Transcript Rheumatoid Arthritis … a revolution in treatment

Update in rheumatology
2014
Dr Patrick Kiely PhD FRCP
Consultant Physician and Rheumatologist
St George’s Hospital
London
Overview
• Regional rheumatism
– Common problems and solutions necks, shoulders, backs, hips
and gait
• Treat to target in rheumatology T2T
– Gout: urate lowering and new drugs
– Rheumatoid arthritis
• Biologic therapies
• Chronic inflammation and cardiovascular risk
• PMR and steroid induced osteoporosis
– Vitamin D, bisphosphonates and when to stop
– Strontium and denosumab
• ANA
• Statins
Neck pain and poor sleep
Common problem:
• Pain in region of neck, occiput and shoulder
girdle
• Sleep disturbance
• Non-restorative sleep
• Sometimes neuropathic
UL symptoms
– Tingling, burning, numbness
– Usually unilateral
– Unusual to describe weakness
Cervical spondylosis
Neck pain and poor sleep
Solution:
• Stabilise the neck in bed
– Memory foam pillow
– Soft collar
• Amitriptyline
– 10mg → 50mg
– 2 hrs before bedtime
• Surgery: only if persistent neuropathic symptoms,
and weakness, and MRI lesion to treat
Stiff, restricted and painful shoulder
Common problem:
• Pain in region of shoulder, & upper arm
• Differentiate frozen shoulder, rotator cuff
tendonopathy and AC joint pain
Supraspinatus tendonopathy
• Painful arc through abduction
• Loss of end of range flexion and internal rotation
• External rotation PRESERVED
Supraspinatus tendonopathy
Impingement on the tendon from
•
Osteophytic acromioclavicular joint
•
Osteophytic lateral acromium
Supraspinatus tendonopathy
Treatment
• Mobilisation exercises
• Injection with steroid x 2
• Arthroscopic subacromial
decompression
Frozen shoulder
• Check external rotation
– Early and severe restriction
• All other movements also very restricted
Frozen shoulder
Glenohumeral injection
... in early phase only
‘hydrodilatation’
Nothing else worthwhile
All cases make a full recovery eventually, up to 3 years in some
Unexplained leg pain
not the hip or knee....
• Spinal stenosis
• Trochanteric bursitis
• Adverse hind foot biomechanics
Spinal stenosis
• Buttock and posterior thigh
pain with standing and walking
– Uni or bilateral
– May radiate lower
• Relieved sitting down
– unlike ischaemic claudication
• No problem in bed
Trochanteric bursitis
•
•
•
•
Patient invariably says ‘my hip’
Lateral proximal thigh pain
Female > Male
Worse standing from chair, walking
and lying on affected side
• May radiate to knee or below
• Hip movements good, sore at extreme
external rotation
• Very tender over the
trochanter and with
resisted abduction
Trochanteric bursitis
Trochanteric bursitis management
• Exercises
• Weight loss and Pilates
• Injection
• Surgery
Leg pains, but hips and
knees OK – think feet and
altered biomechanics ...
Back pain management
• Red flags (fracture, metastasis, lymphoma, IBP)
–
–
–
–
Extremes of the age spectrum – be alert !
Severe pain, localised pain, worsening
Sleep disturbance and/or morning stiffness
Anorexia and weight loss, fever and sweats
– Refer if in doubt
• Inflammatory back pain (Ank spond)
–
–
–
–
–
Suspect the diagnosis – refer – mean 7 years diagnostic delay
MRI SI joints and spine – not X-ray
Low impact exercises
NSAIDs and PPI ... ultimately anti-TNF
Physio, hydrotherapy
Treat – to – target
in rheumatology T2T
Gout
• If serum uric acid lowered to 300 mmol/L the risk of
recurring acute attacks of gout will be virtually
abolished, and tophi will dissolve
sUA
300
360
420
480
540
% with attack in 1 yr
10
20
40
55
75
1
6
No. attacks/yr
• Rate of dissolution of tophi correlates with absolute
sUA concentration
Indications for urate-lowering therapy:
Dont forget – the vast majority of patients with hyperuricaemia
never get gout; this is not a diagnostic test
–
–
Asymptomatic hyperuricaemia is not an indication for urate-lowering agents
It is a trigger to think about the metabolic syndrome
Commence urate lowering measures if:
1.
Recurrent troublesome acute attacks
(eg 3 or more per year)
2.
3.
Tophaceous deposits
Gout with evidence of erosive change
4.
5.
6.
7.
Gout associated with interstitial nephropathy
Uric acid stone formation
Acute uric acid nephropathy
Prophylaxis against tumour lysis syndrome in patients receiving chemotherapy
(rasburicase may also be considered in this situation)
Urate lowering options
• Dietary modification
• only a modest effect on sUA, eg 10-15% reduction with a
low-purine diet
• Consult the UK gout society diet sheet
– Stop beer and fructose rich drinks, wine is neutral
• Stop/switch therapies which elevate sUA
Effects of different types of alcohol
on serum uric acid
Results similar in men and women, and at lower and higher levels of BMI.
Fructose
Only CHO known to ↑ SUA
Men who drink two or more
sugary soft drinks a day
have an 85% higher risk of gout than
those who drink less than one a month.
• US sales: soft drinks 1977 – 1997 ↑ 61%
• Single largest food source of calories
• Diet drinks – OK
Cheers…
Urate lowering drug therapies
• required for most patients
– slow titration to target sUA in all cases
– T2T 300mmol/L
– Co-prescribe colchicine to prevent flare
– Allopurinol
– Febuxostat
– Benzbromarone
Vitamin C
Fenofibrate
Losartan
Rheumatoid Arthritis
GPs see newly presenting patients
THINK Inflammatory Arthritis if
Peripheral small joints involved (MCP, PIP,MTP)
Symmetrical involvement
Early morning stiffness
Soft tissue swelling or effusion
NSAIDs help
Not an emergency ...
but an URGENCY to refer
‘erosions’ occur early in RA,
commonly >50% at a year
Poor prognostic markers at diagnosis:
• Large number of involved joints
• RF strong positive
• ACPA (CCP), strong positive
• Smoking
• Early erosions
• High disability scores
What does this mean ?
Loss or change in employment NRAS 2007 survey
% of those respondents who gave up
work early because of their RA
How many years after RA was diagnosed
did you have to stop working?
30
25
20
15
10
5
0
Within a
year
Within 3
years
Within 6
years
6-10 years
Over 10
years
Not stated
Personal cost .. financial, self esteem, physical & mental
Societal cost .. tax contributor to tax receiver
So what can treatment do ..
We have moved from therapeutic nihilism
• ‘token’ drug treatment – too little too late
• nurturing the patient towards inevitable disability and
demise
To the possibility that
• newly diagnosed patients can be ‘cured’
• in existing patients, progression of damage can be
halted and quality of life recovered
• But to achieve this … we need to intervene aggressively
Starting treatment early
Lard LR et al (Leiden) Am J Med 2001; 111:446
Rheumatoid arthritis patients
• Cohort 1 (1993-1995) delayed treatment strategy, n = 109
• Delay between 1st clinic visit and first DMARD mean 123 (50 –
273) days
• Cohort 2 (1996-1998) early treatment strategy, n = 97
• Delay between 1st clinic visit and first DMARD mean 15 (14 –21)
days
• Majority treated with HCQ or SSZ, monotherapy
Lard et al: early (15 days) versus delayed (4 months)
therapy in early RA
Lard et al: early (15 days) versus delayed (4 months)
therapy in early RA
RA guideline
Key priorities
for implementation
• Referral for specialist treatment
– Refer for specialist opinion any person with suspected
persistent synovitis of undetermined cause
– Refer urgently if any of the following apply:
• The small joints of the hands and feet are affected
• More than one joint is affected
• There has been a delay of 3 months or longer between onset
of symptoms and seeking medical advice
Conclusion 1
Treating early makes a big difference
UK practice ?
Early Rheumatoid Arthritis
Network (ERAN)
638 newly diagnosed
patients 2002 – 2007
Mean time from symptom
onset to start of therapy
8 months
Waterford
Starting treatment not so early
mono or combination therapy ?
FinRA Co study
(Mottonen, Arthritis Rheum 2002; 46: 894)
• Early Rheumatoid arthritis patients (< 2 years)
• DMARD sequential monotherapy versus
Combination MTX/SSZ/HCQ therapy, including prednisolone
• Delay in institution of DMARD
Monotherapy:
median 7 months symptoms
< 4 months in 23/86, 27%
Combination:
median 6 months symptoms
< 4 months in 26/79, 33%
FinRA Co: early versus delayed therapy
in early RA:
2 year remission rates
Fundamental concept
Minimizing cumulative inflammation (inflammation-time AUC)
improves all outcomes
This means
Detect & refer early
50
45
CRP (mg/L)
40
35
Placebo + MTX
30
Infliximab + MTX
25
20
15
10
5
0
0
2
6
10 14 22 30 38 46 54 62
Weeks
78
104
Treat early, with a
fast acting agent
to suppress
inflammation
quickly
Refer on the basis of history and examination
Don’t wait for blood results to decide whether to refer;
ESR/CRP may be normal, RF may be negative
No point doing X-rays – we use US if in doubt about synovitis
Bolus steroid (Depomedrone 120mg) if cant get early appointment
Intervening aggressively
• Using therapies to maximum advantage
– Starting as soon as possible after RA onset
– Combination therapies
– Biologic therapies
• Principles of ‘TIGHT’ control T2T
RA guideline
Key priorities
for implementation
• Disease modifying and biological drugs
– In newly diagnosed – offer a combination of DMARDs
(including MTX and at least one other DMARD, plus
short term steroids) as 1st line treatment asap, ideally
within 3 months of onset of persistent symptoms
– If combination DMARD therapy is not appropriate, start
DMARD monotherapy placing greater emphasis on fast
escalation to a clinically effective dose rather than on the
choice of DMARD
– Once sustained & satisfactory levels of disease control are
achieved then cautiously try to reduce drug doses to levels
that still maintain disease control
Tight control/Treat-2-target T2T
• Aim to suppress inflammation to a low level / remission
– use a valid objective measure of current RA activity
– decide on a ‘target’ outcome
• A protocol dictates whether to increase or decrease
treatment; not doctor-patient conspiracy
• Assess frequently (monthly – 6 weekly)
• Use adequate treatment
– fast acting induction regime
• Steroids currently available (evidence for anti-TNF agents)
– more than one drug at a time
Tight control
Ticora study (Grigor, Lancet 2004; 364:263)
• Rheumatoid arthritis patients
• Disease duration <5 years, mean 19-20 months
• Routine care: n=55
• visits every 3 months
• sequential monotherapy or combination therapy allowed
• Tight control: n=55
•
•
•
•
•
Target defined – DAS44 score 2.4 (moderate activity)
monthly visits
standardized assessments
protocol driven escalating DMARD therapy
intra-articular and intra-muscular steroids
DAS changes in TICORA Trial
Tight vs. conventional p<0.0001
(after month 3)
6
DAS score
5
Conventional monotherapy
4
3
2
1
Tight control
0
0
6
12
18
Months treatment
Grigor et al. Lancet 2004
TICORA: Number of patients responding at
18 months assessment
(intention to treat analysis)
Intensive
group
Routine
group
Odds ratio
(95% CI)
p value
(n = 55)
(n = 55)
EULAR good
response
45 (82%)
24 (44%)
5.8 (2.4 – 13.9)
<
0.0001
EULAR remission
36 (65%)
9 (16%)
9.7 (3.9 - 23.9)
<
0.0001
ACR 20 response
50 (91%)
35 (64%)
5.7 (1.9 - 16.7)
<
0.0001
ACR 50 response
46 (84%)
22 (40%)
6.1 (2.5 - 14.9)
<
0.0001
ACR 70 response
39 (71%)
10 (18%)
11 (4.5 - 27)
<
0.0001
Change of DAS-28 between usual care and tight control,
according to a fixed-effects model
Grigor et al. (3)
Goekoop-Ruiterman et al. (29)
Verstappen et al. (18)
Protocolized tight control
Van Hulst et al. (28)
Fransen et al. (27)
Monitoring with protocolized
treatment adjustments
Fransen et al. (8)
Monitoring without protocolized
treatment adjustments
Non-protocolized tight control
-0.4
-0.2
0
0.2
0.4
0.6
0.8
1.0
1.2
1.4
1.6
1.8
2.8
Data are presented as MD in change of DAS-28 between usual care and tight control
Overall effect is presented as a WMD in change of DAS-28 between usual care and tight control
Schipper LG et al. Rheumatol. 2010; 49: 2154–2164
Biologics Nomenclature
-iximab
Chimeric antibody
Infliximab
-zumab
Humanized antibody
Tocilizumab
-umab
Human antibody
Adalimumab, Golimumab
-cept
Etanercept, Abatacept
Fusion protein
Evolution of monoclonal antibodies
Murine Antibody
Human
Chimaeric Antibody
Humanised Antibody
Fully Human Antibody
70% Human
95% Human
100% Human
Mouse
Anti-TNF agents
•Adalimumab
•Etanercept
•Certolizumab
•Golimumab
•Infliximab
Anti-B cell
•Rituximab
Anti-IL6
•Tocilizumab
T cell co stimulation
inhibitor
•Abatacept
NICE RA commissioning algorithm.
http://www.nice.org.uk/media/B66/97/RA3.
1WithGolimumab.pdf
Chronic inflammation and
cardiovascular risk
• Independent risk factor for atheromatous disease
• SLE – 50 x increased risk MI/CVA
• RA – 4 x increased risk
– this means careful control of traditional risk factors to
‘diabetic’ targets
– Bp <130/80, LDL < 2.6
– greater emphasis on robustly suppressing
inflammation – we must try harder
PMR
• Age: 50 +, usually 70 +
• Raised ESR and normal CRP ?
– Anaemia, paraprotein
• Initial dose of prednisolone:
– 15mg, sometimes 20mg
• Taper and duration
– One month initial dose
– Aim for 10mg at 2-3 months, 1mg less per month down to 5mg by 8 months
– Hold at 5mg for 18 months, then 1mg less per month down to zero by 2
years
Mimics:
• Co-prescriptions
• hypothyroid
– Vitamin D and bisphosphonates
• menopause
– Vitamin C
• chronic sepsis
– Enquire about varicella immunity
• malignancy
• osteomalacia
Steroid induced osteoporosis
• Bone prophylaxis
–
–
–
–
Vitamin D3 T2T
>80 nmol/L: 1000U/day
50 – 80 nmol/L: 5000U/day
<50 nmol/L: 20,000U 3x weekly
– Bisphosphonates
When to stop bisphosphonates
• Risk benefit becomes adverse > 5 years
– ONJ and atypical femoral fractures (often bilateral)
When to stop bisphosphonates
• 5-10 years
• Consider what has happened since the patient
was started on a bisphosphonate
– NO fracture and Osteopenia – STOP
– NO fracture and Osteoporosis – HOLIDAY
(use FRAX if patient anxious)
– FRACTURE – switch to an alternative bone
sparing drug
• Denosumab, Strontium or Teriparatide
• depending on T score, co-morbidity and NICE guidance
What about Strontium ranelate ?
• Venous thromboembolic risk
• Cardiovascular safety risk
– serious cardiac disorders, including MI: RR 1.6 (1.07–2.38) cf placebo
– Contraindicated in patients with: ischaemic heart disease, peripheral arterial
disease, cerebrovascular disease; a history of these conditions, or in patients with
uncontrolled hypertension
• ... for every 1,000 patient-years of treatment there are 4 additional serious heart
problems and 4 more cases of thromboses,
• whereas the drug has only a ‘modest’ benefit in terms of fracture prevention,
preventing around 5 non-spinal fractures, 15 new spinal fractures and 0.4 hip
fractures for every 1,000 patient-years.
• The PRAC therefore recommended the drug ‘be suspended until there are new data
showing a favourable balance in a defined group’.
• The CHMP considered that the cardiovascular risk in patients taking Strontium can
be managed by restricting its use to patients with no history of heart and circulatory
problems and limiting its use to those who cannot take other medicines approved for
the treatment of osteoporosis. In addition, patients treated with Strontium should be
screened and monitored regularly, every 6 to 12 months.
What about Denosumab ?
• NICE TA 204 – recommended in patients:
• unable to comply with the special instructions for administering
alendronate and either risedronate or etidronate, or have an
intolerance of, or a contraindication to, those treatments and
• who have a combination of T-score, age and independent clinical
risk factors for fracture (parental history of hip fracture, alcohol
intake of ≥4 units per day, and RA)
Threshold T scores for Denosumab treatment
Number of independent
Age (years)
risk factors
0
1
2
65-69
Not recommended
-4.5
-4.0
70-74
-4.5
-4.0
-3.5
75 or older
-4.0
-4.0
-3.0
ANA ?
• Measure this in the correct clinical context
– You are wondering about a connective tissue disease
SLE
Alopecia
Malar rash
Oral ulcers
Raynaud’s
Arthralgia
Myositis
Sjogren’s
Dry eyes and
mouth
Fatigue
Arthralgia
Raynaud’s
CTD
Scleroderma
Raynaud’s, Reflux
Thick skin
Arthralgia
Muscle
weakness
Rash
Raynauds
Dyspnoea
Weak swallow,
aspiration
Titer interpretation:
• 1 in 80 – likely normal
up to 15% of healthy
population have a
positive ANA
• if titer > 1 in 80
→ ENA, ds DNA, C3/4
Statins and myopathies
• Myalgia 2 – 11%
• Myositis with raised CK 0.5%
• Rhabdomyolysis 0.1% (new antibody HMGCoA)
• Increased risk :
– Dose effect
– Statins metabolised by cytochrome P450 (CYP) 3A4
Inhibitors will increase serum levels: Simva & Atorva
– Elderly (reduced metabolism)
– CKD, hepatic disease, xs alcohol
Statins and CYP3A4 inhibitors
• Simvastatin and Atorvastatin (not Pravastatin)
• Avoid CYP3A4 inhibitors
– Grapefruit juice, diltiazem, verapamil, clarithromycin,
erythromycin, fluconazole, itraconazole and
ketoconazole
Thank you
• Regional rheumatism
– Common problems and solutions necks, shoulders, backs,
hips and gait
• Treat to target in rheumatology T2T
– Gout: urate lowering and new drugs
– Rheumatoid arthritis
• Biologic therapies
• Chronic inflammation and cardiovascular risk
• PMR and steroid induced osteoporosis
– Vitamin D, bisphosphonates and when to stop
– Strontium and denosumab
• ANA
• Statins