate disease markers on MRI , immunologic parameters in peripheral blood and CSF , as well as safety in patients with MS after discontinuation of natalizumab therapy . Methods : This study is a longitudinal and serial cross-sectional assessment , in which 23 patients who were treated with natalizumab in the context of two phase III clinical trials were originally enrolled . A subgroup of patients was followed over 14 months . The annual relapse rate , neurologic disease progression assessed by the Exp and ed Disability Status Scale , disease surrogate markers on MRI , cellular and humoral immune markers in peripheral blood and CSF , and adverse events of the drug were monitored . Results : With regard to clinical disease activity , neuroimaging , and immune responses , the majority of patients in our cohort were stable . Decreased lymphocyte cell numbers and altered cell ratios returned to normal 14 months after cessation of natalizumab . No infectious complications were observed . Conclusion : This is the first long-term follow-up of patients who discontinued natalizumab .  We did not observe a clinical , radiographic , or immunologic rebound phenomenon after discontinuation of natalizumab therapy The objective of this study is to characterize the timing and extent of radiologic MS disease recurrence during the 24-week natalizumab treatment interruption period in RESTORE . RESTORE was a r and omized , partially placebo-controlled exploratory study .  Natalizumab-treated patients with no gadolinium-enhancing ( Gd+ ) lesions at screening ( n = 175 ) were r and omized 1:1:2 to continue natalizumab ( n = 45 ) , switch to placebo ( n = 42 ) , or switch to other therapies ( n = 88 ) for 24 weeks .  MRI assessment  s were performed every 4 weeks . Predictors of increased numbers of Gd+ lesions during natalizumab treatment interruption were evaluated . The numbers of Gd+ lesions were compared with retrospectively collected pre-natalizumab MRI reports and data from  placebo-treated patients from two historical r and omized clinical trials .  Gd+ lesions were detected in 0 % ( 0/45 ) of natalizumab patients , 61 % ( 25/41 ) of placebo patients , and 48 % ( 39/81 ) of other-therapies patients during the r and omized treatment period . Gd+ lesions were detected starting at week 12 ; most were observed at week 16 
    Output:
    
Conclusions : Results from the present review and meta- analysis can help to profile patients who are at greater risk of post-NTZ disease reactivation .