Treatment of arthritis and connective tissue disease
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Treatment of Arthritis and Connective Tissue Disease. Dr Sin é ad Harney Dept of Rheumatology CUH/UCC 10-03-11. Outline. How to treat Rheumatoid Arthritis? How to treat Connective Tissue Disease/Vasculitis?. Rheumatoid Arthritis: Treatment dilemma 1.

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Treatment of arthritis and connective tissue disease

Treatment of Arthritis and Connective Tissue Disease

Dr Sinéad Harney

Dept of Rheumatology CUH/UCC

10-03-11


Outline

Outline

  • How to treat Rheumatoid Arthritis?

  • How to treat Connective Tissue Disease/Vasculitis?


Rheumatoid arthritis treatment dilemma 1

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


Rheumatoid arthritis treatment dilemma 1contd

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


Rheumatoid arthritis treatment plan summary

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


Rheumatoid arthritis treatment dilemma 2

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


Treatment of arthritis and connective tissue disease

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


Treatment of arthritis and connective tissue disease

  • What system must you investigate more ?

    A. Cardiovascular

    B. Neuropsychological

    C. Endocrine

    D. Gastrointestinal


Rheumatoid arthritis treatment dilemma 2 contd

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

Medications for RA

  • Nonsteroidal anti-inflammatory drugs (NSAIDs)

  • Corticosteroids (steroids)

  • Disease-modifying antirheumatic drugs (DMARDs)

  • Biologics

  • Combination of any of the above therapies


Nsaids

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

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)


Treatment of arthritis and connective tissue disease

  • 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 o f conventional combination treatment

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

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. 1998;53:27–32. Moreland. Rheum Dis Clin North Am. 1998;24:579–591.


Optimising treatment

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


Early disease

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


Tnf inhibitors

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


Moderate versus severe disease

Moderate versus Severe disease

  • 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)

  • This was also shown in 4 Etanercept trials and was independent of disease duration


Induction regimes

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


Switching

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


Ra dilemma 3

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

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


Treatment of arthritis and connective tissue disease

  • 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


Abatacept aim and attain studies

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 – ABA+MTX vs Placebo + MTX

  • 29% ACR 70 at 1yr, less x ray progression

  • 2 year data similar


Treatment of arthritis and connective tissue disease

ATTAIN – Studied TNF failures

  • 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

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 didn’t show increased risk of SAEs with rituximab or abatacept but, did with anakinra in high doses in pts with co-morbidities


Ctd case 1

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

Objective Findings

  • Proximal muscle tenderness without objective weakness

  • Tender right temporal scalp region

  • Normal visual acuity

  • HELPFUL INVESTIGATIONS?


Case 1

Case 1

  • Hb ↓, ESR↑( usually > 40)

  • CK normal

  • DIAGNOSIS?


Case 11

Case 1

  • Diagnosis:

    Giant cell arteritis with polymyalgia rheumatica


Case 12

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


Answer

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


Case 2

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 21

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?


Case 22

Case 2

  • Hb↑ , WCC normal , ESR ↑

  • U + E normal

  • ANA weakly positive

  • Syphilis serology negative

  • CXR normal

  • CT brain normal

    DIAGNOSIS?


Case 23

Case 2

  • Diagnosis: Takayasu’s arteritis

  • Differential diagnosis of aortic arch syndrome : relapsing polychondritis, syphilitic aortitis

  • Imaging to assist with diagnosis?


Case 3

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 31

Case 3

  • 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 32

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 33

Case 3

  • How would you confirm the diagnosis?

  • Is there any virus associated with this disease?

  • Name 2 possible medical treatments.


Case 34

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


Case 35

Case 3

  • Steroids

  • Cyclophosphamide (for organ specific disease eg renal involvement)


Case 4

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 41

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?


Case 42

Case 4

  • Bechet’s disease


Case 43

Case 4

  • What are the recognised features of this condition?

  • What is the nature of the rash in his antecubital fossa?


Case 44

Case 4

  • 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

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

Case 5 contd

  • SLE

  • Rx – NSAIDS, Steroids, anti-malarials,

  • MMF , Cyclophosphamide

  • AZA

  • Rituximab


Case 6

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 61

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 62

Case 6

  • A. An echocardiogram and blood cultures

    • Echocardiogram showedvegetations on the valves

    • Blood cultures were positivefor Staph aureus


Don t guess

Don’t Guess

  • ALWAYS look for mimics of vasculitis that have specific treatments

*


Case 7

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 71

Case 7

C. Open lung biopsy


Case 8

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


Treatment of arthritis and connective tissue disease

  • Nonulcerating palpable purpura over the lower extremities

  • Remainder of the examination is unremarkable


Treatment of arthritis and connective tissue disease

  • 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


Treatment of arthritis and connective tissue disease

  • 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


Treatment of arthritis and connective tissue disease

  • B. Have her seen immediately

    • DON’T 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


Guidelines about treatment

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


Summary points

Summary Points

  • 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


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