natgillin/translations-raw huggingface dataset:
I postmarketingerfaring har der været rapporter om patienter, herunder rheumatoid faktor positive patienter, som har udviklet andre autoantistoffer i forbindelse med udslæt som er kompatibel med subaktiv kutan lupus eller diskoid lupus ved klinisk præsentation og biopsi.
There have been rare reports of patients, including rheumatoid factor positive patients, who have developed other autoantibodies in conjunction with a lupus-like syndrome or rashes that are compatible with subacute cutaneous lupus or discoid lupus by clinical presentation and biopsy.
Der har været postmarketingsrapporter om pancytopeni og aplastisk anæmi, hvoraf visse havde dødelig udgang (se afsnit 4. 4).
There have been postmarketing reports of pancytopenia and aplastic anaemia, some of which had fatal outcomes (see section 4.4)
36 Laboratorieundersøgelser
Laboratory evaluations
Baseret på resultaterne fra kliniske undersøgelser vil det normalt ikke være nødvendigt med specialle laboratorieundersøgelser i tillæg til omhyggelig medicinsk behandling og tilsyn med patienterne.
Based on the results of clinical studies, normally no special laboratory evaluations are necessary in addition to careful medical management and supervision of patients.
I undersøgelser, hvor voksne patienter blev behandlet samtidig med Enbrel og anakinra, blev der observeret en større hyppighed af alvorlige infektioner sammenlignet med Enbrel alene, og 2% af patienterne (3/ 139) udviklede neutropeni (absolut neutrofiltælling < 1000/ mm3).
In studies when adult patients received concurrent treatment with Enbrel plus anakinra, a higher rate of serious infections compared to Enbrel alone was observed and 2% of patients (3/ 139) developed neutropenia (absolute neutrophil count < 1000 / mm3).
Uønskede virkninger hos pædiatriske patienter med polyartikulær juvenil idiopatisk artrit
Undesirable effects in paediatric patients with polyarticular juvenile idiopathic arthritis
Typen af infektioner, som blev observeret i kliniske undersøgelser med patienter med juvenil, idiopatisk artrit i alderen 2 til 18 år, var generelt milde til moderate og svarende til dem, som almindeligvis ses hos ambulante, pædiatriske populationer.
40 The types of infections seen in clinical trials in juvenile idiopathic arthritis patients aged 2 to 18 years were generally mild to moderate and consistent with those commonly seen in outpatient paediatric populations.
Alvorlige rapporterede bivirkninger omfattede varicella med tegn og symptomer på aseptisk meningitis, som forsvandt under eftervirkninger (se også afsnit 4. 4), appendicit, gastroenteritis, depression/ personlighedsforstyrrelse, sår på huden og oesofagitis/ gastritis.
Severe adverse events reported included varicella with signs and symptoms of aseptic meningitis, which resolved without sequelae (see also section 4.4), appendicitis, gastroenteritis, depression/ personality disorder, cutaneous ulcer, oesophagitis/ gastritis, group A streptococcal septic shock, type I diabetes mellitus, and soft tissue and post-operative wound infection.
I kliniske undersøgelser omkring juvenil idiopatisk artrit var der 4 indberetninger om makrofag - aktiverings- syndrom.
There were 4 reports of macrophage activation syndrome in juvenile idiopathic arthritis clinical trials.
37 Farmakoterapeutisk klassifikation:
Pharmacotherapeutic group:
ATC- kode: L04AB01
L04AB01
Etanercept er en kompetitiv inhibitor af TNF- binding til celleoverfladereceptorer og hæmmer dermed TNF’ s biologiske aktivitet. TNF og lymfotoksin er pro- inflammatoriske cytokiner, som binder sig til to adskilte celleoverfladereceptorer:
Etanercept is a competitive inhibitor of TNF-binding to its cell surface receptors and thereby inhibits the biological activity of TNF.
55 - kilodalton (p55) og 75- kilodalton (p75) tumornekrosefaktorreceptorer (TNFR).
TNF and lymphotoxin are pro- inflammatory cytokines that bind to two distinct cell surface receptors: the 55-kilodalton (p55) and 75-kilodalton (p75) tumour necrosis factor receptors (TNFRs).
TNF og lymfotoksin eksisterer hovedsageligt som homotrimere, og deres biologiske aktivitet er afhængig af tværbinding af celleoverflade TNF- receptorer.
41 TNF and lymphotoxin exist predominantly as homotrimers, with their biological activity dependent on cross-linking of cell surface TNFRs.
Dette afsnit indeholder data fra fire randomiserede, kontrollerede undersøgelser af voksne med reumatoid artrit, en undersøgelse af polyartikulær juvenil idiopatisk artrit, en undersøgelse af voksne med psoriasis artrit, en undersøgelse af voksne med ankyloserende spondylitis, en undersøgelse af pædiatriske patienter med plaque psoriasis og fire undersøgelser af voksne med plaque psoriasis.
This section presents data from four randomised controlled trials in adults with rheumatoid arthritis, one study in polyarticular juvenile idiopathic arthritis, one study in adults with psoriatic arthritis, one study in adults with ankylosing spondylitis, one study in paediatric patients with plaque psoriasis, and four studies in adults with plaque psoriasis.
Resultaterne af dette kontrollerede forsøg blev angivet i procentvis forbedring af reumatoid artrit ved anvendelse af American College of Rheumatology’ s (ACR) kriterier for respons.
The results of this controlled trial were expressed in percentage improvement in rheumatoid arthritis using American College of Rheumatology (ACR) response criteria.
Enbrel 62% og 59%, placebo 23% og 11% ved henholdsvis 3 og 6 måneder; ACR 50:
Enbrel 62% and 59%, placebo 23% and 11% at 3 and 6 months respectively; ACR 50:
Der blev besvaret et spørgeskema om helbredstilstand
Enbrel was significantly better than placebo in all components of the ACR criteria as well as other measures of rheumatoid arthritis disease activity not included in the ACR response criteria, such as morning stiffness.
38 (SHT), omfattende handicap, vitalitet, mentalhygiejne, generel sundhedstilstand og helbredsstatus for arthritis- afhængige underområder hver 3. måned under forsøget.
A Health Assessment Questionnaire (HAQ), which included disability, vitality, mental health, general health status, and arthritis-associated health status subdomains, was administered every 3 months during the trial.
Efter ophør med Enbrel vendte symptomerne på artrit almindeligvis tilbage inden for en måned.
After discontinuation of Enbrel, syptoms of arthritis generally returned within a month.
Gentoptaget behandling med Enbrel efter ophør i op til 24 måneder resulterede i samme størrelse af respons som hos patienter, som fik Enbrel uden behandlingsafbrydelse, baseret på resultater fra åbne undersøgelser.
Re-introduction of treatment with Enbrel after discontinuations of up to 24 months resulted in the same magnitudes of response as patients who received Enbrel without interruption of therapy based on results of open-label studies.
Fortsat, varig respons er set i op til 48 måneder i åbne, forlængede undersøgelser hos patienter som fik Enbrel unden afbrydelse.
Continued durable responses have been seen for up to 48 months in open-label extension
Erfaring med længerevarende behandling findes ikke.
42 treatment trials when patients received Enbrel without interruption; longer-term experience is not available.
Effekten af Enbrel blev sammenlignet med mehotrexat i et randomiseret, aktivt kontrolleret forsøg med blindet radiografisk evaluering som primært mål hos 632 vosne patienter med aktiv reumatoid artrit (< 3 års varighed), som ikke tidligere var blevet behandlet med methotrexat.
The efficacy of Enbrel was compared to methotrexate in a randomised, active-controlled study with blinded radiographic evaluations as a primary endpoint in 632 adult patients with active rheumatoid arthritis (< 3 years duration) who had never received treatment with methotrexate.
RADIOGRAFISK PROGRESSION:
RADIOGRAPHIC PROGRESSION:
SAMMENLIGNING AF ENBREL vs METHOTREXAT HOS PATIENTER MED REUMATOID ARTRIT AF < 3 ÅRS VARIGHED
COMPARISON OF ENBREL vs METHOTREXATE IN PATIENTS WITH RA OF < 3 YEARS
I en anden aktivt- kontrolleret, dobbeltblind, randomiseret undersøgelse blev klinisk effekt, sikkerhed og radiografisk progession hos patienter med reumatoid artrit behandlet med Enbrel alene (25 mg to gange om ugen), methotrexat alene (7, 5 til 20 mg om ugen, median dosis 20 mg) og en kombination af Enbrel og methotrexat påbegyndt samtidig, sammenlignet hos 682 voksne patienter med aktiv reumatoid artrit af 6 måneder til 20 års varighed (median 5 år), som havde en mindre end
In another active-controlled, double-blind, randomised study, clinical efficacy, safety, and radiographic progression in RA patients treated with Enbrel alone (25 mg twice weekly), methotrexate alone (7.5 to 20 mg weekly, median dose 20 mg), and of the combination of Enbrel and methotrexate initiated concurrently were compared in 682 adult patients with active rheumatoid arthritis of 6 months to 20 years duration (median 5 years) who had a less than satisfactory response to at least 1 disease-modifying antirheumatic drug (DMARD) other than methotrexate.
Gruppen af patienter i behandling med Enbrel i kombination med methotrexat havde signifikant højere ACR 20, ACR 50, ACR 70 respons og forbedring af DAS score ved både 24 og 52 uger end patienterne i hver af enkeltterapi grupperne (resultater vises neden for).
43 Patients in the Enbrel in combination with methotrexate therapy group had significantly higher ACR 20, ACR 50, ACR 70 responses and improvement for DAS and HAQ scores at both 24 and 52 weeks than patients in either of the single therapy groups (results shown in table below).
RESULTER FOR KLINISK EFFEKT EFTER 12 MÅNEDER:
CLINICAL EFFICACY RESULTS AT 12 MONTHS:
A:
a:
Patienter, som ikke gennemførte 12 måneder af undersøgelsen, blev betragtet som ikke - responderende. b:
Patients who did not complete 12 months in the study were considered to be non- responders. b:
Værdier for sygdoms aktivitets score (Disease Activity Score, DAS) er middelværdier. c: remission er defineret som DAS < 1, 6
Values for DAS are means. c:
40 RADIOGRAFISK PROGRESSION:
44 RADIOGRAPHIC PROGRESSION:
SAMMENLIGNING AF ENBREL vs METHOTREXAT vs ENBREL I KOMBINATION MED METHOTREXAT HOS PATIENTER MED REUMATOID ARTRIT AF 6 MÅNEDER TIL 20 ÅRS VARIGHED (12 MÅNEDERS RESULTER)
COMPARISON OF ENBREL vs METHOTREXATE vs ENBREL IN COMBINATION WITH METHOTREXATE IN PATIENTS WITH RA OF 6 MONTHS TO 20 YEARS DURATION (12 MONTH RESULTS)
Blandt patienter, som gennemførte undersøgelsens 24 måneders behandling, var ikke- progressionsraterne henholdsvis 78%, 70% og 62%.
Among patients who completed a full 24 months of therapy in the study, the non-progression rates were 78%, 70%, and 61%, respectively.
Sikkerhed og effekt af 50 mg Enbrel (to gange 25 mg subkutan injektion) indgivet en gang om ugen blev undersøgt i en dobbeltblind, placebo- kontrolleret undersøgelse med 420 patienter med aktiv reumatoid artrit.
The safety and efficacy of 50 mg Enbrel (two 25 mg SC injections) administered once weekly were evaluated in a double-blind, placebo-controlled study of 420 patients with active RA.
Patienterne fik fortsat en stabil dosis af et enkelt nonsteroidt anti- inflammatorisk præparat og/ eller prednison (< 0, 2 mg/ kg/ dag eller maksimum 10 mg).
45 inflammatory drug and/ or prednisone (< 0.2 mg/ kg/ day or 10 mg maximum).
I anden del blev patienterne med klinisk respons på dag 90 randomiseret til at forsætte med Enbrel eller få placebo i fire måneder for at 41 evaluere, om sygdommen blussede op.
In part 2, patients with a clinical response at day 90 were randomised to remain on Enbrel or receive placebo for four months and assessed for disease flare.
Doser på 25 mg Enbrel (baseret på dosisundersøgelser hos patienter med reumatoid artrit) eller placebo blev indgivet subkutant to gange om ugen i 6 måneder.
Doses of 25 mg Enbrel (based on dose-finding studies in patients with rheumatoid arthritis) or placebo were administered SC twice a week for 6 months.
42 RESPONS HOS PATIENTER MED PSORIASIS ARTRIT I PLACEBO- KONTROLLEREDE FORSØG% af patienter
46 RESPONSES OF PATIENTS WITH PSORIATIC ARTHRITIS IN PLACEBO-CONTROLLED TRIAL Percent of Patients
Livskvaliteten hos patienterne med psoriasis artrit blev bedømt på hvert tidspunkt ved brug af HAQs invaliditetsindeks.
Quality of life in psoriatic arthritis patients was assessed at every timepoint using the disability index of the HAQ.
43 Behandling med Enbrel resulterede i forbedret fysisk funktion i den dobbeltblinde undersøgelsesperiode, og denne bedring blev fastholdt i den forlængede undersøgelse på op til 2 år.
47 Enbrel treatment resulted in improvement in physical function during the double-blind period, and this benefit was maintained during the longer-term exposure of up to 2 years.
Der er ikke udført undersøgelser af patienter med psoriasis artrit, som blev behandlet med 50 mg en gang om ugen.
No study has been performed in patients with psoriatic arthritis using the 50 mg once weekly dosing regimen.
RESPONS FRA PATIENTER MED ANKYLOSERENDE SPONDYLITIS I EN PLACEBO- KONTROLLERET UNDERSØGELSE Procent patienter
48 RESPONSES OF PATIENTS WITH ANKYLOSING SPONDYLITIS IN A PLACEBO-CONTROLLED TRIAL Percent of Patients
a: p < 0. 001, Enbrel vs.
a: p < 0.001, Enbrel vs.
Placebo
Placebo b: p = 0.002, Enbrel vs. placebo
44 placebo- kontrolleret undersøgelse med 356 patienter med aktiv ankyloserende spondylitis.
In a fourth study, the safety and efficacy of 50 mg Enbrel (two 25 mg SC injections) administered once weekly vs 25 mg Enbrel administered twice weekly were evaluated in a double-blind, placebo-controlled study of 356 patients with active ankylosing spondylitis.
Patienterne var ≥ 18 år.
49 Study 1 was a Phase 2 study in patients with active but clinically stable plaque psoriasis involving  10% of the body surface area that were  18 years old.
45 PASI 50
wk 12 wk 12 wk
I studie 2 var der også en periode uden behandling, hvor patienter, som efter 24 uger havde opnået en forbedring på mindst 50% på PASI, fik stoppet behandlingen.
50 Study 2 also had a drug withdrawal period during which patients who achieved a PASI improvement of at least 50% at week 24 had treatment stopped.
For patienter, som fik 50 mg én gang om ugen i hele underøgelsen, fortsatte effekt- responsen med at forbedres, så 71% opnåede PASI 75 i uge 24.
For patients who received 50 mg once weekly throughout the study, the efficacy responses continued to improve with 71% achieving PASI 75 at week 24.
PASI 75) end patienter, der var randomiseret til placebo.
At week 12, more patients randomised to Enbrel had positive efficacy responses (e. g., PASI 75) than those randomised to placebo.
sPGA ” klar ” eller ” minimal ”, n (%) Forkortelse: sPGA: static Physician Global Assessment a. p < 0, 0001 sammenlignet med placebo
sPGA “ clear” or “ minimal”, n (%)
Antistoffer mod Enbrel
51 Antibodies to Enbrel
Middel serumkoncentrationsprofilerne ved steady- state hos behandlede patienter med reumatoid artrit var henholdsvis Cmax på 2, 4 mg/ l vs 2, 6 mg/ l, Cmin på 1, 2 mg/ l vs 1, 4 mg/ l, og partiel AUC på 297 mgh/ l vs 316 mgh/ l for Enbrel 50 mg en gang om ugen (n=21) vs Enbrel 25 mg to gange om ugen (n=16).
Mean serum concentration profiles at steady state in treated RA patients were Cmax of 2.4 mg/ l vs 2.6 mg/ l, Cmin 1.2 mg/ l vs 1.4 mg/ l and partial AUC of 297 mgh/ l vs 316 mgh/ l for 50 mg Enbrel once weekly (n=21) vs 25 mg Enbrel twice weekly (n=16), respectively.
I en åben, enkeltdosis, dobbeltbehandling, cross- over undersøgelse med sunde frivillige, blev etanercept, når
In an open-label, single-dose, two- treatment, crossover study in healthy volunteers, etanercept administered as a single 50 mg/ ml injection was found to be bioequivalent to two simultaneous injections of 25 mg/ ml.
Selvom der er eliminering af radioaktivitet i urinen efter indgivelse af radioaktivt mærket etanercept til patienter og frivillige, blev der ikke observeret forøgede etanercept- koncentrationer hos patienter med akut nyre - eller leversvigt.
52 Although there is elimination of radioactivity in urine after administration of radiolabelled etanercept to patients and volunteers, increased etanercept concentrations were not observed in patients with acute renal or hepatic failure.
Enbrel fremkaldte ikke dosisbegrænsende eller målorgantoksicitet hos cynomolgus- aber efter subkutan indgivelse to gange ugentligt i 4 eller 26 uger i træk med en dosis (15 mg/ kg), som resulterede i AUC- baserede serumkoncentrationer af stoffet, der var over 27 gange højere end dem, der blev opnået hos mennesker ved den anbefalede dosis på 25 mg.
Enbrel did not elicit dose-limiting or target organ toxicity in cynomolgus monkeys following twice weekly subcutaneous administration for 4 or 26 consecutive weeks at a dose (15 mg/ kg) that resulted in AUC-based serum drug concentrations that were over 27-fold higher than that obtained in humans at the recommended dose of 25 mg.
Mannitol, sakkarose og trometamol.
Mannitol Sucrose Trometamol
48 6. 2 Uforligeligheder
6.2 Incompatibilities
Kemisk og fysisk stabilitet er vist at være 48 timer ved 2oC – 8oC.
Chemical and physical stability has been demonstrated for 48 hours at 2 – 8 C.
Hvis det ikke anvendes umiddelbart, er opbevaringstiden brugerens ansvar og bør normalt ikke være mere end 6 timer ved 2oC – 8oC, med mindre opblandingen har fundet sted under kontrollerede og validerede aseptiske forhold.
If not used immediately, storage times are the responsibility of the user and should normally not be longer than 6 hours at 2 – 8 C, unless reconstitution has taken place in controlled and validated aseptic conditions.
Opløsningen skal være klar og farveløs til bleg gul, uden klumper, flager eller partikler.
The solution should be clear and colourless to pale yellow with no lumps, flakes or particles.
Detaljeret vejledning om forberedelse og indgivelse af rekonstitueret Enbrel findes i indlægssedlen, afsnit 7, ” Vejledning til forberedelse og indgivelse af Enbrel ”
Comprehensive instructions for the preparation and administration of the reconstituted Enbrel vial are given in the package leaflet, section 7, "Instructions for preparation and giving an injection of Enbrel."
50 1.
55 1.
Etanercept er et humant tumornekrosefaktorreceptor p75 Fc- fusionsprotein, som er fremstillet ved rekombinant DNA- teknologi i et Chinese hamster ovary (CHO) mammaltekspressionssystem.
Etanercept is a human tumour necrosis factor receptor p75 Fc fusion protein produced by recombinant DNA technology in a Chinese hamster ovary (CHO) mammalian expression system.
51 Ankyloserende spondylitis Behandling af voksne med alvorlig aktiv ankyloserende spondylitis, hvor responsen på konventionel behandling har været utilstrækkelig.
Treatment of adults with severe active ankylosing spondylitis who have had an inadequate response to conventional therapy.
Alternativt kan 50 mg indgives en gang om ugen, hvilket har vist sig at være sikkert og effektivt (se afsnit 5. 1).
Alternatively, 50 mg administered once weekly has been shown to be safe and effective (see section 5.1).
Psoriasis artrit og ankyloserende spondylitis:
Psoriatic arthritis and ankylosing spondylitis
Plaque psoriasis:
57 Plaque psoriasis
52 Ovenstående anbefalinger vedrørende behandlingsvarighed bør følges, hvis gentagen behandling med Enbrel er indiceret.
If re-treatment with Enbrel is indicated, the above guidance on treatment duration should be followed.
4. 4 Særlige advarsler og forsigtighedsregler vedrørende brugen
58 4.4 Special warnings and precautions for use
Når patienterne bliver vurderet med hensyn til infektioner, bør patientens risiko for relevante opportunistiske infektioner (f. eks. eksponering for endemisk mykose) tages med i overvejelserne.
In evaluating patients for infections, the patient’ s risk for relevant opportunistic infections (e. g., exposure to endemic mycoses) should be considered.
Det anbefales, at udførelsen af disse undersøgelser noteres i patientens ’ Patientkort ’.
It is recommended that the conduct of these tests should be recorded in the patient’ s alert card.
53 Hepatitis B- virus reaktivering Der er indberetninger om reaktivering af hepatitis B- virus (HBV) hos patienter, som er kroniske bærere af denne virus, og som er i behandling med TNF- antagonister, herunder Enbrel.
Reactivation of hepatitis B virus (HBV) in patients who are chronic carriers of this virus who are receiving TNF-antagonists including Enbrel has been reported.
Allergiske reaktioner Der er hyppigt rapporteret om allergiske reaktioner associeret med indgivelse af Enbrel.
Allergic reactions associated with Enbrel administration have been reported commonly.
Allergiske reaktioner har inkluderet angio- ødem og urticaria, alvorlige reaktioner er forekommet.
Allergic reactions have included angioedema and urticaria; serious reactions have occurred.
I en undersøgelse med 49 voksne patienter med reumatoid artrit, som blev behandlet med Enbrel, var der ingen tegn på nedsættelse af tardiv overfølsomhed, nedsættelse af immunoglobulin - niveauer eller ændring i optællingen af effektorcellepopulationer
In a study of 49 adult patients with rheumatoid arthritis treated with Enbrel, there was no evidence of depression of delayed-type hypersensitivity, depression of immunoglobulin levels, or change in enumeration of effector cell populations.
I de kontrollerede dele af de kliniske undersøgelser med TNF- antagonister blev der observeret flere tilfælde af lymfom blandt patienter, der fik en TNF- antagonist, sammenlignet med kontrolpatienterne.
60 In the controlled portions of clinical trials of TNF-antagonists, more cases of lymphoma have been observed among patients receiving a TNF-antagonist compared with control patients.
54 Vaccinationer Levende vacciner bør ikke gives samtidigt med Enbrel.
Live vaccines should not be given concurrently with Enbrel.
I denne undersøgelse var de fleste psoriasis artrit patienter behandlet med Enbrel i stand til at rejse en effektivt B- celle immunrespons mod pneumokok polysakkarid vaccine, men aggregrattitrene var moderat lavere, og få patienter havde dobbelt stigning i titrene i sammenligning med patienter, som ikke fik Enbrel.
In this study most psoriatic arthritis patients receiving Enbrel were able to mount effective B-cell immune response to pneumococcal polysaccharide vaccine, but titers in aggregate were moderately lower and few patients had two-fold rises in titers compared to patients not receiving Enbrel.
Alle patienter og forældre/ plejere skal informeres om, at hvis patienten udvikler tegn eller symptomer, som kan pege på bloddyskrasi eller infektioner (f. eks. vedvarende feber, øm hals, blå mærker, blødning, bleghed) mens de er i behandling med Enbrel, skal de omgående søge læge.
All patients and parents/ caregivers should be advised that if the patient develops signs and symptoms suggestive of blood dyscrasias or infections (e. g., persistent fever, sore throat, bruising, bleeding, paleness) whilst on Enbrel, they should seek immediate medical advice.
CNS sygdomme Der har været sjældne rapporter om CNS demyeliniseringslidelser hos patienter behandlet med Enbrel (se afsnit 4. 8).
There have been rare reports of CNS demyelinating disorders in patients treated with Enbrel (see section 4.8).
Selvom der ikke har været foretaget nogle kliniske studier for at evaluere Enbrel behandling af patienter med multipel sclerose, har kliniske studier af andre TNF antagonister hos patienter med multipel sclerose vist forøgelse i sygdoms aktiviteten.
Although no clinical trials have been performed evaluating Enbrel therapy in patients with multiple sclerosis, clinical trials of other TNF antagonists in patients with multiple sclerosis have shown increases in disease activity.
En omhyggelig risiko/ benefit evaluering, incl. neurologisk vurdering, anbefales, når Enbrel udskrives til patienter med eksisterende eller begyndende CNS demyeliniseringssygdomme, eller til patienter som vurderes at have en øget risiko for at udvikle demyeliniseringssygdom.
A careful risk/ benefit evaluation, including a neurological assessment, is recommended when prescribing Enbrel to patients with pre-existing or recent onset of CNS demyelinating disease, or to those who are considered to have an increased risk of developing demyelinating disease.