Title: Treatment of Arthritis and Connective Tissue Disease
1Treatment of Arthritis and Connective Tissue
Disease
- Dr Sinéad Harney
- Dept of Rheumatology CUH/UCC
- 10-03-11
2Outline
- How to treat Rheumatoid Arthritis?
- How to treat Connective Tissue Disease/Vasculitis?
3Rheumatoid Arthritis Treatment dilemma 1
- 34-year-old woman with 3-year history of RA
- 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
4Rheumatoid Arthritis Treatment dilemma 1contd
- Assessment
- Very active disease in spite of aggressive
combination therapy - Evidence of extensive joint destruction
- Treatment options are many
- 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,
Anti-IL6
5Rheumatoid Arthritis Treatment Plan Summary
- A variety of treatment options are available
- Treatment plan should match
- The current disease activity
- The documented and anticipated pace of joint
destruction
6Rheumatoid ArthritisTreatment 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
7 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
8- What system must you investigate more ?
- A. Cardiovascular
- B. Neuropsychological
- C. Endocrine
- D. Gastrointestinal
9Rheumatoid ArthritisTreatment 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
10Medications for RA
- Nonsteroidal anti-inflammatory drugs (NSAIDs)
- Corticosteroids (steroids)
- Disease-modifying antirheumatic drugs (DMARDs)
- Biologics
- Combination of any of the above therapies
11NSAIDs
- 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 gt Valdecoxib gt Celecoxib (ACR 2005)
- Concomitant aspirin use negates GIT protective
benefits of COX 2 inhibitors - Jury still out on lots of COX2 inhibitors issues
12Combination or monotherapy with DMARDs?
- Many trials dont show superiority of
traditional combination DMARD therapy over
monotherapy - Some dont 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)
- MTXSSZHCQ vs. SSZHCQ vs. MTX alone (O Dell)
13- Studies 1999-2000 showed only two where
combination therapy was superior - MTXSSZHCQPRED vs. MTX or other DMARD with or
without steroid (Mottonen) - MTXSSZHCQ 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.
14TICORA trial of conventional combination treatment
- Tight control was better with intensive
monitoring - 50 needed to be on MTXSSPHCQ
- Also, MTX and IA steroids were needed in the
tight control group - 2/3s needed dose escalation
15New Biologics
- Infliximab ( chimeric monoclonal antibody to TNF)
- Etanercept (soluble TNF receptor)
- Adalimumab (humanised monoclonal antibody to TNF)
- Rituximab (anti-CD 20 )
- Abatacept
Rozman. J Rheumatol. 1998532732. Moreland.
Rheum Dis Clin North Am. 199824579591.
16Optimising treatment
- 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
17Early disease
- Studies have shown that MTX and TNF blockers are
clinically similar but, x-ray progression is less
in the TNF group - This has been shown with both Etanercept and
Adalimumab
18TNF Inhibitors
- 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
19Moderate versus Severe disease
- ADA MTX for 4 years showed that clinical
remission (DAS-28 lt2.6) is achieved after 6
months in those with moderate disease (DAS-28
lt5.1), and 9 months in those with severe disease
(DAS-28 gt5.1) - This was also shown in 4 Etanercept trials and
was independent of disease duration
20Induction Regimes
- 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
21Switching
- Anecdoctal evidence shown that TNF switching
works - Inflix changing to Ada works in secondary
non-responders - Inflix changing to Enb works in primary
non-responders - Larger RCTS needed
22RA 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?
23Beyond TNF Inhibitors
- Abatacept
- Rituximab
- Tocilizumab anti IL-6
- HuMax Selective CD-20 B cell depletion
- 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
24- Atacicept Inhibitor of B Lymphocyte
- Only at trial stage
- Certolizumab PEGylated anti-TNF
- Enhanced pharmacokinetics with decreased
clearance and enhanced half-life - Trials underway
- 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
25Abatacept AIM and ATTAIN studies
- 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 ABAMTX vs Placebo MTX
- 29 ACR 70 at 1yr, less x ray progression
- 2 year data similar
26- ATTAIN Studied TNF failures
- ABADMARD 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 ABAMTX and Inflix MTX
- Equal efficacy
- Fewer serious SAEs, serious infections and
infusions rxns and discontinuations in ABA grp
27Rituximab
- 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 didnt show
increased risk of SAEs with rituximab or
abatacept but, did with anakinra in high doses in
pts with co-morbidities
28CTD -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?
29Objective Findings
- Proximal muscle tenderness without objective
weakness - Tender right temporal scalp region
- Normal visual acuity
- HELPFUL INVESTIGATIONS?
30Case 1
- Hb ?, ESR?( usually gt 40)
- CK normal
- DIAGNOSIS?
31Case 1
- Diagnosis
- Giant cell arteritis with polymyalgia
rheumatica
32 Case 1
- 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
33 Answer
- D. Treat now with prednisolone at 40 to 60 mg
per day and schedule temporal artery biopsy for
next week - Patients with symptoms of PMR may have temporal
arteritis - Sudden visual loss may occur in TA
- The visual loss is usually not reversible
34Case 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 GPs (80/50)
- WHAT WOULD YOU LOOK FOR ON EXAMINATION?
35Case 2
- 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?
36Case 2
- Hb? , WCC normal , ESR ?
- U E normal
- ANA weakly positive
- Syphilis serology negative
- CXR normal
- CT brain normal
- DIAGNOSIS?
37Case 2
- Diagnosis Takayasus arteritis
- Differential diagnosis of aortic arch syndrome
relapsing polychondritis, syphilitic aortitis - Imaging to assist with diagnosis?
38Case 3
- A 56 year old man presented to AE 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?
39Case 3
- Investigations
- Hb 10.6g/dl
- WCC 12109/l
- ANCA negative
- ANA negative
- Plts 242109/l
- ESR 60
- CRP 72
- Albumin 30
- What is the most likely diagnosis?
40Case 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
41Case 3
- How would you confirm the diagnosis?
- Is there any virus associated with this disease?
- Name 2 possible medical treatments.
42Case 3
- 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
43Case 3
- Steroids
- Cyclophosphamide (for organ specific disease eg
renal involvement)
44Case 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.
45Case 4
- 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?
46Case 4
47Case 4
- What are the recognised features of this
condition? - What is the nature of the rash in his
antecubital fossa?
48Case 4
- Orogenital ulceration
- Recurrent uveitis
- Arterial and venous thrombosis
- Recurrent thrombophlebitis
- Erythema nodosum
- Non-erosive arthritis
- Neurological involvement such as TIAs, 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.
49Case 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?
50Case 5 contd
- SLE
- Rx NSAIDS, Steroids, anti-malarials,
- MMF , Cyclophosphamide
- AZA
- Rituximab
51Case 6
- A 26-year-old woman presents with progressive
weight loss, fevers to 39C, 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
52Case 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
53Case 6
- A. An echocardiogram and blood cultures
- Echocardiogram showedvegetations on the valves
- Blood cultures were positivefor Staph aureus
54Dont Guess
- ALWAYS look for mimics of vasculitis that have
specific treatments
55Case 7
- A 43-year-old woman has a presumptive diagnosis
of Wegeners 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
56Case 7
57Case 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 - 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
58- Nonulcerating palpable purpura over the lower
extremities - Remainder of the examination is unremarkable
59- You order a chest x-ray, CBC, urinalysis, ESR,
and metabolic screen - She is scheduled to return next Tuesday
- You receive the following results inthe
afternoon - Hgb 8.9 ESR 115
- creatinine 1.6
- UA 20 to 30 RBC
- 3 protein no casts
- Chest x-ray
- multiple infiltrates
60- 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 forMonday
- D. Call in a prescription for prednisolone at40
mg bid until she is seen on Tuesday
61- B. Have her seen immediately
- DONT HESITATE
- For significant major organ dysfunction of
unknown duration in suspected vasculitis - Evaluate immediately
- Therapy will depend on obtaining a specific
diagnosis - Patients can clinically deteriorate suddenly
62Guidelines about treatment
- 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
63Summary Points
- When a patient has a complex multisystem
inflammatory picturethink 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