Drugs is not everything; Take environment and socioeconomy into

account

Lars KlareskogRheumatology Unit and Rheumatlogy Clinic

Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden

Meet the professor session Kochi Nov 2016

Accidents in childrenRagnar BerfenstamProfessor in Public Health

• In the 1950.ties accidents were the most common cause of severe handicap and death in children

• Ragnar Berfenstam (pediatrician and professor of public health in Uppsala) investigated the environment involved in the accidents.

• He not only collected and published these data. He contributed t to changing these environments

•Accidents leading to handicap and death dimininished drastically in Sweden

An Early Example of Research, Medicine and Prevention

Uppsala University

EIRA (Epidemiological Investigation of risk factors for RA); A population-based case control study based on a national incident

RA registry in Sweden

from 1996

Register for early RAn=19.000 Anti-Rheumatic

Therapy In Sweden

”ARTIS”n=26.000

EIRA(Epidemiologic

Investigation of risk factors for RA

n=4.000

Healthy contolsn=5.600

Case control study

from1999

• Patient research partners contribute in defining problems; → Which modifiable risk factors for disease ? → What is important ?• Collection of information:

→Questionnaire: information on environment/life style among cases and controls→ DNA/plasma/sera genetic immunological and “biomarker” information

EIRA Epidemiologic Investigation of risk factors for RA

Genes Environment/life style

Life time riskfor disease

Genetic end environmental risk factors for subsets of RA

Prevention and treatment of RA in a longitudinal perspective

Tor Olofsson et al. Ann Rheum Dis 2014;73:845-853

Results of treatment – not so good as we wish – here measured by sick leaveAnd very different for different groups of our patients

Early RA registry

Sick leave registry

1 | 63 | 73 | 48 | 184 | 9.47 | 10.98 | 7.22 | 27.67 | 34.24 | 39.67 | 26.09 | | 21.58 | 28.97 | 39.67 | ---------+--------+--------+--------+ 2 | 94 | 68 | 28 | 190 | 14.14 | 10.23 | 4.21 | 28.57 | 49.47 | 35.79 | 14.74 | | 32.19 | 26.98 | 23.14 | ---------+--------+--------+--------+ 3 | 12 | 15 | 4 | 31 | 1.80 | 2.26 | 0.60 | 4.66 | 38.71 | 48.39 | 12.90 | | 4.11 | 5.95 | 3.31 | ---------+--------+--------+--------+ 4 | 21 | 23 | 9 | 53 | 3.16 | 3.46 | 1.35 | 7.97 | 39.62 | 43.40 | 16.98 | | 7.19 | 9.13 | 7.44 | ---------+--------+--------+--------+

36

43

3739

2729

0

5

10

15

20

25

30

35

40

45

methotrexate n=626 TNF inhibitors n=301

% g

ood

resp

onde

rs

Never Past CurrentSmoking status

p=0.52

p=0.03

p=0.95

p=0.05

Current smoking determines influecnes response to therapy Extensive ongoing efforts in ”omics” research but with meager results

Saevarsdottir S et al, Arthritis & Rheumatism, 2011

Register for early RAn=19.000 Biologics

Registry(ARTIS)

n=23.000

Use of registries and associatedbiobanks to analyse:• Clinical characteristics• Pharmacogenomics• Biomarkers• Environment/life style factors

Main Results (also when including ”omics): Current smoking is the most important

determinant for bad response

smokerssmokers

Percent good responders

metotrexate TNF-blockade

S W EF O T

Saevarsdottir S et al, ARD 2014

Smoking is the dominant predictors of joint destruction

Sedentary< 2 hours PA/week

Moderate exercise≥ 2 hours PA/week

Regular moderate exerciseExercise 1-2 times/week, at least 30 minutes

Regular work-outExercise 3 times/week,

at least 30 minutes

ExerciseQuestionnaire: Which of the following alternatives fits best to your physical activity (PA) 5 years ago?

8%

46%

26%

20%

Sandberg M et al, ARD 2014

Saedis Saevarsdottir

Disease activity (DAS28)

Physician assessment(4 categories)

Pain (VAS)

Functional impairment (HAQ)

Physical activity at leisure time OR* 95% CI OR* 95% CI OR* 95% CI OR* 95% CI

Sedentary 1.00 Ref. 1.00 Ref. 1.00 Ref. 1.00

Ref.

Moderate 0.84 0.30 - 1.59 0.92 0.49 – 1.74 0.90 0.48 - 1.68 1.04 0.55 -1.98

Regular moderate 0.58 0.30 – 1.12 0.66 0.33 – 1.30 0.60 0.31 -1.16 0.98 0.50 - 1.92

Regular / work-out 0.41 0.20 - 0.82 0.58 0.28 – 1.19 0.52 0.26 -1.04 0.49 0.24 - 0.99

P-value for trend <0.01 0.02 <0.01 <0.01

The higher the level of physical activity, the lower the likelihood of having disease activity measures above median

Logistic regression was used to calculate odds ratios (OR) with 95% confidence interval (95%CI) of having outcome measures above median level, adjusted for potential confounders (sex, age, year, smoking, body mass index, alcohol consumption, socioeconomic status, vegetable intake and physically demanding work 5years before diagnosis).

Sandberg et al Ann Rheum Dis. 2014 Aug;73(8):1541

Obese have only half the chance to accomplish a good clinical response (to anything) as compared to normal weight people

Saedis SaevarsdottirSandberg M et al Ann Rheum Dis. 2014 May 12.

Some more conclusions• Optimisation of treatment (treat to target etc) requires

knowledge on effects of environment/life style in addition to knowledge of drugs, timing and measurement of outcome

• Any type of biomarker development risks to provide a new biomarker for smoking (or BMI, or diet etc) if you do not have information on environment/life style

• Great opportunities for better use of today´s therapies !!

Traditional outcome measures do not cover everythingA case of mine

• 18 years: Swollen ancle and finger joints, positive RF/CCP. Diagnosis RA. Treatment with low dose cortisone, NSAID:s, sulphasalazine, methotrexate

• 20 years: Worsening of disease, pain and destruction (X-ray) left wrist. Treatment with methotrexate, choroquine, prednisolone (did not tolerate sulfasalazine)

• 25 years: Clinical improvement, only 3 swollen joints but continued destruction, worst in left wrist

A young woman

Hö

Vä

Briefly after diagnosis(at 20 years of age)

Hö

After 5 years of treatmentwith methotrexate, suphasalazine, cyclosporin,cortisone)

Hö

Vä

X-rays of wrists

Hö

What to do ?

• Be satisfied with the improvement (only three joints are now affected; left wrist, PIP II and left ancle joint; no increase in CRP) ?

What to do ?

• Be satisfied with the improvement (only three joints are now affected; left wrist, PIP II and left ancle joint) ?

• BUT – The young woman is training to become a concert violonist !

So – what happened ?

• 24 years of age. Gets TNF-blockade (etanercept)

• 25 years: No continued destruction, no morning stiffness. Begins musical conservatorium

• Now: Part-time musician. No more destruction

Hö

Vä

Shortly after disease onset

HöVä After 5 years of treatment

with conventional DMARD:s

Hö

Vä After 6 years additionaltreatment with TNF-blockade

Thoughts

• Which outcome meaasures to use in the single individual patient ?• Impact of guidelines for the individual patient ?