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Presentazione di PowerPoint
I nuovi farmaci per
le patologie
articolari
Journal Club
Complessità e innovazione in Geriatria
24 Giugno 2011
Angela Cassinadri
Le patologie articolari
INFIAMMATORIE
•Artrite reumatoide
•Spondiloartriti sieronegative
•Artriti croniche giovanili
•Artriti batteriche e virali
•Gotta
•Condrocalcinosi
•Morbo di Paget
DEGENERATIVE
•Osteoartrosi
•Osteoporosi
Che cosa è cambiato nella
cura?
Gli antichi egizi
utilizzavano le foglie di
Mirto (2500 a.C.)
Ippocrate prescriveva la corteccia del
salice bianco per il dolore (400 a.C.)
Guillaume de Baillou,
nel 1578, suggerì che il
“reumatismo” era un
problema muscoloscheletrico sistemico
(Liber de Rheumatismo et
Pleuritide dorsali)
Thomas Sydenham,
il padre della
medicina inglese,
identificò numerose
malattie reumatiche
(1680)
Augustan Jacob Landrè-Beauvais descrive, per
la prima volta, i sintomi e i segni dell’artrite
reumatoide (1800)
Charles Frèdèric
Gerhardt sintetizzò
una forma instabile
ed impura di acido
acetilsalicilico (1853)
Felix Hoffman perfeziona
l’acido acetilsalicilico,
che prende il nome
commerciale di
ASPIRINA, grazie alla
Bayer (1897)
Renè Leriche descrive il primo caso di
osteoporosi (Sindrome di Sudek 1900)
L’aurotiomaleato di disodio (sali d’oro) viene
utilizzato nella cura dell’artrite reumatoide e
rappresenta il primo DMARD (diseasemodifying antirheumatic drug) (1920)
Negli anni 50-70 l’FDA approva i
successivi DMARD:
Metotrexato
Prednisone
Sulfasalazina
Azatioprina
Plaquenil
I bifosfonati vennero sviluppati all’inizio del XIX
secolo, ma iniziarono ad essere studiati e utilizzati
in riferimento a patologie articolari soltanto negli
anni 60.
Sir John Vane suggerisce
che i FANS (ASA e
ibuprofene) agiscono
tramite inibizione della
sintesi delle prostaglandine
(1970)
Nel 1974 l’FDA approva
l’utilizzo dell’Ibuprofene
nella cura dell’artrite
reumatoide
Needleman, nel 1991, pubblica la scoperta di altre
isoforme di FANS e, nel 1992, il naprossene viene
approvato dall’FDA
Nel 1997 l’FDA approva il
Rituximab (Mabthera).
Arava (Leflunomide), Enbrel
(Etanercept), and Celebrex
(Celecoxib) vengono approvati
dall’FDA come trattamento per
l’artrite reumatoide (1998)
Remicade (Infliximab) viene
approvato dall’FDA nel 1999
Dal 1990 ad oggi molti altri farmaci sono
stati approvati dall’FDA con indicazioni al
trattamento dell’osteoporosi (Alendronato,
Risendronato, Pamidronato, Acido
Zalendronico e Ibandronato)
Osteoporosi
È una malattia sistemica dello scheletro caratterizzata da
riduzione della massa ossea ed alterazione della
architettura microscopica del tessuto osseo che comporta
una maggiore fragilità ed un maggior rischio di frattura.
Colpisce una donna su quattro dopo i 50 anni
Nell’Unione Europea, il 40% delle donne e il 13% degli
uomini dopo i 50 anni, ha una frattura concomitante a
fragilità ossea
2 milioni di uomini soffrono di osteoporosi
1/5 di tutte le fratture di femore
1 uomo su 6, dopo i 90 anni, ha una frattura di femore
Age and Osteoporotic Fractures
Incidence/100,000 person-years
4,000
Men
Women
3,000
Hip
Hip
2,000
Vertebrae
Vertebrae
1,000
Colles'
35–39
>85
Age group, year
Cooper C. Epidemiology of Osteoporosis. Chapter 49:IV. Metabolic
Bone Diseases. Am Soc for Bone & Min Research 2003.
Colles'
>85
60
50
Hip Fracture Cases
40
All Participants
30
20
10
0
1800
1600
1400
1200
1000
800
600
400
200
0
No. of participants
No. of hip fracture cases
> 50% of hip fractures occur in patients with Tscores ≥ 2.5
Total Hip T-Score
Wainwright SA 2005
Treatment Options in Osteoporosis
Antiresorptive drugs
• Bisphosphonates
etidronate
alendronate
risedronate
ibandronate
• SERMs
raloxifene
• Calcitonin
Effect of alendronate on risk of
fractures
18
Patients with new
fractures after 3 years of
treatment (%)
16
Alendronate n=1022
RR 0.53
( 95% Cl 0.41 – 0.68 )
Placebo n=1005
14
12
10
8
RR 0.52
( 95% Cl 0.31 – 0.87 )
6
4
RR 0.49
( 95% Cl 0.23 – 0.99 )
2
0
Vertebral fractures
(p=0.001)
Wrist fractures
(p=0.05)
Adapted from: Rizzoli. R: Atlas of Osteoporosis. (Second
Edition). Curr Med Group 2005.
Hip fracture
(p=0.05)
Effect of risedronate on incidence of new
vertebral and non-vertebral fractures
Placebo
Incidence of new vertebral
fractures (%)
32
RR 0.51
( 95% Cl
0.36-0.73 )
28
18
RR 0.59
( 95% Cl
0.43-0.82 )
24
20
16
12
8
4
0
Incidence of new non-vertebral
fractures (%)
34
Risedronate 5 mg/day
RR 0.67
( 95% Cl
0.44-1.04)
16
14
RR 0.61
( 95% Cl
0.39 – 0.94 )
12
10
8
6
4
2
0
Vert-MN
Years 0-3
P<0.001
Vert-NA
Years 0-3
P<0.003
Vert-MN
Years 0-3
NS
Vert-NA
Years 0-3
P=0.02
Vert-MN results adapted from Reginster et al.Osteoporosis International 2000; 11.83-91.
Vert-NA results adapted from Harris ST et al. JAMA 1999; 282: 1344–1352.
Effect of ibandronate on incidence
of vertebral fractures
12
RR 0.50
( 95% Cl
0.34 – 0.74)
Fracture incidence (%)
10
RR 0.38
( 95% Cl
0.25 – 0.59)
8
RR 0.44 ( 95% Cl 0.26 – 0.73 )
6
4
2
RR 0.42
( 95% Cl
0.17-1.02 )
RR 0.39 ( 95% Cl 0.23 – 0.67
* )
*
*
†
0
Year 1
*p<0.001 versus placebo
†p<0.0017 versus placebo
Year 2
Year 3
Daily ibandronate (2.5 mg), n=982
Intermittent ibandronate (20 mg), n=982
Placebo, n=982
Adapted from: Rizzoli. R: Atlas of Osteoporosis. (Second Edition). Curr Med Group 2005.
Chestnut CH 3rd, Skag A, Christiansen C; J Bone Miner Res 2004; 19;1241-1249.
Change from baseline (%)
Quarterly IV IBN is superior to daily oral IBN
2.5 mg daily
2 mg q 2 months
3 mg q 3 months
6
5
4
3
2
1
0
Lumbar
spine
Total
hip
Femoral
neck
Delmas et al. Arthritis & Rheumatism 54(6): 1838–1846 2006
Trochanter
BMD Increases With Alendronate and
Risedronate at 24 Months in FACT
Alendronate (N=375)
Risedronate (N=375)
Total Hip
p < .001
3.0 %
1.3 %
Bonnick et al. JCEM 91(7):2631-2637, 2006
BMD Increases With Alendronate and
Risedronate at 24 Months in FACT
Lumbar Spine
Alendronate (N=372)
Risedronate (N=379)
5.2 %
p < .001
3.4 %
Bonnick et al. JCEM 91(7):2631-2637, 2006
Treatment Options in Osteoporosis
Antiresorptive drugs
• HRT
• Bisphosphonates
etidronate
alendronate
risedronate
ibandronate
zolendronato
• SERMs
raloxifene
• Calcitonin
Anabolic drugs
• PTH (teriparatide)
Dual Action Bone Agents
(DABAs)
• Strontium ranelate
Monoclonal antibody
• Denosumab
• HORIZON Pivotal Fracture Trial
• multi-national, multi-center, RCT
• 7,736 women age 65-89 with T-score < -2.5 or
fracture plus T-score < -1.5
• calcium 1000-1500 mg/day vit D (400-1200
IU/day)
• zoledronic acid IV infusion 5 mg
Cumulative Incidence (%)
ZOL reduces hip fracture
3
Placebo (n = 3861)
ZOL 5 mg (n = 3875)
41%*
(17%, 58%)
P = .0024
2
1
0
0
3
6
9
12
15
18
21
24
27
30
33
Time to First Hip Fracture (months)
*Relative risk reduction (95% confidence interval) vs placebo
36
ZOL reduces vertebral fractures
Cumulative Incidence (%)
3
Placebo (n = 3861)
ZOL 5 mg (n = 3875)
77%
(63%, 86%)
P < .0001
2
1
0
0
3
6
9 12 15 18 21 24 27 30 33 36
Time to First Clinical Vertebral Fracture (months)
*Relative risk reduction (95% confidence interval) vs placebo
Cumulative Incidence (%)
ZOL reduces non-vertebral fractures
12
25%
Placebo (n = 3861)
ZOL 5 mg (n = 3875)
10
(13%, 36%)
P = .0002
8
6
4
2
0
0
3
6
9
12 15 18 21 24 27 30 33 36
Time to First Clinical Non-vertebral Fracture (months)
*Relative risk reduction (95% confidence interval) vs placebo
Il frammento 1-34 del Paratormone
(Teriparatide) e l’Ormone
Paratiroideo 1-84, somministrati a
donne in menopausa con almeno una
frattura vertebrale, si sono entrambi
dimostrati in grado di ridurre
significativamente il rischio di frattura
vertebrale ed il solo Teriparatide ha
mostrato un effetto significativo sulla
riduzione delle fratture non vertebrali.
Lumbar Spine BMD (% change)
Change in Lumbar Spine BMD
15
*
*
PTH+HRT
12
n
HRT
*
*
9
*
6
*
3
0
n
n
n
6
12
n
n
n
n
18
24
30
36
-3
3
Time (months)
Cosman, et al JBMR 2001
P<0.05
*
Change in Total Hip BMD
PTH+HRT
5.0
*
*
n HRT
*
4.0
3.0
2.0
1.0
0.0
n
n
6
12
n
n
n
n
n
-0.5
3
18
24
30
36
Time (months)
Cosman, et al. JBMR 2001
* P<0.05
Strontium reduces the risk of
vertebral fracture (SOTI)
Patients (%)
- 41%*
35
30
NNT = 9
25
20
- 49%*
15
Protelos® 2 g/day
10
placebo
5
0
First year
0-3 years
RR=0.51, 95%CI [0.36 ; 0.74] * p<0.001 RR=0.59, 95%CI [0.48 ; 0.73] * p<0.001
% patients with OP-related
major
non-vertebral fractures over 3
years
Strontium ranelate reduces nonvertebral fracture risk (TROPOS)
19%
*
12
10
95% Cl 0.660.98
8
6
4
2
0
Placebo
n=2537
Strontium ranelate
n=2555
1. Reginster JY, Seeman E, De Vernejoul MC, et al. J Clin Endocrinol Metab 2005; 90(5): 2816-2822.
2. Reginster JY, Hoszowski K, Roces Varela A et al. Bone 2003; 32(5): S94.
* p=0.031
Strontium ranelate reduces hip fracture in
patients at higher risk (> 74 yr-old and T-score <2.4) TROPOS
8
7
Patients (%)
6
5
36%*
n=1977
Strontium ranelate 2 g/day
n=982
Placebo
n=995
4
3
2
1
0
0-3 years
ITT, over 3 years: RR = 0.64 95% CI 0.412; 0.997 ] *p = 0.046
1. Reginster JY, Seeman E, De Vernejoul MC, et al. J Clin Endocrinol Metab 2005; 90(5):2816-2822.
Artrite reumatoide
L’artrite reumatoide è una poliartrite infiammatoria
cronica, anchilosante e progressiva a patogenesi
autoimmunitaria, a carico delle articolazioni
sinoviali.
Si differenzia dall'osteoartrosi perché interessa
inizialmente la membrana sinoviale e non la
cartilagine, colpisce con meno frequenza e in età
più giovane rispetto all'osteoartrosi.
Sono più colpite le donne (rapporto 3:1). Interessa
l'1-2% della popolazione e il numero dei casi
aumenta con l'età, infatti è colpito il 5% delle
donne oltre i 55 anni (primo picco tra
l’adolescenza e il 4º e 5º decennio; secondo
picco tra i 60 e 70 anni.
I criteri di diagnosi
(2010 ACR / EULAR Rheumatoid Arthritis Classification Criteria)
A. N° ARTICOLAZIONI INTERESSATE
1 grande articolazione
2-10 grandi articolazioni
1-3 piccole articolazioni con o senza grandi art.
4-10 piccole articolazioni con o senza grandi art.
> 10 articolazioni + almeno una piccola art.
score 0
score 1
score 2
score 3
score 5
B. SIEROLOGIA (è necessario almeno 1 test)
FR negativo e ACPA negativi
FR a basso titolo o ACPA a basso titolo
FR ad alto titolo o ACPA ad alto titolo
score 0
score 1
score 2
C. REAGENTI DI FASE ACUTA (necessario almeno 1 test)
PCR normale e VES normale
PCR elevata o VES elevata
score 0
score 1
D. DURATA DEI SINTOMI
< 6 settimane
> 6 settimane
score 0
score 1
Per classificare un paziente con artrite reumatoide definita è necessario un
punteggio totale uguale o maggiore di 6.
Guidelines ACR 2002
• Patient education
• The start of DMARDS within 3 months of
diagnosis for most patients (aggiornamento 2008)
• The consideration of NSAIDS as part of the
treatment plan
• The consideration of local or low-dose systemic
steroids
• A consultation with a physical and/or
occupational therapist for non-pharmacological
treatment (joint protection, conservation of
energy, range of motion and strengthening
exercises)
Treatment: the earlier the better
Delayed Treatment
Early Treatment
(median treatment lag time = 123 days; n = 109)
(median treatment lag time = 15 days; n = 97)
Change in Sharp Scores
12
10
8
6
4
2
0
0
6
12
18
24
Months
Patients were treated with chloroquine or azathioprine
Lard LR, et al. Am J Med. 2001;111:446–451.
Biologic DMARD’s – Genetically Engineered
Targeted Molecules Similar or Identical to
Naturally Occurring Molecules
• TNFα antagonists:
o Adalimumab (Humira)
o Etanercept (Enbrel)
o Infliximab (Remicade)
• Suppress T-Cell activation
o Abatacept (Orencia)
• Anti B-Cell monoclonal antibody
o Rituximab (Rituxan)
Characteristics of Biologics
Etanercept
Enbrel
Infliximab
Remicade
Adalimumab
Humira
Abatacept
Orencia
Rituximab
Rituxan
Target
TNF
TNF
TNF
T-Cell Activation
B-Cell
Half Life
3-5 Days
8-10 Days
10-20 Days
13-16 Days
19 Days
Construct
Human
Chimeric
Human
Human
Chimeric
Dosing
Once Biweeklyweekly
Once every 4-8
weeks
Once every 1-2
weeks
Once Monthly
Twice every 6-12
months
Route
Sub-Cut
I.V.
Sub-Cut
I.V.
I.V.
Etanercept
• L’etanercept è una proteina di fusione, ottenuta tramite
tecniche del DNA ricombinante, ottenuta dall'unione del
recettore umano p75 per il fattore TNF-alfa con la
frazione Fc dell’immunoglobulina umana IgG1. La
proteina funziona da recettore solubile per il TNF-alfa e
possiede un’affinità di legame per il TNF-alfa più alta di
quella degli altri recettori solubili.
• È il primo antagonista del TNF rilasciato per l’AR
• Ha un effetto rapido
Response to etanercept (Enbrel) in elderly
patients with rheumatoid arthritis: a retrospective
analysis of clinical trial results. Rheumatol April 2003 30(4)
OBJECTIVE: Approximately 3% of the US population over the age of 65 years has
rheumatoid arthritis (RA). We compared the safety and efficacy of etanercept (Enbrel) in
patients with RA who were > or = 65 years to those < 65 years in open-label and doubleblind, randomized clinical trials.
METHODS: Patients from 4 double-blind, randomized controlled trials and 5 open-label
trials were included in this retrospective analysis. Patients were grouped by age (< 65 or
> or = 65 yrs) at time of study entry. All patients received etanercept subcutaneously
twice weekly. Improvement in signs and symptoms was assessed by the proportion of
patients who achieved the American College of Rheumatology definition of improvement
(ACR 20). The ACR 50 and ACR 70 responses were calculated in an analogous fashion.
Safety was assessed at regularly scheduled visits.
RESULTS: Of 1128 patients enrolled in etanercept trials, 197 (17%) were > or = 65
years of age. Clinical response was rapid and sustained and did not differ between age
groups. At one year, 69% of patients < 65 years and 66% of patients > or = 65 years met
the ACR 20. Forty percent of the patients > or = 65 years met the ACR 50 and 17% met
the ACR 70. Etanercept was well tolerated. Although injection site reactions, headache,
and rhinitis occurred somewhat more frequently in younger patients, the overall rates
and types of other adverse events were comparable in both groups.
CONCLUSION: Etanercept is a new treatment option for older patients with RA and
has substantial benefit and comparable safety regardless of patient age.
Response to etanercept (Enbrel) in elderly
patients with rheumatoid arthritis: a
retrospective analysis of clinical trial results.
>65 anni
35
35
30
30
25
25
Joint count
Joint count
<65 anni
20
15
10
5
20
15
10
5
0
0
0
3
6
9
12
Months
0
3
6
9
12
Months
swollen joint
tender joint
swollen joint
tender joint
A long-term, open-label trial of the safety and efficacy
of etanercept (Enbrel) in patients with rheumatoid
arthritis not treated with other disease-modifying
antirheumatic drugs
Ann Rheum Dis 2006;65:1578-1584
Objective: To evaluate the long-term safety and efficacy of etanercept in patients with rheumatoid
arthritis.
Methods: 549 patients entered this 5-year, open-label extension study and received etanercept 25
mg twice weekly. All patients showed inadequate responses to disease-modifying antirheumatic drugs
before entry into the double-blind studies. Safety assessments were carried out at regular intervals.
Primary efficacy end points were the numbers of painful and swollen joints; secondary variables
included American College of Rheumatology (ACR) response rate, Disease Activity Score and acutephase reactants. Efficacy was analysed using the last-observation-carried-forward approach.
Results: Of the 549 patients enrolled in the open-label trial, 467 (85%), 414 (75%) and 371 (68%)
completed 1, 2 and 3 years, respectively; 363 (66%) remained in the study at the time of this analysis.
A total exposure of 1498 patient-years, including the double-blind study, was accrued. In the openlabel trial, withdrawals for efficacy-related and safety-related reasons were 11% and 13%, respectively.
Frequent adverse events included upper respiratory infections, flu syndrome, rash and injection-site
reactions. Rates of serious infections and malignancies remained unchanged over the course of the
study; there were no reports of patients with central demyelinating disease or serious blood
dyscrasias. After 3 years, ACR20, ACR50 and ACR70 response rates were 78%, 51% and 27%,
respectively. The Disease Activity Score score was reduced to 3.0 at 3 months and 2.6 at 3 years from
5.1. A sustained improvement was found in Health Assessment Questionnaire scores throughout the
3-year time period.
Conclusion: After 3 years of treatment, etanercept showed sustained efficacy and a favourable
safety profile.
Rheumatology 2007
Infliximab
• È un anticorpo monoclonale chimerico di tipo IgG1 per il
75% di tipo umano e per il 25% di tipo murino.
• Il meccanismo di azione sembra essere l’inibizione del
TNFalfa circolante e quello transmembrana così come la
lisi delle cellule producenti TNF attraverso la fissazione
del complemento, citotossicità anticorpo-dipendente e
apoptosi dei linfociti T causata dalla porzione IgG1 Fc
dell’anticorpo.
Combination of infliximab and methotrexate therapy for
early rheumatoid arthritis: a randomized, controlled
trial.
OBJECTIVE: To compare the benefits of initiating treatment with methotrexate (MTX) and infliximab
(anti-tumor necrosis factor alpha [anti-TNFalpha] monoclonal antibody) with those of MTX treatment
alone in patients with rheumatoid arthritis (RA) of < or =3 years' duration.
METHODS: RA patients were eligible if they had active disease and no prior treatment with MTX or a
TNFalpha inhibitor. One thousand forty-nine patients were randomly assigned in a 4:5:5 ratio to 3
treatment groups: MTX-placebo, MTX-3 mg/kg infliximab, and MTX-6 mg/kg infliximab. MTX dosages
were rapidly escalated to 20 mg/week, and infliximab or placebo infusions were given at weeks 0, 2,
and 6, and every 8 weeks thereafter through week 46.
RESULTS: At week 54, the median percentage of American College of Rheumatology improvement
(ACR-N) was higher for the MTX-3 mg/kg infliximab and MTX-6 mg/kg infliximab groups than for the
MTX-placebo group (38.9% and 46.7% versus 26.4%, respectively; P < 0.001 for both comparisons).
Patients in the MTX-3 mg/kg infliximab and MTX-6 mg/kg infliximab groups also showed less
radiographic progression than those receiving MTX alone (mean +/- SD changes in van der Heijde
modification of the total Sharp score at week 54: 0.4 +/- 5.8 and 0.5 +/- 5.6 versus 3.7 +/- 9.6,
respectively; P < 0.001 for each comparison). In addition, physical function improved significantly more
in the MTX-3 mg/kg infliximab and MTX-6 mg/kg infliximab groups than in the MTX-placebo group.
Infliximab therapy was associated with a significantly higher incidence of serious infections, especially
pneumonia.
CONCLUSION: For patients with active RA in its early stages, combination therapy with
MTX and infliximab provides greater clinical, radiographic, and functional benefits than
treatment with MTX alone.
Arthritis Rheum. 2004 Nov;50(11):3432-43.
Discontinuation of infliximab after attaining low disease
activity in patients with rheumatoid arthritis: RRR
(remission induction by Remicade in RA) study.
OBJECTIVE: To determine whether infliximab might be discontinued after achievement of
LDA in patients with RA and to evaluate progression of articular destruction during the
discontinuation.
METHODS: 114 patients with RA who had received infliximab treatment, and whose
Disease Activity Score, including a 28-joint count (DAS28) was <3.2 (LDA) for 24 weeks,
were studied.
RESULTS: The mean disease duration of the 114 patients was 5.9 years, mean DAS28 5.5
and mean modified total Sharp score (mTSS) 63.3. After maintaining LDA for >24 weeks
by infliximab treatment, the drug was discontinued and DAS28 in 102 patients was
evaluated at year 1. Fifty-six patients (55%) continued to have DAS28<3.2 and 43%
reached DAS<2.6 at 1 year after discontinuing infliximab. For 46 patients remission
induction by Remicade in RA (RRR) failed: disease in 29 patients flared within 1 year and
DAS28 was >3.2 at year 1 in 17 patients. Yearly progression of mTSS (DeltaTSS)
remained <0.5 in 67% and 44% of the RRR-achieved and RRR-failed groups, respectively.
The estimated DeltamTSS was 0.3 and 1.6 and Health Assessment QuestionnaireDisability Index was 0.174 and 0.614 in the RRR-achieved and RRR-failed groups,
respectively, 1 year after the discontinuation.
CONCLUSION: After attaining LDA by infliximab, 56 (55%) of the 102 patients with
RA were able to discontinue infliximab for >1 year without progression of
radiological articular destruction.
Ann Rheum Dis. 2010 Jul;69(7):1286-91.
Adalimumab
• È un anticorpo monoclonale
• Si lega selettivamente al TNF e ne neutralizza la
funzione biologica bloccando la sua interazione con i
recettori del TFN di membrana cellulare, p55 e p75.
Adalimumab modula anche le risposte biologiche che
sono indotte o regolate dal TFN, inclusi i cambiamenti
dei livelli delle molecole di adesione responsabili della
migrazione dei leucociti.
Abatacept
• È una proteina di fusione
• Modula un segnale chiave di costimolazione
necessario per la completa attivazione dei linfociti
T e riduce la proliferazione delle cellule T e la
produzione di citochine infiammatorie, legandosi
a CD80 e CD86
Rituximab
• È un anticorpo monoclonale
• Agisce sui linfociti B, legandosi selettivamente ai
CD20.
Questi trial dimostrano che i
“nuovi” farmaci per l’Artrite
Reumatoide funzionano,
ma…
“I had come to an entirely
erroneous conclusion,
which shows my dear
Watson, how dangerous
it always is to reason
from insufficient data”

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