Beruflich Dokumente
Kultur Dokumente
No
January 2005
ffi
dtb
d
Treatnent Notes
complications, such as bleeding or perforation of gastric or duodenal ulcers.l ln September 2004, newly released evidence about cardiovascular risk with rofecoxib led Merck Sharp & Dohme to voluntarily withdraw the drug worldwide.2 This has raised questions about the balance of benefit and risk with coxibs in general.
Here we iscuss the evidence relating to the gastrointestina
Ia
with
Background
Conventional (non-selective) NSAIDs inhibit rwo
isoforms ofthe enzyme ryclo-orygenase (CO)0
The coxibs
-COX-1
The withdrawal ofrofecoxib left three orally administered coxibs arailable in the UK for the treamrent ofpatients with OA or RA - celecoxib, Vetoricoxib and Vvaldecoxib. A fourth, lumiracoib, has beeo iicensed but not launched in the UK for the matment of patients with OA.
Coxibs differ from one another in various ways, and cannot be assumed to have identical clinical effects. Celecoxib and valdecoxib are sulfonamides. Etoricoxib and rofecoxib are methylsulfones. Lumiracoxib, a phenylacetic acid derirztive, is structurally diffcrent from the othercoxibs and more closely resembles diclofenac.r'r None of the coxibs
and COX-2.1r COX-1 is expressed continuouslyin most tissues and, in the stomach, catalyses production of prostaglandins that protect the gastric mucosa. COX-2 is
inflammatory stimuli, and catalyses production ofprostaglandins that mediate inflammation.' Inhibition of COX-1 is thought to be the main way in which NSAIDs cause gastrointestina[ damage. ro Anti-infl ammatory effrcacy is believed to result from inhibition of COX-2. At therapeutic doses, coxibs inhibit COX-2 but not COX-1, so it was postulated that they should relieve inflammationwith less gastrointestinal toxiciry than conventional NSAIDs. However, selective iohibition of COX-2 appears more complex than first suggested, as COX-2 has many other functions besides its role in inflammation.r In the vascular endothelium, it mediates production ofprostaglandin
their physicochemical properties (e.g. acidiry lipophilicity) and pharmacokinetic characteristics (e.g. rate of absorp-
vasodilator and inhibitor ofboth platelet aggregation and proliferation of vascular smooth muscle cells. Convenely, COX-1 mediates synthesis ofthromboxane A,, a vasoconstrictor and stimulator ofboth platelet aggregation and vascular proliferation.t6 Both isoforms are probably important in vascular homeostasis and rcgulation of platelet function. Both are also expressed in the kidney and are thought to have important roles in health and conditions of renal stress (such as hypovolaemia).r Exa
PGI,
tion and elimination). Lumiracoxib is shortest-acting (elimination half-life around 5 hours), and etoricoxib
longest-acting (half-life 20-26 hours).1')
Clinical efficacy
Published randomised controlled trials of coxibs in patients with OA and RA have, in general, demonstrated anti-inflammatory efficacy similar to that ofcomparator NSAIDs.tt rr We know of only one trial that has shown
perimental evidence suggests that COX-2 may help to protect the myocardium during ischaemia,s and may also be involved in the healing ofgastric ulcers.'
superior efficacy.
12 weeks and
In that
involved 815 patients with RA, etoricoxib 90mg daily was more effective on all main endpoints than
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naproxen 500mg twice daily.rn We know of no convincing evidence that, atoptimal effecdve doses, any one coxib is superior to another in patients with OA or RA.
Rofecoxib
Gastrointestinal effects
Dyspeptictype symptoms
Among all patients started on conventional NSAIDs,
around 15-4O26 experience dppepsia, nausea or abdominaJ pain, and up to 1006 change or discontinue treatment as a result.rt Such symptoms often occur without endoscopic evidence ofmucosal damage. In published doubleblind comparative snrdies, dyspeptic symptoms seem to occur at a similar or slightly lower rate with coxibs than with conventional NSAIDs, prompting treatment discontinuation in around 2--6% and 4-8%, respectively II rr'rr'rr'r'q There are few data on gastrointestinal tolerabilit_v ofcoxibs in patients who are unable to tolerate conventional N SAIDs.
months), the rate ofgasroduodenal perforation or obstruction, proven symptomatic ulcer, and upper gastrointestinal bleeding ('PLIBs') - the primary outcome measure - !!?s lower in the rofecoxib group than in the naproxen group (2.7 vs. 4.5 per 100 patient-years, relative risk [RR] 0.5, 95% CI 0.3-0.6).This corresponds to a number needed to treat (NNT) of42. The rate ofconlirmed ulcer complications (perforation, obstmction, severe bleeding) was also lower on rofecoxib (0.6 vs. 1.4 per 100 patient-years, RR 0.4, 950,6 CI 0.2-O.8; NNT 125).
Celecoxib
Endoscopic u lceration
Gastric or duodenal ulcers can be detected endoscopicallyin around 10-20% ofpeople on regulardoses ofcon-
The Celecoxib Long-term Arthritis Safety Study (CLASS) was originally planned as two separate
randomised controlled trials both involving patients with OA or RA." One study was to compare celecoxib 400mg twice daily (four times the usual dose for OA, twice the maximal dose for RA) with ibuprofen 800mg three times daily, taken for 15 months. The other was to compare celecoxib 400mg twice dailywith diclofenac 75mg twice d?ily for 12 months. Controversially, the findings were published as a single three-arm study involving 8,059 patients, and only included data from the first 6 months extrapolated to a predicted 1-year rate.': This analysis and prcsentation have been heavily criticised,ri not least because, in realiry almost all ulcer complications that occurred after 6 monthswere in patients taking celecoxib.rtl
ventional NSAIDs.'r' An additional 20-400% have mucosal erosions. The incidence of endoscopic ulceration and erosions durin8 treatment with coxibs is much lower (around 5-70,6), comparable to that with placebo,
and does not rise with increasing doses of coxibs.
r'r'rr"rr
rr
cause
symptoms or complications. However, some authorities consider it a surrogate marker for the risk of a clinical complication, such as bleeding or perforation. Indirect support for this comes from a 6-month double-blind study
Use
Severe gastrointestina I toxicity ofNSAIDs is associated with around a fourfold increase in the incidence of severe upper gasrointestinal
ulcer complications (e.g. bleeding and perforation) compared with the rate in non-users of NSAIDs.2i Bleeding
an
NSAID-induced ulcer and such complications account for an estimated 700 to 2,000 deaths in the UK each year.ru 2t The risk persists throughout treatment,r5 and is
increased by a previous history ofgastroduodenal ulceration; use ofhigher doses of NSAIDs; co-prescription of
daa for the first 6 months, the repon predicted a lower 1-year incidence ofconfirmed syrnptomatic ulcers and ulcer complications with celecoxib than with conventional NSAIDs (2.08 rs. 3.54, p=0.02; NNT 68).rr However, for the designated primary outcome measure ofulcer complications alone, the predicted l-year incidence did not differ significandy between the groups, either for the study population as a whole (0.76% with celecoxib w. 1.45010, p=Q.99; o, for the subgroup ofpatients (around 2S6) who were receiving low-dose aspirin for cardiorascular prophylaxis (2.01026 with celecoxib w. 2.12%, p=0.fi). For patients not taking aspirin, the predicted 1-1ear incidence ofulcer complications was lower in t]re celecoxib group (0.447o rs. 1.27%, RR 0.35, 950,6 CI0.14-0.98; NNT 120).I Howwer, even in this subgroup, subsequendy released actual (rather than prediaed) results at 12 months showed no significant difference.rl
Based on
corticosteroids, anticoagulants or aspirin; and the presence ofother significant diseases.r5 r'The absolute risk is highest in people aged over 65 years. The risk ofsevere gastrointestinal toxicity in people taking coxibs has been investigated in large randomised controlled trials in which serious gastrointestinal events were the primaryoutcome. Fully published studies ofthis kind
are available for rofecoxib, celecoxib and lumiracoxib,
Lumiracoxib
The Therapeutic Arthritis Research and Gastrointestinal Event Tiial (TARGET) randomised a total of18,325 patients with OA to two similar double-blind 'substudies', each lasting 52 weeks.]r In one, patients received randomised treatment with lumiracoxib 400mg daily (two to four times the usual dose for OA) or ibuprofen 800mg thrce times daily.In the other, patients receircd lumiracoxib 400mg daily or naproxen 500mg twice daily. In all,24% ofpatients were receiving low-dose aspirin at trial entryt1 The primary
but
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outcome measure was the difference in time to definit or probable upper gasftointestinal ulcer complication (clinically significant bleeding, perforation or obsruction). For the overall population, fewer patients on lumaricoxib had a definite or probable ulcer complication (0.32% vs. 0.91% in the combined NSAID groups, hazard ratio [HR] 0.34,95%Cl0.224.52; NNT 169). In patients not taking aspirin, the rate ofulcer complications was also lower with lumiracoxib than with comparator NSAIDs (0.20%
Cardiovascular effects
An important unexpected finding of the trrIGOR study
was a significantly higher incidence ofmyocardial infarc-
tion with rofecoxib than with naproxen (0.4% vs.0.1%, RR 5.0, 95% CI 1.72-14.29). "'The findings sparked debate as to whether they represented a harmful effect of
rofecoxib or a protective (aspirin-like) effect ofnaproxen, or were due to chance. They highlighted concern about the potential for adverse cardior.ascular effects with coxibs in general, and with rofecoxib in particular.
NNT 139). In
those on aspirin, the rate did not differ significantlv between the groups (0.69% vs. 0.88%). "
There are seyeral ways in which matment with a COX-2 selective inhibitor might, in theory increase cardiovascular
risk in susceptible patients, compared with conventional NSA-IDs or no treatrne nt.i6 Inhibition ofCOX-2 could leave
patients exposed to unopposed pro-thrombotic effects of COX- 1-mediated production ofttrromboxane Ar. A coxib might block potentially prctective effects ofCOX-2 on ischaemic mrocardium or on atherogenesis. Also, coxibs'eF fects on blood pressure and renal function could tum out to be more detrimental than those ofconventional NSAIDs.
ofmatrnent
1
(2.57% rs. 0.63%). The liver abnormalities were considered severe in 5 patients on lumiracoxib and 3 on other NSfDs. I
Other data Individual efficary studies with coxibs have generally been
too small to detect or exclude significant treatment effects on the rate ofseverc ulcer complications. However, several pooled anallses ofsuch nials have suggested a lower rate of these events with coxibs than with various NSAIDs.ri " Such anall,ses often have crucial limitations. They tend to
Besides the
Evidence of harm with rofecoxib \rlGOR study, a number ofclinical and epi-
demiological studies have signalled possible harmflrl cardiovascular effects with rofecoxib. Some have found more
marked increases in blood pressure than with comparable doses ofcelecoxib or naproxen.t''2 AJso, a retrospective study in elderly patients found that hospital admission for congestive cardiac failure rvas significantly more likely in those treated with rofecoxib than with celecoxib (RR 1.8, 95% CI 1.4-2.4)." Three epidemiological studies have suggested an increased risk ofacute cardiac events in patients given rofecoxib in high doses (above 25mg daily).''r'rt In one, the incidence of acute myocardial infarction or cardiac death in new users ofthe drug at such doses was almost twice that in non-users of anti-inflammatory drugs (24 vs. 13 events per 1,000 patient-years, RR 1.93,95% CI 1.09-3.43).| A second study suggested an increased riskofacute myocardial infarction in patients aged over 65 years during the first 90 davs ofrofecoxib therapy (most marked with doses over 25mg daily) compared with celecoxib or no NSAID.6A recent case-control study, commissioned by the US Food and Drug Administration, found that current use ofrofecoib in doses above 25mg daily was associated with a threefold increase in the risk of an acute cardiac event, compared with the rate in people who last used anyNSAJD more than 60 days previously (odds ra-
Two retrospective studies, using very large population databases in Canada and the UK, respectively, have also
suggested a lower risk for upper gasuointestinal haemor-
rhage among patients prescibed coxibs compared with the risk in patients given cqnventional NSAIDs.ri}The Canadian study found a fourfold higher rate ofhospital admission for such events in pcople aged over 65 years newly prescribed a conventional NSAID, compared with those prescribed celecoxib, despite a higher prevalence of risk factors in those given celecoxib.r3 However, such studies are prone to a number ofconfounding factors and potential biases, so provide less robust evidence than do large prospecrive srudies. Furrhermore, a recent retrospective analysis using the same Canadian database, found ttrat the use ofanti-inflammatory drugs among elderlypeople had risen by 41% since the introduction of coxibs (the
increase being entirely amibutable to this drug group) and hospital admissions for upper gasrointestinal bleeding had risen by 10%.*) This suggests that prescribing precautions for such high-risk groups may be being disregarded too readily in the beliefthat coxibs are 'safe'.
tio [OR] 3.15,95% CI 1.14-8.75) or compared with current use ofcelecoxib (OR 3.69, 95% CI 1.30-10.45).r5
with NSAIDs.
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The authors of a recent cumulative meta-analJsis of all randomised controlled trials comparing rofecoxib with
NSAID or placebo in patients with chronic musculoskeletal disorders (18 trials, a total of 20,742 patients)
concluded that clear evidence for an increased riskof myocardia.l infarction with rofecoxib was present by the end of 2000.rr According to this anahsis, the relative risk (2.30, 950,6 C\ 1-224.33) appeared uninlluenced by trial duration or whether patients in control groups received placebo, naproxen or a non-naproxen NSAJD.{i
apparent treatmentassociated increase in cardiovascular events is unique to rofecoxib or applies to other COX-2 selective drugs, and whether it applies to all patients or only to a subset, such as those with known risk factors for vascular disease.
In CLASS, the
ofcardiorascular events (0.90,6 with celecoxib vs. 1.0026) or myocardial infarction (0.3% vs.0.3%) in the study population as a whole.rr Nor were there any differences in the
aspirin and non-aspirin zubgroups. The incidence ofhypertension was lower in the celecoxib group than in the com-
bined NSAJD group (1.7% vs.2.3%, p<0.05), and fewer patients on celecoxib had an increase in plasma creatinine (O.7% w. 1.2%, p<0.05).r') Funhermore, epidemiological studies have not suggested an increased risk ofmyocardial infarction in patients receiving celecoxib.'""5
The most important element in gastroprotection is to ensure that patients at high risk, and those with noninflammatory disorders, are not exposed unnecessarily to NSAIDs, including coxibs. Paracetamol, given in hrll dosage, should be tried first, and if an NSAID is needed it should be given in the lowest dose and for the shortest time necessaryr
(separately or combined) in the incidence of the prospectively defined composite endpoint ofnon-fatal or silent myocardial infarction, stroke or cardiovasc,ular death.J, Nor was there any significant difference in the incidence ofmyocardial infarction in patients receiving lumincoxib or ibuprofen, for the groups
groups.
as a
Various gastroprotective dlugs are commonly coprescribed with NSAIDs to help prevent severe gastrointestinal complications. The most widely used are
proton pump inhibitors, such as omeprazole. Proton pump inhibitors reduce endoscopically diagnosed mucosal damage and are effective for healing NSAID-induced ulcers. However, no prospective outcome studies have demonstrated that co-prescription ofthese drugs with NSAIDs reduces the riskofsevere gastrointestinal complications.r'
More myocardial infarctions occurred in patients on lumiracoxib (18 wents,0.38% ofpatients) than in those on naproxen (10 events,0.21%). This apparent excess risk was not significant, either in the group as a whole (HR 1.77,
950/6
subgroup
(HR
1.36,
950.6 CI0.47-3.93)or non-aspirin subgroup (HR 2.37,95% CI 0.7,{-7.55).'s Mean systolic blood pressure rose less on
recent meta-analysis of strategies for the prevcntion of NSAID-associated gastrointestinal toxicity concluded that only misoprostol had definitely been shown to reduce the likelihood of severe gastrointestinal complications." In a 6-month double-blind randomised trial involving 8,843 patients with RA, co-prescription ofmisoprostol with conventional NSAID reduced the risk of severe complications
It
is important to note that neither CLASS nor TARGET was powered to identifr an effect of celecoxib or
vs.
lumiracoxib, respectively, on cardiovascular endpoints. Furthermore, neither study lasted as long as 18 months the point at which the adverse cardiovascular outcomes became apparent in the rofecoxib study in patients with
colorectal polyps, that ultimately led to its worldwide withdrawal. Fully published long-term data on cardiovascular safety are lacking for valdecoxib or etoricoxib in patients
42 events, OR 0.60, 95% CI 0.3H.98).r' Disadvantages ofmisoprostol include that it has to be taken two to four times daily and commonly causes troublesome diarrhoea.
Conclusion
Unqualified assertions that COX-2 selective inhibitors
(coxibs) are, as a class, 'safer' NSAIDs are untenable on current evidence. Coxibs seem possibly less likely than con-
withOAorRA.
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ventional NSAIDs to cause dyspeptic-type s,.rnptoms and are associated with fewer endoscopically visible gastroduodenal ulcers or erosions. Epidemiological data also suggest a lower likelihood of upper gastrointestinal bleeding with celecoxib than with conventional NSAIDs. However, long-term outcome studies have not demonstrated a significant reduction in major ulcer complications (such as bleeding or perforation) wittr celecoxib compared with commonly uscd NSAIDs, and there are currently no firlly published trials of this kind for Vetoricoxib or Yvaldecoxib. When given for up to 1 year, lumiracoxib (which has not yetbeen launched in the UK) causes fewer ulcer complications than ibuprofen or naproxen. However, the number needed to treat is high, and even this advantage is lost in patients who take low-dose aspirin for cardiovascular
prophylaxis. Also,
as
This risk has not been adequately evaluated for any currentlylicensed coxib at therapeutic doses.
We can see few, if any, situations in which a coxib is unequivocally indicated. All NSAIDs, including coxibs, should be avoided, wherever possible, in patients at high risk of
gastrointestinal complications. We see potential hazards in prescribing a coxib to a patient who is at risk from cardiorascular disease, and no advantage for patients taking low-dose aspirin for cardic*asc,trlar prophylaxis. Anti-inflammatory dmgs, including coxibs, should be prescribed at tle lowest effective dose and in accordance with the plecautions set out in the summary ofproduct characteristics current at the time. The patient should be carcfirlly monitored and rwiewed regulady to aroid unnecessary rqrcat prescriptions. Any suspected advene reactions with coiba should be reponed to the Comminee on Safety of Medicines on a Yellow Card.
experience
rofecoxib has demonstrated, there maybe a'trade-off'between befter gastrointestinal tolerability with coxibs and a
[M--meta-analysis; R=randomised controlled trial]
,I82000r
38, 81 6.
a\d
dwnaN a/finiij
2. \,fig, )L. Deat Dntor Letter. Merck SharD & Dohme, I october 2004. 3. Wamerl0etal Nonslercid drug selectivites lor cyclo,orygenase- I ratter
than cyclo ory8enase-2 are assocaated with human gastrointestiialtoxic,ty,
al
witi
patients
th rheumatoid arthritrs.
Afilll in
ytn
analysis. Pr&
lla, i{crd
ll89-98 $le9
of the
-
4. 5. 6. 7. 8.
22. liunt
RH
ll Etd
lMZNl
cyclo'oygenase-2-selr.live
Ph arnacol
fhet
frgl
2003: I7,201-10.
I709-ll.
Solonon DH et
23.
Silverstein
tt
al
inhibito.s
adx
ls receivrng nonsteroidal
iilardion
in older
adulb. Oi,ruh
,l/r./ l&pr.o/
M
lnal
Arn
2001,2r,
rs
24
/)p
Bolli R el al. Discovery of a ncn functon ol cyclooxygenase (C0m-2, C0X-2 is a cardroprotective protein tfiat allevratEs ischemra/rcMlushn injury a0d medlates
iE
9.
10.
R
,es2003:
25.
9:2207-ll.
Hinz 8, Brune l(. Pain and osteoarthritis: new drugs and mechanisms. Cun qpin Rheunatol 20Mt 16, 628-31.
tE
lgg0s.
ll.
bwili
26.
Hawley CJ, Langman Ml. tion-steroidal anti,inllammatory drugs: overall ris*s afld management. tamplementary roles lor C0X-2 inhibilors and
proton pump inhibitors. 6rt2003i 52, 600,8.
inte slina I
27
adatisl
Blower At
d al
[meryenc] admissions
fu
12.
Dee*s JJ et al. Efiicacy, tolerability, and upper gasbointestlnal sarety of celecoxib lor lreatmenl 0l osteoadhritrs and rheumatoid
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2003i 19:725-36. M
Hemiodez-Diaz S, Garcia Roddguez l-A. Steroids and nsk ol upper gastrointestinal complicalions . An .l Epidemiot200lt 153, 1089 93
Bombardier C et al. Crmparison ol upper Sastrointeslinal toxicity of rofecorib and naproxen in pallents
14.
Edrards ,E el al. Etlicacy and salety ol valdecoxib lor lrcatmenl 0, osteoarthritis and rheumatoid ar$ritjs: systematic review ot randomised
controlled tnals. fr,,;, 2(04:
Brh
rheumaloid
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arthdtis. Engll
Lled
286-96
2000,343, rs20-8
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R 16.
31.
Lu
Ht, 2000. Stat st/cal reviever bneling dnungnt lot the advisoty
lree fonline]. Available: http,//w\iw.lda.8ov/ohrms/doctets/acl01/ lAccessed
illr.i,ted200l; Il0(suppl3A),6
tie t eatnent
0f rieumatoid
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comr
1623-30
dyspepsra,
bneling86TTbl_0,4-stats.doc.
attlifis.
J Rheumatol2002:29:
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17. 18.
fie
t; I l0
(suppt
lA | 12,3S.
a randomized
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l2-modl
data in a clinical
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19.
tral ol
34. laniP
tB
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2 (C0X-2) inhibrtor rofecoxib compared with nonselectiye CoX-l and C0X,2 inhibilors in osteoarhritis.,4rc, hlten Med 20OO: 160: 2998-3003
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indicates thal this may not be the case. 8n./ 2002; 324, t Z87-8.
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LanSrnan
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AJida\ce or
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use
ol
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36. 37.
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l75l-6.
inliblfi.
44. 45.
RayWA et al. C0X-2 selective non- steroidal ant'inflammatory drugs afld dsk ol sedous coronary heart disease. laacel2002; 360, Graham Dl et al, 2004.
strointestina I u lcer
l07l-3.
iisl
vik C0l-2
38.
l haemo flhage in
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MacDooald ll\,t et al. Channelling blas and the incidence of gastrointestinal haemofihage in users ol meloxicam, coxibs, and older, non-specific non-
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49.
Hoopr l- et
al
The effectiveness ol
lie
prevention 0l
dr!8s:
Lactobacillus and Bifidobacterium species, might help to prevent and treat atopic disorders by altering intestinal microflora.l We have recently reviewed the use of probiotics for gastrointestina I disorders.2 Here, we look at whether they have a place in the prevention and treatment of atopic diseases.
Background
The so-called'hlgiene hypothesis' suggests that a lack ofexposure to infections in early life predisposes people to atopic diseases.lt One postulated ocplaration is that a lack ofstimulation by infectious agents oflhelper 1 cell-mediated (T1pe 1) immune response in early life leads to an inability to counterT-helper 2 cell-mediated (Type 2) allergic response.oAnother suggestion is that a lack ofexposure to infection in early life may contribute to the differences in intestinal flora seen benveen people with and without atopic diseases; people with atopic disease have been found to have more Clostidium species and fewer Bitldobacterium species in their stools.o
In one trial
assessing primary prevention ofatopic disease in children, 159 pregnant women with a family history of atopy (eczema, rhinitis or asthma; the only inclusion criterion) were randomised to two capsules ofeither Lactobacillus rhannosus GG (1 x 10t0 colony-forming units lcful daily) or placebo, for 2-4 weela before expected deliveryrl
In-vitro and in-vivo research has found that some probiotics may stimulate anti-inflammatory and anti-allergic responses,r'i
3
suggesting
continue to rake their allocated treatment or it was given direcdy to the infants (capsule contents mixed with water). The rationale for this approach was based on previous research suggesting that giving breast-feeding infants probiotics containin g L. rhamoosus GG direcdy, or giving it to their mothers, resulted in similar amounts of tlis organism in infant faeces.")The exact mechanism for this is unknown.In all,62 of the mothers who breast-fed continued to take either the probiotic (30) or placebo (32)."The
mean time ofexclusive and tota.l time ofbreast-feeding were similar inboth groups. Children were examined during the neonatal period and at3,6,12,1'8 and24 months old.
with atopic diseases. One theory is that these effects may be due to the ability ofprobiotic organisms to restore to
normal the altered intestinal permeability and flora, characteristically found in chi.l&en with atopic eczema and food allergy.r's'r" Other suggestions include that Probiotics enhance digestive tract-specific IgA responses, Promote the digestive tract's defence barrier mechanisms, and reduce cytokines associated with allergic inflammation.'
eczema (the
primary
outcome measure) in the 132 infantswho completed the study was lower in the probiotic group (23% rt. 46% in the placebo group, relative risk [RR] 0.51, 95% CI 0.32-0.84).11 Abo, fewer breast-feeding infants in the probiotic group had developed atopic ecztma at 24 months (15% rs. 47% in the placebo group, RR
0
Clinical efficacy
Several published
.32,95ok Cl0.124.85).t'|
double-blind randomised controlled nials have investigated whether probiotics can help to prevent or treat atopic diseases.lE'o
study, a total of53 in the probiotic group and 54 of68 (796) in the
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atopic eczema had been diagnosed in fewer chil&en in the probiotic group than in the placebo group (26% rs. 46%, RR 0.57, 95% CI 0.33-{.97). However, it is not clear from the trial report whether or to what extent any ofthe children had taken probiotics during the intervening period.
though 56% ofthc parients taking the probiotic believed their symptoms had improved compared with 15% of
those on placebo (p=0.001).
A srudy involving
One trial
Cowt milk
diet and the infants were given an exensivelv hy&ollsed whey-based formula milk that either did or did not contain L. rhamnosus GC (5 x 10s cfir,/g), for 1 month. In all, 13
infants in the probiotic group and 14 in the control group completed the snrdy and were included in the analysis. The severity of atopic eczema was assessed clinically using the ralidated SCORAD (SCORing Atopic Dermatitis) index
established by the European Task Force on Atopic Dermatitis.r'There was no significant difference in mean SCORAD
scores at baseline
Patients were treated for 5.5 months: 2.5 months before the pollcn season, 1 month during the season (May) and 2 months after. They were instructed to keep a symptomand- medication diary during the week{ong run-in period, the bi-rch-pollen sezrson and for 3 weeks afterwards. Patients evaluated their slnptoms on a 0-10 scale, recording eye, nasal and lung s1'rnptoms separately. The symptom
scores for each ofthese were orpressed as weeldy sums (scale
0-70 for each). Compared with placebo, the active treatmentdid not affect symptoms during the birch-pollen season or during the subsequent 2 months.
tillen significandy in infants in the probiotic group (from 26 to 15, p=0.008) but not in those in the control group (from 21 to 19, P=0.89). However, the difference between the groups with regard to change in scores was not reported and, at 2 months, the SCORAD scores in the two groups were similar (16 with the probiotic and 14 with the control).
had
A second trial compared the effects of fermented milk cortiring Lactobacillus paracasei-33 (2 x 10, cfu,/bottle) with milk containing no probiotic (both given for 30 days) on the qualiry oflife of80 children with perennial allergic rhinitis.l6 The mean age of participalts was 16
years in the probiotic group and 14 years in the control group.In all,60 were given thc probiotic-containing milk
In another study, 27 breast-fed infants (mean age 4.6 months) atopic cczema werc weaned on to a hydrolysed whey formula with or without one of two probiotic strains, L. rhamnosus GG (3 x 10' cfi-r/g) or Bifdobacteium lactis Bb-12 (1 x 10' cfir/g), for 6 months.rr The primaw outcome measures were the cytent, severity and subjective symptoms (pruritus and sleep loss) ofatopic eczema (assessed using the SCORAD index). After 2 months, the SCORAD scores had fallen more in both probiotic groups compared to the control group (p=0.002). The score was 16 before the study began, and fell in the B. /acas Bb-12 group to 0 and in the L. rhamnosusGG group to 1, compared to 13.4 in the control group. However, at 6 months, the SCORAD scores were similar in all groups.
witl
and 20 were given the control milk. A modified questionnaire on paediatric rhinoconjunctivitis and quality of lift (the primarv outcome measure) was given to all the children or theirparents at each clinical visit. At 30 days, scores for overall quality oflife had improved more in the probiotic group, both in terms offrequency of symptoms
(p=0.037) and level ofbother they caused (p=0.022).
Unwanted effects
In one trial, unwanted gastrointestinal effects were seen with heat-inactirated I. rlramnosus GG,lrwhile another trial re-
or heat-inactivated I. rlamnosusGG, or formula alone in 35 infants (mean age 5.5 months) with atopic eczema and allergy to cow's milkrr Recruitment was prematurely stopped after complaints from children's parents concerning advirse gastrointestinal symptoms (e.g. diarrhoea),which occurred only among the group given heat-inactivate d L. rhamnosus GG. Why this group developed these symptoms is unclear. SCORAD scores fell significantly but similarly in all tfuee groups during the 2-month study period.
l.
A fourth trial, involving 58 children (mean age 5.2 years) wirh atopic eczema and lasting 6 weeks. evaluared rhe
clinical effecrs of rwo Lactobacillus strains (lyophilised L. rhamnosus 19070-2 and Lactobacillus rciteri DSM 722460,101" cfu of each strain twice daily) compared with number of micro-organisms rhat a probiotic product placebo.r'At 6 weeks, the SCORAD siore (the primary should contain.r or the most appropriate ,egi-en ro p.e_ outcome measure) had not changed in either group, al_ vent or treat atopic disorders. DTB
Vol
able from supermarkets, pharmacies and health food shops. In the UK, probioric preparations are classified as foods or food supplements so, unlike for medicines, there is no statutory regulation ofthe quality of commercially available probiotic preparations. This is reflected in disl crepancies between the claims made by some manufac_ rurers and rhe findings ofinvestigators as ro the amount ofviable bacreria preseni in certain products..-r, ,and rype We know o[ no pubtished guidance on the optimum
43
No
January 2005
Conclusion
Evidence from one trial suggests that the probiotic l,aaobaclus rhamnosus GG, when taken by a women during preg nancy and then eitler continued during breast-feeding or
lM=meta-analysis; R:ra0domised controlled triall
given to the baby, may help to prevent atopic eczema in children with a family history ofatopy This needs con6.rmation. Thcrr is no corvincing evidence that probiotic trcatrnent helps chjldren with established atopic eczema, or prerrcnts the development of, or helps to control, allergic rhinitis or asthmaR 14.
Rosenleldt v et al. Etfect oi gtobioic Lactobacillus stains in children with
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alopic demalit,s. I Alerg Clin i/r/rurol 2003; I I l, 389-95. R 15. flelin I etal.l{0 ellect ol oraltreatmlrt wth an intesti[albactenalstrain. Lactobacillus kannosus\AICC 53103), on birch-pollen allerBlr a placebocontrolled double blind study. Allerg2002: 51 : 243-6.
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RosedeldtV et al. Etlect 0l probiotics on gastrointestinal symptoms and small antestinal pemeability in children 2004; 145:612 6.
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January 2005