Case%20Report

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Case Report

• 39-year-old white male, diagnosed with Rf
  rheumatoid arthritis at the age of 17, presented
  to his primary care physician with shortness of
  breath and intermittent nausea.
• He had reduced his daily prednisone dose from
  20 mg to 10 mg because of nausea, was on
  diclofenac 50 mg bid, tramadol 100 mg tid.

Peter Härle et al, Department of Internal
Medicine I, University of Regensburg,
Franz-Josef-Strauss-Allee , 11,
D-93042 Regensburg, Germany
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• In addition to steroid therapy, several different
  disease-modifying drugs were given over the years
  since diagnosis, including sulfasalazine, oral
  gold, chloroquine, methotrexate, and
  TNF-inhibitors.
• A total of 16 orthopedic operations had been
  performed including excision of rheumatic
  nodules, tendon repair, and bilateral knee- and
  unilateral hip-replacement.

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• On exam, he showed signs of extensive rheumatoid
  arthritis, most marked on hand, foot, and
  shoulder joints as well as rheumatic nodules on
  both elbows.
• HR regular at 105/min
• BP 130/90 mm Hg
• ESR 82 mm/h

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• A CT-scan and echo revealed a pericardial
  effusion (1.5 cm), a thickened pericardium
  (5 mm), and basal bilateral low-grade lung
  fibrosis.
• Diuretic therapy and increased prednisone dose
  controlled his symptoms
• The pericardial effusion was almost undetectable
  4 weeks later.

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• Four months later, he was admitted to the
  hospital because of a sudden onset of abdominal
  pain.
• A perforated NSAID/steroid-induced ulcer was
  diagnosed and the patient required emergency
  surgery.
• During anesthesia, severe cardiovascular problems
  developed including low blood pressure,
  tachycardia, and pre-renal kidney failure.
• A left and right heart catheterization was
  performed subsequently which showed a cardiac
  index of 2.4 l/min/m2, equalization of elevated
  left and right ventricular diastolic pressures.

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• Coronary angiography revealed a 75 obstruction
  of the diagonal branch.
• An MRI-scan showed a thickened pericardium
  (5 mm), a small pericardial effusion, enlarged
  right atrium, and bilateral pleural effusions.

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• Patient was diagnosed with constrictive
  pericarditis without a hemodynamic relevant
  pericardial effusion.
• He was referred to CT Surgery
• Pericardectomy was suggested.
• The patient was informed about the prognosis of
  this RA-associated complication but declined
  surgery and was discharged in improved physical
  condition.

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• Repeated hospitalizations were necessary because
  of clinically dominant right heart failure.
• On his last admission, p/w cachexia, extensive
  edema, tachycardia of 122/min, blood pressure of
  105/55 mm Hg, orthopnea, and ascites.
• Follow-up heart catheterization revealed a
  reduced ventricular function with a cardiac index
  of 1.46 l/min/m2.

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• Surgical intervention was recommended repeatedly
  but the patient still declined any further
  procedures.
• In the following weeks, the patient had three
  episodes of renal failure attributable to low
  median blood pressure (4060 mm Hg) together with
  diuretic therapy
• Intermittently required vasopressor medication.
• The CT-scan of the chest did not show a
  hemodynamically relevant pericardial effusion.

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• Fig. 1.  This CT-scan was conducted without
  contrast because of recurring prerenal kidney
  failure. A thickened pericardium (5 mm) could be
  seen next to a small pericardial and bilateral
  pleural effusion. The pericardial effusion did
  not seem to be of hemodynamic relevance

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• Pt was noted to be adrenally insufficient and
  have pancreatic insufficiency
• In the following weeks, cardiovascular and renal
  functions were increasingly difficult to
  stabilize and intermittent dialysis was
  necessary.
• He developed a DVT despite the use of
  prophylactic heparin and a bilateral pneumonia
  despite broad-spectrum antibiotic therapy.
• The patient died in septic shock combined with
  multi-organ failure.

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• The patient died 2 years after the onset of
  extra-articular cardiac symptoms.
• Pericarditis is a frequent extra-articular
  manifestation of rheumatoid arthritis showing a
  post-mortem prevalence of 3050.
• These findings correlate well with
  echocardiographic diagnosis in living patients.
  However, clinically relevant symptoms are rare
  with a prevalence of 0.063 of all RA patients
• This case demonstrates the devastating course of
  progressive constrictive pericarditis under sole
  medical therapy and emphasizes the importance of
  early radical pericardectomy to avoid progression
  of disease and secondary complications with fatal
  outcome.

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Rheumatoid ArthritisJulie Schwartzman, MD

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Rheumatoid Arthritis

• A systemic, inflammatory polyarthritis that leads
  to joint destruction, deformity, and loss of
  function
• Several potentially severe extra-articular
  manifestations
• Pathology of RA involves the synovial membranes
  and periarticular structures of multiple joints,
  resulting in
• Pain
• Swelling
• Stiffness
• Uncontrolled inflammation that can lead to
  irreversible damage and deformity
• Functional limitation

ACR Subcommittee on RA Guidelines. Arthritis
Rheum. 200246328346 Goronzy JJ, Weyand CM.
In Klippel JH, et al, eds. Primer on the
Rheumatic Diseases. 12th ed. Atlanta, GA
Arthritis Foundation 2001209217 Anderson RJ.
ibid. 218225 Arnett FC, et al. Arthritis Rheum.
198831315324.
I.2
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ACR 1987 Classification Criteria For Rheumatoid
Arthritis

• Patients Must have Four of Seven Criteria
• Morning Stiffness Lasting at Least 1 Hour
• Swelling in 3 or More Joints
• Swelling in Hand Joints
• Symmetric Joint Swelling
• Erosions or Decalcification on X-Ray of Hand
• Rheumatoid Nodules
• Abnormal Serum Rheumatoid Factor
• Must Be Present at Least 6 Weeks

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Epidemiology of RA

• Prevalence 0.5 - 2
• 2 3 times more prevalent in women
• Increased prevalence with advancing age
• 100,000 200,000 New Cases/yr
• 4 6 million current cases of RA

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Mode of Onset

• Monoarticular 21
• Oligoarticular 44
• Polyarticular 35

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Site of Onset

• Joint Involvement
• MCP, PIP
• Wrist
• Knees
• Shoulders
• Ankles
• Feet
• Elbows
• Hips

• Mean of Patients
• 91
• 78
• 64
• 65
• 50
• 43
• 38
• 17

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Course of Disease

• Clinical remission 10
• Intermittent 15 - 20
• Progressive 70 - 75

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Extra-articular Manifestations of Rheumatoid
Arthritis
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Sceritis
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Secondary Sjögrens Syndrome

• SICCA
• Pleuritis/ Pericarditis
• Ro/La positive
• Hypergammaglobulinemia

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Vasculitis

• Digital vasculitis
• Cutaneous ulceration
• Peripheral neuropathy
• Mononeuritis multiplex

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Pulmonary Involvement

• Pleural Disease
• Interstitial fibrosis
• Nodules
• Pneumonitis

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Cardiac Involvement

• Pericarditis
• Myositis
• Endocardial Inflammation
• Conduction Defects

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Articular Manifestations Synovial Fluid Analysis

• Straw colored to slightly cloudy
• WBC 5000 25,000/ mm3
• Rheumatoid Factor
• Elevated protein
• Decreased glucose

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Laboratory Presentation

• Leukocytosis
• Eosinophilia
• Thrombocytosis
• Mild Anemia
• ESR gt 30 mm/hr
• Normal renal and hepatic function
• Negative ANA
• Rheumatoid Factor

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Anti-Cyclic Citrullinated Peptide(CCP)
Antibodies

• High diagnostic specificity (gt98) and
  sensitivity
• Presence in 65 of early RA, with the same
  specificity
• Prognosis value linked to the most erosive forms

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Differential Diagnosis

• Infectious Arthritis
• Thyroid Disease
• Malignancies
• Polymyalgia Rheumatica
• Hemochromatosis

• Seronegative polyarthritis
• Psoriatic Arthritis
• Reiters Syndrome
• Chondrocalcinosis
• Gout
• Behcets Syndrome

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Baseline Evaluation

• 43 yo AAF came to PMD, reports 4 mo. h/o
  bilateral wrist and knee pain.
• Occasional swelling in wrists and knuckles
• No PMH
• Takes tylenol for pain w/o relief
• BASELINE EVALUATION
• Important questions

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Baseline Evaluation of Patients

• Subjective/History
• Degree of joint pain/swelling symmetry? joints
  involved?
• Presence/Duration of morning stiffness
• Presence of fatigue
• Limitation of function
• H/o SICCA symptoms? Recent GI/GU infection?
  Sexual Activity?

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Baseline Evaluation of Patients

• Physical Exam
• Essential Assessments

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Baseline Evaluation of Patients

• Physical Examination
• Documentation of actively inflamed joints
• Documentation of mechanical joint problems loss
  of motion, crepitus, instability, deformity
• Documentation of extra-articular manifestations
• Optho, cardiac, pulmonary, rash, LAD

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Baseline Evaluation of Patients

• LABS/STUDIES

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Baseline Evaluation of Patients

• Laboratory
• ESR /C-reactive protein
• Rheumatoid factor/Anti-CCP Ab
• ANA, Subserologies?
• Complete blood cell count
• Renal function and electrolytes
• Hepatic panel
• Urinalysis
• Synovial fluid analysis
• Consider HIV, Uric Acid

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Baseline Evaluation of Patients

• Radiography
• Wrist and hands
• Feet
• Other symptomatic joints

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Rheumatoid Arthritis Classification of Function

• Class I No Limitations
• Class II Adequate for Normal Activities
  Despite Joint Discomfort or
  Limitation of Movement
• Class III Inadequate for Most Self-Care and
  Occupational Activities
• Class IV Largely or Wholly Unable to
  Manage Self-Care Restricted to Bed or
  Chair

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ACR20/50/70/90 Response Criteria

• A 20, 50, or 70 or 90 improvement in
• Swollen joint count, AND
• Tender joint count, AND
• At least three of the following
• Patients global assessment of disease activity
• Physicians global assessment of disease activity
• Patients assessment of pain
• Acute-phase reactants (ESR or CRP)
• Patients assessment of disability (HAQ)

Felson DT, et al. Arthritis Rheum.
199538727735 Felson DT, et al. Arthritis
Rheum. 19984115641570.
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Health Assessment Questionnaire (HAQ)

• Widely accepted, validated, rheumatology-specific
  instrument to assess physical function in RA
• Gold standard
• 20 questions covering 8 activities
• Dressing and grooming, arising, eating, walking,
  hygiene, reaching, gripping, activities of daily
  living

OMERACT Outcome Measures in Rheumatoid
Arthritis Clinical Trials
Buchbinder R et al. Arthritis Rheum.
1995381568-1580. Sullivan FM et al. Ann Rheum
Dis. 198746598-600.
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Disease Activity Score 28 (DAS28)
Assessment of Improvement or Response
DAS28 0.56 ?(t28) 0.28 ?(sw28) 0.70
Ln(ESR) .014GH

• t28 number of tender joints among 28 joints
• sw28 number of swollen joints among 28 joints
• ESR erythrocyte sedimentation rate (mm/hour)
• GH general health status using a 100-mm
  visual analog scale (VAS)

High disease activity ? 5.1, low disease activity
? 3.2, remission ? 2.6
DAS28 Simplified disease activity score Prevoo
ML, et al. Arthritis Rheum. 1995384448.
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Sharp Scores of Radiographic Progression

• Erosion scores
• 17 joints of each hand/wrist
• 6 joints of each forefoot
• Scale 05 Total score 0230
• Joint space narrowing (JSN) scores
• 16 joints of each hand/wrist
• 5 joints of each forefoot
• Scale 04 Total score 0168
• Total Sharp score
• Add erosion and JSN scores
• Total score 0398

Sharp JT, et al. Arthritis Rheum.19852813261335
van der Heijde DM, et al. J Rheumatol.
19952217921796.
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Prognostic Markers in RA

• Early Markers
• Generalized onset with numerous joints involved
• Systemic involvement including fatigue, fever,
  weight loss, morning stiffness
• Elevated CRP or ESR
• Positive test for rheumatoid factor/Anti-CCP
• Early erosions, JSN
• HLA-DR4 genetic marker

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Prognostic Markers in RA

• Later Markers
• Involvement of more joints
• Increased morning stiffness
• Rheumatoid factor 1160 or greater
• Anemia and thrombocytosis

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Prognostic Markers in RA

• Definitive Markers
• Subcutaneous nodules
• Detection of erosions on x-ray

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The Importance of Early Diagnosis

• RA is progressive, not benign
• Structural damage and disability occurs within
  first two to three years of disease
• Slower progression of disease is linked to early
  treatment with DMARDs, Biologic Agents

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RA Progression
Severity (arbitrary units)
0
5
10
15
20
25
30
Duration of Disease (years)
Adapted from Kirwan JR. J Rheumatol.
200128881886.
I.6
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Joint Erosions Occur Early in RA

• Up to 93 of patients withlt2 years of RA may
  have radiographic abnormalities
• Erosions can bedetected by MRI within 4 months
  of RA onset
• Rate of progression is significantly more rapid
  in the first year than in the second and third
  years

Maximum Joints Affected
Hand
MTP
All
Year
Fuchs HA et al. J Rheumatol. 198916585-591. McQu
een FM et al. Ann Rheum Dis. 199857350-356. van
der Heijde DM et al. J Rheumatol.
1995221792-1796.
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Treatment The Earlier the Better
Delayed Treatment(median treatment lag time
123 days n 109) Early Treatment (median
treatment lag time 15 days n 97)
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12
10
8
Change in Median Sharp Score
6
4
2
0
0
6
12
18
24
Time (months)
Patients were treated with chloroquine or
azathioprine. Lard LR, et al. Am J Med.
2001111446451.
I.16
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The Goals of Treatment

• Eliminate synovitis and disease activity
• Improve symptoms
• Prevent joint damage
• Prevent or reduce disability
• Prevent or reduce other adverse outcomes

Adapted from Wolfe F et al. J Rheumatol.
2001281423.
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Current Treatment Options

• Nonsteroidal Anti-inflammatory Drugs (NSAIDs)
• Corticosteroids
• Disease Modifying Anti-rheumatic Drugs (DMARDs)
• Biologic Agents

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Potential Toxicity of NSAIDs

• COX-1
• Gastrointestinal toxicity
• Platelet dysfunction
• COX-1 and COX-2
• Decreased renal blood flow
• Hepatic dysfunction
• CNS toxicity dizziness, tinnitus, confusion,
  anxiety
• Hypersensitivity
• COX-2
• Increased risk of cardiovascular disease
• Increased risk of thrombosis

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Traditional DMARDs

• Cyclosporine
• Parenteral/oral gold
• Azathioprine
• D-penicillamine
• Minocycline

• Methotrexate (MTX)
• Hydroxychloroquine
• Leflunomide
• Sulfasalazine

Not approved by the FDA for the treatment of
RA. ACR guidelines for the management of
rheumatoid arthritis. Arthritis Rheum.
200246328-346.
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Methotrexate - Dosage

• Initiation 7.5 mg once weekly
• Maximum 25 mg once weekly
• Route po, SQ

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Methotrexate - Potential Toxicity

• Hematologic
• Teratogenic
• ?Carcinogenic

• Stomatitis
• Alopecia
• Pulmonary
• Hepatic- check LFTS q 6 weeks then q 3 mo when on
  stable dose

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Leflunamide - Arava

• Can be given with loading dose 100mg qd x 3 days,
  then 10-20mg po qd
• Monitor CBC, LFTs
• Teratogenic
• Cholestyramine is given if rapid removal is
  necessary

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Antimalarials

• Hydroxychloroquine - plaquenil
• Initiation 400 600 mg qd
• Maintenance 200 mg qd
• Chloroquine
• Initiation 500 mg qd
• Maintenance 250 mg qd
• Potential Toxicities GI, Retinopathy

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Sulfasalazine

• Dosage
• 2 3 gm qd in 2 3 divided doses
• Potential toxicity
• Hematologic
• Monitor CBC q2 weeks the first 3 months of
  therapy
• Hepatic
• Monitor hepatic function monthly

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Inhibition of Cytokines
Adapted with permission from Choy EH, Panayi GS.
N Engl J Med. 2001344907916.
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TNF Blocking Therapies
Etanercept Infliximab
Adalimumab Characteristic (ENBREL?) (REMICADE?
(HUMIRA) Class sTNFR TNF MAb
TNF MAb Construct Recombinant Chimeri
c MAb Recombinant fusion protein
human
MAb Half-life 4 days 810 days
1020 days Binding target TNF/LT?
TNF TNF Administration 50 mg 310 mg/kg 40
mg SC IV with MTX SC Once weekly Every 48
weeks Every other week
Some patients not taking concomitant MTX may
derive additional benefit fromincreasing the
dosing frequency of adalimumab to 40 mg every week
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• Rituximab (chimeric murine-human anti CD20 Ab)
• in combination with methotrexate is indicated
  to reduce signs and symptoms in adult patients
  with moderately- to severely- active rheumatoid
  arthritis who have had an inadequate response to
  one or more TNF antagonist therapies.

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Figure 2 B-cell functions are inhibited following
cell depletion by rituximab
Salama AD and Pusey CD (2006) Drug Insight
rituximab in renal disease and transplantation Nat
Clin Pract Neprol 2 221230 doi10.1038/ncpneph0
133
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Abatacept CTLA-4Ig
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ACR Treatment Algorithm
RHEUMATOLOGIST
Establish diagnosis of RA early
PCP
Initiate therapy
Periodically assess disease activity
Adequate response
Inadequate response
Change/add DMARDs
Suboptimal MTX response
MTX naïve
Othermonotherapy
Combination
Biologics
Othermonotherapy
Combination
MTX
Monotherapy
Combination
Multiple DMARD failure
Symptomatic and/or structural joint damage
Adapted from ACR guidelines for the management
of rheumatoid arthritis. Arthritis Rheum.
200246328-346.
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• Questions
• Case report

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Case Report

• 57-year-old man was admitted to a hospital
  affiliated with dyspnea and dry cough lasting 2
  weeks.
• He had previously been diagnosed with rheumatoid
  arthritis, manifested by painful swelling of the
  joints 2 years prior to admission.
• The patient was being treated with prednisone and
  gold.
• Patient with diffuse pulmonary rheumatoid nodules
  and interstitial fibrosis throughout both lungs,
  is described.
• The patient, with articular symptoms and
  seropositivity, exhibited a rapid clinical course
  and died of respiratory failure 3 months after
  the appearance of dyspnea.

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• Chest radiography indicated interstitial
  pneumonitis with bilateral diffuse peripheral
  shadows.
• At autopsy, numerous rheumatoid nodules and
  interstitial fibrosis had destroyed both lungs,
  such that no residual normal pulmonary tissue
  remained.
• It is believed that this was an extremely rare
  case exhibiting large numbers of rheumatoid
  nodules throughout the lungs.
• Findings with this patient indicate that, in
  patients with rheumatoid arthritis, clinical
  interstitial pneumonitis confirmed
  radiographically does not exclude the existence
  of rheumatoid lung nodules.