Transcript treatment of arthritis and CTD2011

Treatment of Arthritis and
Connective Tissue Disease
Dr Sinéad Harney
Dept of Rheumatology CUH/UCC
10-03-11
Outline
 How
 How
to treat Rheumatoid Arthritis?
to treat Connective Tissue
Disease/Vasculitis?
Rheumatoid Arthritis:
Treatment dilemma 1
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34-year-old woman with 3-year history of RA
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Morning stiffness = 3 hours
2 to 3+ swelling of MCP, PIP, wrist, elbow, knee, and
MTP joints
Ulnar deviation, swan neck deformities, decreased
ROM at wrists, nodules on elbows
RF positive, x-rays show erosions of wrists and
MCP joints bilaterally
• Currently on low-dose prednisone + MTX, SSZ,
and hydroxychloroquine
Rheumatoid Arthritis:
Treatment dilemma 1contd
•
Assessment
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Very active disease in spite of aggressive
combination therapy
Evidence of extensive joint destruction
Treatment options are many
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Step-down oral prednisone, 60 mg qd tapered to 10
mg qd over 5 weeks, can be used for immediate relief
of symptoms
Consider TNF inhibitor – 3 different agents currently
in use
Other biologics include – Anti-CD20, CTLA-Ig, AntiIL6
Rheumatoid Arthritis:
Treatment Plan Summary
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A variety of treatment options are available
•
Treatment plan should match
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The current disease activity
The documented and anticipated pace of joint
destruction
Rheumatoid Arthritis
Treatment dilemma 2

68-year-old woman with 3-year history of RA is
squeezed into your clinic as a new patient

She presents with 4 weeks of increasing fatigue,
dizziness, dyspnea, and anorexia

Her joint pain and stiffness are mild and unchanged

Managed with ibuprofen and hydroxychloroquine until 4
months ago, when a flare caused a switch to diclofenac
and prednisolone
Rheumatoid Arthritis:
Treatment dilemma 2 contd

Past history: Peptic ulcer 10 years ago and
mild hypertension
 Exam shows a thin, pale apathetic woman
with Temp 98.4ºF, BP 110/65, pulse 110 bpm
 Symmetrical 1+ synovitis of the wrist, MCP,
PIP, and MTP joints
 Exam of the heart, lungs, and abdomen is
unremarkable
 What
system must you investigate more
?
A. Cardiovascular
B. Neuropsychological
C. Endocrine
D. Gastrointestinal
Rheumatoid Arthritis:
Treatment dilemma 2 contd
Clues of impending disaster
High risk for NSAID gastropathy
Presentation suggestive of blood loss
Pale, dizzy, weak
Tachycardia, low blood pressure
No evidence of flare in RA to explain
recent symptoms of increased fatigue
Medications for RA
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Nonsteroidal anti-inflammatory drugs
(NSAIDs)
Corticosteroids (steroids)
Disease-modifying antirheumatic drugs
(DMARDs)
Biologics
Combination of any of the above
therapies
NSAIDs
 NSAIDs can help relieve not only pain but
inflammation as well
 NSAIDs have not been shown to slow the joint
destruction of RA
 Side effects
 Recent controversies involving Cox-II therapy
 FDA Advisory panel view of gradient of CVS risk
Rofecoxib > Valdecoxib > Celecoxib (ACR
2005)
Concomitant aspirin use negates GIT protective
benefits of COX 2 inhibitors
Jury still out on lots of COX2 inhibitors issues
Combination or monotherapy
with DMARDs?

Many trials don’t show superiority of traditional
combination DMARD therapy over monotherapy

Some don’t control for glucocorticoid use

A review of studies between 1992-1997 did not show
any benefit of most combinations over monotherapy –
 exceptions being MTX and CSA vs MTX alone
(ACR 20 48% vs. 16%) (Tugwell et al)
 HCQ and MTX vs. MTX alone (Ferraz et al)
 MTX+SSZ+HCQ vs. SSZ+HCQ vs. MTX alone (O
Dell)

Studies 1999-2000 showed only two where
combination therapy was superior
 MTX+SSZ+HCQ+PRED vs. MTX or other DMARD
with or without steroid (Mottonen)
 MTX+SSZ+HCQ vs. double or mono of these drugs
(Calguneri). Study biased in favour of combo as
inferior mono used in one third of pts.

Review of studies since 2000 have shown that step-up
therapy of Leflunomide +MTX is superior but, with
significant toxicity.
A caveat is that some of the studies have weaker
DMARD and more active pts in monotherapy arm.

TICORA trial of conventional
combination treatment
Tight control was better with intensive
monitoring
 50% needed to be on MTX+SSP+HCQ
 Also, MTX and IA steroids were needed in
the tight control group
 2/3’s needed dose escalation

New Biologics
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Infliximab ( chimeric monoclonal antibody
to TNF)
Etanercept (soluble TNF receptor)
Adalimumab (humanised monoclonal
antibody to TNF)
Rituximab (anti-CD 20 )
Abatacept
Rozman. J Rheumatol. 1998;53:27–32.
Moreland. Rheum Dis Clin North Am. 1998;24:579–591.
Optimising treatment
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Early use of biologics and use as monotherapy
or combination
Combination TNF and MTX in established
disease
TNF blockers in moderate versus severe
disease
Tight control of disease activity
Induction and Maintenance
Switching between biologics
Early disease
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Studies have shown that MTX and TNF blockers
are clinically similar but, x-ray progression is less
in the TNF group
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This has been shown with both Etanercept and
Adalimumab
TNF Inhibitors
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ATTRACT
BEST
TEMPO
Some of the studies done in Early RA
Some studies done in late disease (DMARD
refractory pts
Evidence now for giving TNF blockers early
and inducing remission and then using MTX
as maintenance
Moderate versus Severe
disease
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ADA +MTX for 4 years showed that clinical
remission (DAS-28 <2.6) is achieved after 6
months in those with moderate disease (DAS-28
<5.1), and 9 months in those with severe
disease (DAS-28 >5.1)
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This was also shown in 4 Etanercept trials and
was independent of disease duration
Induction Regimes
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ACR -70 responses of 80% in Inflix + MTX in
ERA at 1 year
HAQ and QOL better too
Should we be inducing remission with anti-TNF
and at 2 years MTX maintenance continued
Larger studies needed
Makes economic sense
Switching

Anecdoctal evidence shown that TNF switching
works
 Inflix changing to Ada works in secondary nonresponders
 Inflix changing to Enb works in primary nonresponders
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Larger RCTS needed
RA Dilemma 3
 MS
is 38
 She has tried MTX, and Combination
treatment with MTX and TNF Inhibitors
 Despite 18 months of treatment her joints
are swollen, she has EMS of 1 hour and
her DAS-28 is 5.2
 What do you do?
Beyond TNF Inhibitors
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Abatacept
Rituximab
Tocilizumab – anti IL-6
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HuMax – Selective CD-20 B cell depletion
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Fully humanised version of Rituximab
ACR-20 of 50% in pts who have failed one or more DMARDs
including TNF blockers
Belimumab – Inhibitor of B Lymphocyte


ACR 20 of 35% in those who have failed one or more DMARDs
including TNF blockers
This cohort had disease for 11 years on avg
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Atacicept– Inhibitor of B Lymphocyte
 Only at trial stage
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Certolizumab – PEGylated anti-TNF
 Enhanced pharmacokinetics with decreased
clearance and enhanced half-life
 Trials underway
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Golimumab – human anti-TNF
 Can be given sc or IV
 27% remission rate in refractory disease
 DAS-28, CDAI, SDAI etc for monitoring response
aswell as HAQ
Abatacept
AIM and ATTAIN studies
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This drug blocks the second signal
transduction between the APC and the T cell,
leading to a decrease of downstream signal
transduction
IV over 30mins, 2 weeks, 4 weeks and monthly
thereafter
AIM – ABA+MTX vs Placebo + MTX
29% ACR 70 at 1yr, less x ray progression
2 year data similar
ATTAIN – Studied TNF failures
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ABA+DMARD vs. Placebo+ DMARD
391 pts, ACR 20 of 50% at 6 months with ACR 70 of
10%
Open label showed similar results
ATTEST – Efficacy and safety trial
 This compared ABA+MTX and Inflix +MTX
 Equal efficacy
 Fewer serious SAEs, serious infections and infusions
rxns and discontinuations in ABA grp
Rituximab
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Anti-CD 20
2 iv infusions two weeks apart
DANCER trial investigated Ritux in MTX
failures
ACR-70 of 20%
A recent meta analysis of RCTs didn’t
show increased risk of SAEs with
rituximab or abatacept but, did with
anakinra in high doses in pts with comorbidities
CTD -Case 1
•
A 68-year-old man presents with complaints of diffuse
muscle pain, weakness, and total body fatigue. He
reports:
• Gradual onset over past 6 months
• Morning stiffness lasting 2 to 3 hours
• Difficulty with getting out of a chair and combing his
hair
• Recent onset of right-sided headache
• Recent onset of jaw pain when eating
ANY IDEAS? FINDINGS ON EXAM?
Objective Findings

Proximal muscle
tenderness without
objective weakness
 Tender right temporal
scalp region
 Normal visual acuity

HELPFUL
INVESTIGATIONS?
Case 1
Hb ↓, ESR↑( usually > 40)
 CK normal
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
DIAGNOSIS?
Case 1
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Diagnosis:
Giant cell arteritis with polymyalgia rheumatica
Case 1
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Based on the clinical findings, what is the most important
next step?
A. Treat now with prednisolone 5 mg bid, and observe
B. Schedule a temporal artery biopsy for tomorrow
morning and use the results to determine whether
prednisone will be used
C. Start an NSAID at maximal dose
D. Treat now with prednisolone at 40 to 60 mg per day
and schedule temporal artery biopsy in the next few
days
Answer
•
D. Treat now with prednisolone at 40 to
60 mg per day and schedule temporal
artery biopsy for next week
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Patients with symptoms of PMR may have
temporal arteritis
Sudden visual loss may occur in TA
The visual loss is usually not reversible
Case 2

27 y.o female, non- smoker c/o 6 month h(x) of
light headedness on hanging out the washing
 1 episode of R arm weakness and numbness
 Generalised aches and pains, weight loss and
night sweats
 Hypotensive at GP’s (80/50)
WHAT WOULD YOU LOOK FOR ON
EXAMINATION?
Case 2
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Sys BP 80mmHg
Diastolic BP not recordable
Absent radial pulses bilat, ↓ R + L brachial
pulses
Absent R carotid pulse
Normal L carotid pulse and normal femoral
pulses
Normal neuro exam
INVESTIGATIONS?
Case 2
 Hb↑ , WCC normal , ESR ↑
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U + E normal
ANA weakly positive
Syphilis serology negative
CXR normal
CT brain normal
DIAGNOSIS?
Case 2
 Diagnosis:
Takayasu’s arteritis
 Differential diagnosis of aortic arch
syndrome : relapsing polychondritis,
syphilitic aortitis
 Imaging
to assist with diagnosis?
Case 3

A 56 year old man presented to A+E with a fever
and difficulty lifting his right foot while walking for
the past few days. He complained of diffuse
myalgia and arthralgia over the previous 4
months. He had lost approximately 6kgs in
weight over this time. He also reported
intermittent testicular pain.

His blood pressure was 178/100. He had a right
sided foot drop and a purpuric rash on his legs.
ANY IDEAS? USEFUL INVESTIGATIONS?
Case 3
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Investigations:
Hb
10.6g/dl
WCC
12*109/l
ANCA negative
ANA
negative
Plts
242*109/l
ESR
60
CRP
72
Albumin
30
What is the most likely diagnosis?
Case 3
 Polyarteritis nodosa. PAN is a rare systemic
vasculitis characterised by necrotizing
inflammation of small and medium sized
arteries. It is a multisystem disease affecting
kidneys, nervous system, gastrointestinal tract,
cardiac and musculoskeletal systems
Case 3
How would you confirm the
diagnosis?
 Is there any virus associated with this
disease?
 Name 2 possible medical treatments.

Case 3
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Coeliac plexus angiogram or renal angiogram may
reveal evidence of hepatic or renal artery aneurysm
and segmental narrowing. Biopsy of affected tissue
shows PMN cells and granulocytes in the artery
wall, with necrotizing inflammation of small and
medium muscular arteries.
ANCA is typically negative.
25% of patients with PAN are Hep B surface
antigen positive
NAME 2 POSSIBLE MEDICAL TREATMENTS
Case 3

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Steroids
Cyclophosphamide (for organ specific
disease eg renal involvement)
Case 4

A 38 year old man was referred to the out- patients
department with symmetrical joint pain involving his
knees and wrists for the last 6 months. He also
complained of a sore mouth, malaise and weight loss of
4kgs over the past 3 months. In his past history he had a
DVT 2 years ago and reported recurrent episodes of
painful, red eyes.

He was initially assessed by his GP, who performed the
investigations below. He developed a red rash in his
right antecubital fossa 2 days after this.
Case 4
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Investigations:
Hb 10g/dl, ESR 40, CRP 67
WCC 8 * 109/l, Plts 220
U + E normal
Antiphospholipid, ANA, Rh factor all negative
What is the most likely diagnosis?
Case 4
 Bechet’s
disease
Case 4
 What
are the recognised features of this
condition?
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What is the nature of the rash in his
antecubital fossa?
Case 4
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Orogenital ulceration
Recurrent uveitis
Arterial and venous thrombosis
Recurrent thrombophlebitis
Erythema nodosum
Non-erosive arthritis
Neurological involvement such as TIA’s, seizures and
meningeal irritation

The rash at the site of a needle prick is known as the Pathergy
reaction or test. It is due to hypersensitivity of the surrounding skin.
An erythematous area develops after 24-48hrs of taking a blood
sample. It is more likely to be positive in active disease and certain
populatins.
Case 5

A 26-year-old woman presents with small joint
arthritis, red rash across cheeks, Hgb 9.3 mg%,
ESR 82 mm/s and alopecia
 She is very tired with her symptoms and started
NSAIDS with some benefit

What is the diagnosis and what drugs would you
use?
Case 5 contd
 SLE
– NSAIDS, Steroids, anti-malarials,
 MMF , Cyclophosphamide
 AZA
 Rituximab
 Rx
Case 6

A 26-year-old woman presents with progressive
weight loss, fevers to 39°C, arthralgias, and
ischemic ulcers on the fingers
 Physical examination reveals an enlarged spleen
and a harsh midsystolic murmur
 Hgb 9.3 mg%, ESR 82 mm/s
 Urinalysis shows 15 to 20 RBCs
Case 6
 Which
of the following would you do first?
A. Echocardiogram and blood cultures
B. Renal biopsy
C. Anti-ds DNA antibody levels
D. C-reactive protein level
Case 6
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A. An echocardiogram and blood cultures
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Echocardiogram showed
vegetations on the valves
Blood cultures were positive
for Staph aureus
Don’t Guess
ALWAYS
look for mimics of
vasculitis that have specific
treatments
*
Case 7

A 43-year-old woman has a presumptive diagnosis of
Wegener’s granulomatosis based on sinusitis with bone
destruction, abnormal chest x-ray, skin rash, and active
urinary sediment. Which biopsy would provide the
highest diagnostic return?
A. Sinus mucosal biopsy
B. Renal biopsy
C. Open lung biopsy
D. Skin biopsy
Case 7
C. Open lung biopsy
Case 8
•
A 32-year-old woman comes in Friday
morning with intermittent skin rash over
the legs for 2 months. Lesions are not
painful and resolve with minimal
discoloration
•
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PMH is positive for chronic sinusitis requiring
antibiotics 3 to 4 times per year
ROS is negative except for a 15-lb weight loss
over the past 2 months

Nonulcerating
palpable purpura over
the lower extremities
 Remainder of the
examination is
unremarkable

You order a chest x-ray, CBC, urinalysis,
ESR, and metabolic screen

She is scheduled to return next Tuesday
• You receive the following results in
the afternoon:
•
Hgb 8.9; ESR 115;
•
creatinine 1.6
•
UA = 20 to 30 RBC;
•
3+ protein; no casts
Chest x-ray =
multiple infiltrates
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 What
should you do now?
A. Order an ANA, ANCA, and anti-ds DNA to be
drawn on Tuesday
B.Have her seen immediately by your
rheumatology consultant
C. Schedule a rheumatology consult for
Monday
D. Call in a prescription for prednisolone at
40 mg bid until she is seen on Tuesday
•
B. Have her seen immediately
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DON’T HESITATE
For significant major organ dysfunction of
unknown duration in suspected vasculitis
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Evaluate immediately
Therapy will depend on obtaining a specific diagnosis
Patients can clinically deteriorate suddenly
Guidelines about treatment
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Tissue damage with vasculitis requires early
diagnosis and treatment
Combinations of high-dose steroids and
cytotoxic drugs are commonly used
Effective treatment can improve outcome
There is a delicate balance between treatment
efficacy and toxicity
Well-defined clinical outcomes are needed to
guide the intensity and duration of treatment
Summary Points
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When a patient has a complex multisystem
inflammatory picture—think vasculitis
If a vasculitic disorder is considered, search for
its cause
Employ tests and biopsies when indicated, but
remember to treat the patient, not the test
Rapid diagnosis and treatment is often organ or
lifesaving
Consider viral associated rheumatic/vasculitis
syndromes when the autoantibody results are
not typical
Treat RA early and appropriately