Treatment of Arthritis and Connective Tissue Disease

1
Treatment of Arthritis and Connective Tissue
Disease

• Dr Sinéad Harney
• Dept of Rheumatology CUH/UCC
• 10-03-11

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Outline

• How to treat Rheumatoid Arthritis?
• How to treat Connective Tissue Disease/Vasculitis?
  

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Rheumatoid 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

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Rheumatoid 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

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Rheumatoid 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

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Rheumatoid 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

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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

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• What system must you investigate more ?
• A. Cardiovascular
• B. Neuropsychological
• C. Endocrine
• D. Gastrointestinal

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Rheumatoid 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

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Medications for RA

• Nonsteroidal anti-inflammatory drugs (NSAIDs)
• Corticosteroids (steroids)
• Disease-modifying antirheumatic drugs (DMARDs)
• Biologics
• Combination of any of the above therapies

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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 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

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Combination 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)

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• 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.

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TICORA 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

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New 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.
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Optimising 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

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Early 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

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TNF 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

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Moderate 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

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Induction 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

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Switching

• 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

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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?

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Beyond 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

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• 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

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Abatacept 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

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• 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

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Rituximab

• 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

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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?

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Objective Findings

• Proximal muscle tenderness without objective
  weakness
• Tender right temporal scalp region
• Normal visual acuity
• HELPFUL INVESTIGATIONS?

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Case 1

• Hb ?, ESR?( usually gt 40)
• CK normal
• DIAGNOSIS?

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Case 1

• Diagnosis
• Giant cell arteritis with polymyalgia
  rheumatica

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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

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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

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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 GPs (80/50)
• WHAT WOULD YOU LOOK FOR ON EXAMINATION?

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Case 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?

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Case 2

• Hb? , WCC normal , ESR ?
• U E normal
• ANA weakly positive
• Syphilis serology negative
• CXR normal
• CT brain normal
• DIAGNOSIS?

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Case 2

• Diagnosis Takayasus arteritis
• Differential diagnosis of aortic arch syndrome
  relapsing polychondritis, syphilitic aortitis
• Imaging to assist with diagnosis?

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Case 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?

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Case 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?

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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

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Case 3

• How would you confirm the diagnosis?
• Is there any virus associated with this disease?
• Name 2 possible medical treatments.

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Case 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

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Case 3

• Steroids
• Cyclophosphamide (for organ specific disease eg
  renal involvement)

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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.

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Case 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?

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Case 4

• Bechets disease

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Case 4

• What are the recognised features of this
  condition?
• What is the nature of the rash in his
  antecubital fossa?

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Case 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.

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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?

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Case 5 contd

• SLE
• Rx NSAIDS, Steroids, anti-malarials,
• MMF , Cyclophosphamide
• AZA
• Rituximab

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Case 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

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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

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Case 6

• A. An echocardiogram and blood cultures
• Echocardiogram showedvegetations on the valves
• Blood cultures were positivefor Staph aureus

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Dont Guess

• ALWAYS look for mimics of vasculitis that have
  specific treatments

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Case 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

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Case 7

• C. Open lung biopsy

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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
• 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

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• Nonulcerating palpable purpura over the lower
  extremities
• Remainder of the examination is unremarkable

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• 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

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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 forMonday
• D. Call in a prescription for prednisolone at40
  mg bid until she is seen on Tuesday

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• 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

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Guidelines 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

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Summary 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