Multiple Sclerosis 2002; 8: 59-63
`www.multiplesclerosisjournal.com
`
`High clinical inflammatory activity prior to the development of secondary
`progression: a prospective 5-year follow-up study
`
`B Casanova*", F Coret*, C Valero’, L Landete’, A PascuaF andJJ Vilchez’
`*Neurology Services of the University Hospital La Fe, Valencia, Spain; *The Clinic University Hospital, Valencia, Spain;
`’The University Hospital, Dr. Peset, Valencia, Spain
`
`Objective: To study if there are different patterns of clinical activity — measured by the annual exacerbation rate (AER) — among
`relapsing—remitting multiple sclerosis (RRMS), “early” secondary multiple sclerosis (SPMS) and “late” SPMS. Methods: A prospective 5-year
`follow-up study in 80 MS patients has been carried out, calculating the AER and the mean expanded disability status scale (EDSS) change
`rate (MCR). Results: A significant difference on the AER, among RRMS, early SPMS and late SPMS, has been found. Conclusions: The
`SPMS has a high clinical inflammatory activity before and during its transformation from a RRMS.
`Multiple Sclerosis (2002) 8, 59-63
`
`Key words: multiple sclerosis; natural history of multiple sclerosis; secondary progressive multiple sclerosis
`
`Introduction
`
`Secondary progressive multiple sclerosis (SPMS) is the
`form of MScharacterised by the presence of acute neuro-
`logical symptoms (exacerbation) and the progressive
`decline in neurological functions without exacerbations.”
`Until now, only two prospective studies in the natural
`history of SPMS have been published.** Of them, only
`the work of Minderhoudet a/* has studied the beginning
`of the progressive stage. They found a faster delta progres-
`sion rate (DPR) early after the first progression year, with a
`slight decline in the following years. The DPRin this study
`was defined as the rate between the increase in expanded
`disability status scale (EDSS) and the disease duration in
`years. Unfortunately, the relapse rate was not reported in
`Miderhoud et al’s research, and its conclusion was that a
`significantrelationship was found between the relapse rate
`and the DPR.
`The purpose of our work has been to studyif there are
`different patterns of clinical activity among patients with a
`recent conversion into SPMS,patients with a more evolved
`SPMS andpatients with relapsing—remitting multiple scle-
`rosis (RRMS).
`
`Subjects and methods
`
`Subjects
`Eighty consecutive nonselected patients, with clinical
`definitive MS diagnosis according to the Poser criteria,*
`were included. A prospective study was carried out for
`
`*Correspondence: B Casanova i Estruch, MD, Neurological
`Service, University Hospital La Fe, Avd Campanar 21,
`Valencia 46009, Spain. E-mail: bcasanovae@ meditex.es
`Received 7 February 2001; revised 24 May 2001; accepted 10
`August 2001
`
`© Arnold 2002
`
`5 years, with an interim analysis of the clinical evolutive
`forms at year 3, followed by a 2-year follow-up for the
`confirmation of the clinical forms. The RRMS patients
`were distributed in two groups accordingto our criterion.
`One group included patients that remained in a RRMS
`form during the first 3 years, and the other group
`included patients that had evolved into a SPMS form
`during this time (Table 1).
`
`Methods
`Visits were scheduled every 3 months, and unscheduled
`visits occurred whenever patients felt a new symptom or
`a worsening of their previous condition. In each visit, the
`EDSS, the Kurtzke’s functional systems and the Ambula-
`tory index were recorded. Progression was defined as an
`increase of one point or more in the EDSS sustained in
`two scheduled visits, ie., for 6 months,
`if EDSS was
`lower than 6.0, or an increase of 0.5 points if EDSS
`was equal or greater than 6.0. After a relapse, the basal
`EDSS employed to consider the progression was calcu-
`lated 3 months after treatment with steroids, and the
`progression were consideredif the aforementionedcriteria
`were accomplished in the next scheduled visit 6 months
`after. Only patients who continued progressing in the
`following 2 years, after the SPMS diagnosis was made,
`were considered for the analysis in order to avoid cases of
`RRMS forms with high clinical activity and sequels. The
`year of conversion was set when the patients reached the
`defined progression criteria. Exacerbation was defined as
`the presentation of a new symptom which lasted more
`than 48 h plus an increase of one point in the EDSS or
`worsening of a previous symptom (except sphinterian
`worsening) without
`the presence of fever or another
`explanation for this worsening. Exacerbations were trea-
`ted with 1 g of intravenous methyl prednisolone per day
`
`10.1191/1352458502ms7730a
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`Clinical inflammatory activity
`B Casanova et al
`ANOVAOF_a60
`
`Table 1 Annual exacerbationrate for patients accordingto the year of conversion (YoC) to SPMS, on the year before (—1 year) and on the
`year after (+1 year)
`eee
`—1 year
`YoC
`Mean AER*
`+1 year
`(A) AERfor the patients who evolved to SPMS on the secondyearoffollow-up
`RRMS(54)
`0.7
`0.5
`Early SPMS(6)
`1.0
`Li
`PES
`0.39
`0.06
`Late SPMS (13)
`0.62
`0.46
`(B) AERfor the patients who evolved to SPMSon the third year offollow-up
`0.45
`0.42
`RRMS(47)
`0.51
`0.34
`0.78
`0.78
`Early SPMS(7)
`0.86
`0.71
`0.55
`0.09
`pee
`0.2
`0.14
`0.26
`0.26
`Late SPMS
`0.4
`0.07
`*Mean AER: mean annual exacerbation rate for the year of conversion and the previous year. **Probability was calculated only between
`RRMSandtheearly SPMS patients because no patients with the late SPMS form were on treatment with interferon-B.
`
`0.3
`0.8
`0.12
`0.07
`
`0.6
`1.0
`0.08
`0.5
`
`for 5 days followed by oral steroids tapering. The study
`was carried out between January 1996 and January 2001.
`In the beginning of the study, only the RRMSpatients
`could be treated with interferon-f; thus, 39 patients (39 of
`61 RRMSpatients, 63.7%) fulfilled the criteria to receive
`this treatment during the first 2 years of the study, 30 in
`the group that remained in the RRMS phase and 9 in the
`“Early SPMS”group. The other 22 RRMS patients refused
`the treatment (four cases) or did not have clinical activity
`defined as the presence of two exacerbations in the
`previous 2 years (18 cases). We calculated the annual
`exacerbation rate (AER) and the annual medium change
`rate (MCR) for progression. MCR wascalculated as the
`difference between the EDDS at the end of the years
`under observation and the basal EDSS divided by the
`number of years under observation;
`it has been estab-
`lished in 0.5 EDSS points for the progressive forms
`(SPMS or PPMS).”
`Wehave studied the AER at the “year of conversion” into
`SPMS,in the previous year and in the following year after
`the transformation. For this purpose, we have studied two
`groupsof patients — the group that evolved to SPMS in the
`second year (six patients) and the group that evolved to
`SPMSin the third year (seven patients). In these two, we
`have observed a high AER during the year of conversion
`and in the previous year, with a decrease in the following
`year (Table 1). We also have examinedthe effectof inter-
`feron-B in the evolution to SPMS, and wehave not observed
`
`any difference (Table 2). We have compared the AER
`between the RRMS andthe early SPMS, but not with the
`late SPMS, because in this group no patients weretreated
`with interferon-f,
`Finally, we have analysed the changes in the median
`changerate on the EDSSfor all groups (RRMS,early SMPS,
`late SPMS and PPMS). A significant difference on the MCR,
`between early SPMS and late SPMS, was foundatthe third
`and fourth year andat the endof the study (P< 0.005 in the
`three MCRs), but not between late SPMS and PPMSpatients
`(Table 3).
`Data were introduced in a database created for this
`purpose and were analysed with the SPSSPC v2.4 statistical
`package. Student’s ttest was used for analysis of means.
`When the distribution was not normal, according to the
`Kolmogorov—Smirnov test or the Shapiro—Wilks test,
`Mann-—Whitney’s U-test was used.
`
`Results
`
`Theinitial distribution of the clinical forms according the
`criteria of Lublin et aJ* was: 61 RRMS (76.3%), 13 SPMS
`(16.3%) and 6 primary progressive MS — PPMS(7.5%).
`Clinical and demographical characteristics are described
`in Table 4. Along the time of this study, 13 patients
`(21.3%) changed from RRMSto SPMS,6 patients at year 2
`and 7 patients at year 3; this group of patients was designed
`as “Early SPMS”. At the end of the study at the third year,
`
`Influenceof interferon-B on the evolution to SPMS
`Table 2
`OSSSSSSSeSSSSSSSFSSSFSSmmsSFffses
`
`(A) Evolution to SPMSin patients with or without interferon-G treatment on the secondyear; P=0.6 (Fisher’s exact test)
`Patients under interferon-B treatment
`35
`Patients without treatment
`19
`
`4
`2
`
`Remained as RRMS
`
`Evolved to SPMS
`
`(B) Evolution to SMPS in patient with or without interferon-G treatmenton the third year; P=0.49 (Fisher’s exact test)
`Patients under interferon-B treatment
`5
`30
`Patients without treatment
`2
`17
`ee
`SSS
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`Clinical inflammatory activity
`B Casanova efal
`
`Table 3 EDSS and MCR forall groups understudy (casesthat did notreach thefifth year of follow-up are missing)
`
`Basal
`EDSS
`EDSS
`EDSS
`EDSS
`EDSS
`AEDSS*
`AEDSS?
`AEDSS’
`
`EDSS
`+1 year
`+ 2 years
`+3 years
`+4 years
`+5 years
`(MCR)
`(MCR)
`(MCR)
`
`(A) EDSSfor the patients who remained in the RRMS form
`Cases
`47
`47
`47
`47
`Missing
`0
`0
`0
`0
`Mean
`2.29
`2.19
`2,32
`2.60
`Median
`2.50
`2.50
`2.50
`2.50
`
`(B) EDSSfor early SPMSpatients
`Cases
`13
`13
`Missing
`0
`0
`Mean
`3.19
`3.11
`Median
`3.00
`3.00
`
`(C) EDSSfor late SPMS patients
`Cases
`13
`13
`Missing
`0
`0
`Mean
`6.00
`6.30
`Median
`6.00
`6.50
`
`(D) EDSS for PPMSpatients
`Cases
`6
`Missing
`0
`Mean
`4.58
`Median
`3.75
`
`6
`0
`5.16
`4.75
`
`13
`0
`4.23
`4.50
`
`13
`0
`6.73
`6.50
`
`6
`0
`5.41
`5.00
`
`13
`0
`5.38
`6.00
`
`13
`0
`7.03
`7.00
`
`6
`0
`5.50
`5.25
`
`47
`0
`2.80
`3.00
`
`13
`0
`5.76
`6.00
`
`13
`0
`711
`7.50
`
`6
`0
`5.75
`5.75
`
`36
`11
`3.02
`2.75
`
`11
`2
`6.27
`6.50
`
`10
`3
`7.14
`7.20
`
`5
`1
`5.60
`6.00
`
`47
`0
`0.10
`0.0
`
`13
`0
`0.73
`0.83
`
`13
`0
`0.34
`0.33
`
`6
`0
`0.30
`0.33
`
`47
`0
`0.12
`0.12
`
`13
`0
`0.64
`0.62
`
`13
`0
`0.27
`0.25
`
`6
`0
`0.29
`0.31
`
`36
`11
`0.14
`0.10
`
`<1
`2
`0.60
`0.60
`
`10
`3
`0.24
`0.29
`
`5
`1
`0.34
`0.40
`
`"Delta rate (MCR) between basal EDSS and EDSSonthethird year. "Delta rate (MCR) between basal EDSS and EDSSonthe fourth year.
`“Delta rate (MCR) between basal EDSS and EDSSatthe endofthe study.
`
`47 patients remained in the RRMS group, but the SPMS
`group (“Early SPMS”and “Late SPMS”) had increased to 26
`patients — 6 patients remained in the PPMS group and 1
`patient had been lost to follow-up. Therefore, 13 patients
`had evolved from RRMS to SPMS (21.3% of the RRMS
`patients), 6 patients in the second year and 7 in the third
`year.
`In the group of the “Early SPMS”, we found an AER of
`1.23 in the first year, 1.0 in the second year and 0.76 in the
`third year, the mean AER for the 3 years being 1.0; whereas
`the AER in the RRMSgroup was0.59 in thefirst year, 0.51
`in the second year and 0.34 in the third year (mean AER for
`the 3 years was 0.4). Differences were significant in each
`year, and also in the mean AER for the 3 years (P=0.01,
`P=0.05, P=0.05 and P=0.01, respectively). When we com-
`pared the AER in these years between early SPMS andlate
`SMPS,we found that AER in late SPMS was 0.6 in thefirst
`year, 0.4 in the second year and 0.07 in the third year, the
`mean AER for the 3 years being 0.3. There were no differ-
`
`ences between RRMS patients and late SPMS exceptat the
`third year. Nevertheless, a trend for the first year, and
`significant differences on the third year and on the mean
`AER for the 3 years, between the early SPMS andlate
`SPMS were reached (P=0.06, P=0.01, P=0.01,
`respec-
`tively). In all cases, Mann—Whitney’s U-test was used
`(Table 5).
`The demographic and clinical characteristics in the
`RRMS groupandthe early SPMS were comparable on the
`age and on the mean evolution time since diagnosis, but
`there was a significant difference on the EDSS at the
`beginning of the study (P=0.02, Student’s #test). Differ-
`ences in the mean evolution time since diagnosis were
`significant between early SPMS group and late SPMS group
`(P=0.04) (Table 6).
`After 5 years of follow-up, five more patients have
`evolved into SPMS in the last 2 years. However, these
`patients have still been analysed in the RRMSgroup until
`confirmation of progression. These patients are responsible
`
`Table 4 Clinical and demographic characteristics of patient at baseline
`
`n (%)
`
`Mean age
`
`Sex (M/F)
`
`Mean age
`at diagnosis
`
`Mean
`evolution time
`
`Mean time
`since progression
`
`Median EDSS(range)
`
`3 (0-5.5)
`-
`7.1%
`28.5
`20/41
`35.8
`61 (76.3)
`RRMS
`SPMS
`13 (16.3)
`46.5
`0/A3
`33.4
`12*
`5
`6 (4-8)
`PPMS
`6 (7.5)
`49
`38
`42.3
`5.1
`-
`3.7 (4-8)
`
`*P=0.04
`
`
`
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`Clinical inflammatory activity
`B Casanovaef al
`een
`62
`
`Table 5 AER for the three groups understudyeee
`n
`AER year 1
`AER year 2
`
`AER year 5°
`
`AER year 3
`
`AERyear 4
`
`47
`13
`13
`
`0.51
`0.59
`RRMS
`0.41
`0.44
`0.34
`1.0
`1.23
`Early SPMS
`0.18
`0.30
`0.76
`0.4
`0.6
`Late SPMS
`0.2
`0.07
`0.07
`0.05
`0.01
`p>
`0.3
`0.4
`0.05
`0.1
`0.06
`P*
`0.9
`0.1
`0.01
`eee
`“The AER at year 5 have been calculated with 36 RRMS, 11 early SPMS and 10 SPMS patients who completedthe 5 years. °P (Mann—
`Whitney’s U-test) between RRMS andearly SPMSpatients. °P (Mann—Whitney’s U-test) between early SPMS andlate SMPSpatients.
`
`for the increase of the MCR in the last 2 years in the RRMS
`group (Table 1).
`
`Discussion
`
`We herein report a prospective study on a cohort of 80
`consecutive, nonselected MS patients. We have studied the
`clinical inflammatory activity of the disease along these
`years and wehave founda significant increase in the AER
`in patients during the year of conversion into SPMS.
`Diagnosis of SPMSis very difficult because there is not a
`moment in which one can determine that a patient “is” in a
`secondary progression, e.g., it may be that a rapid increase
`in the disability be due to an exacerbation or its sequelae,
`and if there are many exacerbations, it is impossible to
`consider progression between bouts. The EDSS was meas-
`ured 3 months after steroid treatment for an exacerbation
`and each 6 months,in order to avoiding a possible factor of
`confusion for a result being secondary to a sequel to an
`exacerbation and not due to real progression. Also, we
`extended the study for 2 years, and considered patients
`with an SPMS form only if the patient would continue
`progressing in the last 2 years of the study. Then the
`diagnosis of SPMS was madein agreement with thecriteria
`of impairmentof one point or more sustainedin twovisits
`separated by 6 months, and 3 months after an exacerbation.
`We assumethat this is not a natural history study
`because many patients (but not all) with initial RRMS,
`and no patients with late SPMS, are in treatment with
`interferon-f. In the caseof the late SPMS patient, treatment
`was not available for this indication, and recently, inter-
`feron-B action over exacerbations in both RRMS and SPMS
`has been shown. For this reason, we cannot compare the
`AER between early SPMS andlate SPMS;nevertheless, the
`
`patients under interferon-f treatment were those who pre-
`sented more accounts of exacerbations ( P= 0.01).
`In our analysis of the clinical activity at the year of
`conversion and on the previous year, results were consistent
`with the globalresults; and in the two groupsofpatients that
`evolved to SPMS on each year of observation, the behavior
`wassimilar, with an increase in the AER at this moment. The
`effect of interferon-B did not seem to influence the conver-
`sion into SPMS; these results are in line with the recent
`analysis on the natural history of the disease reported by
`Confavreux et al,** in which it was shown thatthe evolution
`to SPMS wasnotrelated to the numberof exacerbations.
`With respectto the analysis of the MCR,weconsiderthat
`our results are not comparable between early and late SPMS
`because it has been demonstrated that the EDSS is not a
`lineal scale and the time that a patient is on the range
`between 3.5 and6 is lowerthan at scores near both endsof
`the scale. We think that in our study, the similarity between
`the MCR in the late SPMS and PPMSis an important
`finding, but we do not conclude that a faster conversion
`of three to six EDSS is the expression of a more clinical
`activity, as occurs in the early SPMS.
`The use of steroids did not seem to influence the con-
`version into SPMS sinceall exacerbations had been treated
`similarly (see Methods). Similarly, the use of B-interferon
`did not affect results because 35 patients were in treatment
`for almost 2 years, 7 of which developed SPMS,the differ-
`ence on the AER between them being significant. At the end
`of the 3 years, 28 patients remained as RRMS and7 evolved
`to SPMS;the AER were 0.6 and 1.2, respectively (P=0.001).
`In summary, our results show that there exists an
`increase in the number of exacerbations compared to the
`RRMSandthe late SPMS at the momentof conversion into
`SPMS,in line with the results of Minderhoud et al* We
`
`Table 6 Evolutive characteristics of RRMS patients who remained in RRMS after 3 years, patients who changed their clinical form from
`RRMSto SPMS(early SPMS) and late SPMS patientseee
`
`Initial median
`Mean
`Mean age
`Sex (M/F)
`Mean age
`n
`EDSS
`evolution time
`at diagnosis
`cree
`
`RRMS
`47
`35.4
`15/32
`28.5
`6.5
`2.5*
`Early SPMS
`13
`37.4
`4/9
`28.2
`ners
`o5*
`
`
`
`
`
`
`13 46.5 0/3 33.4 128%Late SPMS 6.0"eee
`Statistical significant differences were reachedin the initial EDSS between RRMSandearly SPMS, the mean evolution time between early
`SPMSand late SPMSandin initial EDSS between early SPMSandlate SPMS. *P=0.03, Mann—Whitney’s U-test. **P=0.04. 'P<0.000,
`Mann~—Whitney’s U-test.
`aD
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`Clinical inflammatory activity
`B Casanova et al
`
`cannot conclude(it was not the objective) that the conver-
`sion to SPMS depends on an increasedclinical activity, as
`measured in the numberof exacerbations, although thereis
`evidence of moreclinical activities at this moment.** We
`proposeto call “Early Secondary Progressive Multiple Scle-
`rosis” the interval of the “year of progression” and the
`following year, because it is during this interval of time
`(and in the previous year) when there is more clinical
`inflammatory activity. The identification of this stage is
`important for patient management and design of future
`trials because the natural evolution after this phase of the
`disease tends to a reduction of the exacerbation and the
`progression rates. Examples of the hypothesis mentioned
`above are the three studies of interferons in SPMS. The
`main difference between them was the time of evolution
`since the beginning of the progressive stage. In the Euro-
`pean interferon beta-1b study,° it was 2.1 years, while in the
`USA interferon beta-1b study® and in the SPECTRIMS,” it
`was 4 years. In these trials, contradictory results were
`obtained apparently. While the European interferon beta-
`1b study showed a reduction in the progression of the
`disability, this objective was not reached at the SPECTRIMS
`and the USA interferon beta-1b studies. One possible
`explanation for these results is that in the European inter-
`feron beta-1b study, a higher numberof patients with more
`inflammatory activity (exacerbations) were included.
`According to the results of several RRMStrials,®° the
`significant lower MCR in the treatment group comparedto
`placebo group hada relationship with the effect of inter-
`feron-B on the disability due to exacerbations, and not with
`a possible effect over the progression. A retrospective study
`of Hughes and SPECTRIMS Group”” after the publication of
`the SPECTRIMS results has approached this issue. They
`classified the SPMS placebo patients in two groups: a
`“relapsing” SPMS group and a “nonrelapsing” SPMS group.
`They found more activity in the exacerbation rate and a
`faster progression in thefirst group.
`On the other hand, our MCR results in the late SPMS and
`in PPMS (between 0.25 and 0.35) are lower than those in
`other published studies. This fact supports the hypothesis
`that there is a similar mechanism responsible for progres-
`sion which is independent of the previous stage of the
`disease, as it has been pointed out by Confavreux et al*™
`Thus, the main difference between the SPMS and the PPMS
`is the disability degree at the beginning of progression.
`To conclude, we should take into accountthat there is a
`higherclinical inflammatory activity in “Early SPMS”; this
`is an important fact for the design of futuretrials, but it is
`
`necessary to confirm our results with a larger cohort of
`patients and a prolonged observational time.
`
`Acknowledgement
`The authors thank Dr Olga Solifio for the review and
`suggestions in this work.
`
`References
`
`1 Lublin FD, Reingold SC, The Advisor Committee on Clinical
`Trials of New Agents in Multiple Sclerosis. Definingtheclinical
`course of multiple sclerosis: results of an international survey.
`Neurology 1996; 46; 907-11.
`2 Confavreux C, Aimard G, Devic M. Course and prognosis of
`multiple sclerosis assessed by the computerised data processing
`of 349 patients. Brain 1980; 103: 281-300.
`3 Minderhoud JM, Van der Hoeven JH, Pnage AJA. Course and
`prognosis of chronic progressive multiple sclerosis. Results of
`an epidemiological study. Acta Neurol Scand 1988; 78: 10-15.
`4 Poser CM,Paty DW, Scheinberg L. New diagnostic criteria for
`multiple sclerosis: guidelines for research protocols. Ann Neu-
`rol 1983; 13: 227-31.
`5 European Study Group on INF B-1b in Secondary Progressive
`Multiple Sclerosis. Placebo-controlled multicentre randomised
`trial of interferon B-1b in treatment of secondary progressive
`multiple sclerosis. Lancet 1998; 352: 1491-97.
`6 Goodking DE, The North American Study Group on Interferon
`B-1b in Secondary Progressive MS.Interferon beta-1b in secon-
`dary progressive MS: clinical and MRI results of a 3-year
`randomized controlledtrial. Neurology 2000; 54: 2352.
`7 The SPECTRIMS Groups. London, UK. SPECTRIMS study (data
`on file). Presented at the 52nd Annual Meeting of the American
`Academy of Neurology, EEUU, San Diego, 29 April-6 May
`2000.
`
`8 The IFNB Multiple Sclerosis Group. Interferon beta-1b is effec-
`tive in relapsing—remitting multiplesclerosis. I: Clinical results
`of a multicenter, double-blind, randomized, placebo-controlled
`trial. Neurology 1993; 43: 655-61.
`9 Freedman MS, The PRIMS Study Group, Ottawa, Ontario,
`Canada. PRIMS4-year results: evidenceof clinical dose effect
`of interferon beta-1° in relapsing MS. Neurology 2000; 54:
`2351.
`
`10 Hughes RAC, SPECTRIMS Group, London, UK. “Relapsing” vs
`“non-relapsing” SPMS: different prognosis and responses to
`interferon therapy in the SPECTRIMS study. Neurology 2000;
`54(Suppl3): S38003.
`11 Confavreux C, Vukusic M, Moreau T, Adeleine. Relapses and
`progression of disability in multiple sclerosis. N Engl J Med
`2000; 343: 1430-38.
`
`SS
`
`Multiple Sclerosis
`
`Petitioner TWi Pharms., Inc.
`EX1015, Page 5 of 5
`
`Petitioner TWi Pharms., Inc.
`EX1015, Page 5 of 5
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