Cholesterol Embolization Syndrome Mimicking Vasculitis:

1
Cholesterol Embolization Syndrome Mimicking
Vasculitis A Case of Lower Extremity
Ulceration with Longstanding Seropositive
Rheumatoid Arthritis.
Samar Charabaty, MD Victoria Shanmugam, MBBS,
MRCP.
Department of Rheumatology, Allergy and
Immunology, Georgetown University Medical Center,
Washington DC.
Georgetown University
Abstract
Hospital Course
We present the case of a 65 - year- old caucasian
man with coronary artery disease, peripheral
vascular disease and rheumatoid arthritis who
develops gangrene of the foot. In this
presentation, we review causes of lower extremity
ulceration associated with rheumatoid arthritis,
and recognize cholesterol crystal embolization
syndrome as a potential complication of
atherosclerosis and mimicker of vasculitis.

• HD 1 right partial calcanectomy.
• HD 4 Total Below the knee amputation.
• HD 10 Patient developed pulmonary embolism and
  was started on anticoagulation.
• HD 11 The skin of the left foot took a mottled
  appearance.
• HD 15 An arteriogram of the lower extremity
  showed PVD and a moderate length near total
  occlusion of the superficial femoral artery (
  figure 2).
• HD 18 A left femoro-popliteal bypass was done
  to re-establish flow to the left lower extremity.
• HD 27 right lower extremity amputation flap
  became gangrenous despite patent vasculature and
  no evidence of infection. The rheumatology team
  was asked to evaluate for vasculitic processes.

Introduction

• Cholesterol crystal embolization (blue toe
  syndrome) is a syndrome in which portions of
  atherosclerotic plaque embolize distally,
  occluding small arteries and causing tissue
  ischemia
• Although this may can occur spontaneously, it is
  often associated with invasive vascular
  procedures such as arteriograms and vascular
  surgery.

Figure 3 Skin biopsy specimen showing
cholesterol clefts in a small arteriole
(Hematoxylin eosin stain).

• Peripheral artery disease
• Atherosclerotic peripheral artery disease is
  more common in rheumatoid arthritis patients than
  healthy controls independent of other
  cardiovascular risk factors.
• Inflammatory markers, glucocorticoid use and
  extra-articular features of rheumatoid arthritis
  are independent risk factors in this
  population.
• Presence of biphasic pulses in the right foot at
  presentation, and intact blood flow to the
  amputation flap all suggested that some other
  factor may be playing a role in the progression
  to gangrene.
• Cholesterol crystal embolism
• Biopsy demonstrating cholesterol clefts in the
  small or medium-sized arteries or arterioles.
  These crescentic or elongated ovoid spaces are
  the result of dissolution of the cholesterol
  crystal during tissue fixation and are
  pathognomic of cholesterol embolization syndrome.

Learning Objectives
1- To review causes of lower extremities
ulceration associated with rheumatoid arthritis.
2- To recognize cholesterol crystal embolization
syndrome as a potential complication of
atherosclerosis and a vasculitis mimicker.

• A full autoimmune came back negative and the
  hypercoagulable work-up revealed an elevated of
  the homocysteine level at 13.5 umol/l (normal
  4.3-11.4), along with heterozygous plasminogen
  activator inhibitor-1 gene mutation (table 1).
• The debrided tissue from the amputation site was
  reviewed in detail, and cholesterol clefts were
  identified in a small arteriole confirming the
  diagnosis of cholesterol crystal embolization
  syndrome (figure 3)
• This patient commenced 20 mg of prednisone, with
  taper over the subsequent weeks.
• LDL apheresis was considered, but deferred due
  to clinical stabilization.
• Since the patient had prothrombotic risk factors
  and a recent pulmonary embolus, the
  anticoagulation was continued. No further
  ischemic events were noted, and patient was
  discharged to a rehabilitation facility.

Case Presentation

• A 65-year-old caucasian man with coronary artery
  disease and bypass surgery in 1995, peripheral
  vascular disease, dyslipidemia and heavy smoking,
  presented 4 months after starting adalimumab for
  longstanding seropositive erosive rheumatoid
  arthritis with a myocardial infarction. He was
  treated with endovascular stenting. Subsequently,
  he developed right foot pain and blue
  discoloration of his toe. His podiatrist treated
  his foot pain with a steroid injection for
  presumed plantar fascitis. He later developed
  progressive ulceration and gangrene of the right
  heel and was admitted at Georgetown for further
  evaluation.
• He denied any systemic symptoms and his
  rheumatoid arthritis was stable with
  approximately one hour of morning stiffness in
  the hands and mild swelling in the
  metacarpophalangeal joints.
• On the heel of the right foot, there was a
  gangrenous ulcer (figure 1), but dorsalis pedis
  and posterior tibialis pulses were biphasic. On
  the left foot there was a submetatarsal blister,
  dorsalis pedis pulse was monophasic and the
  posterior tibialis pulse was absent. There were
  no other skin rashes, livedo reticularis,
  splinter hemorrhages or Bywaters lesions.
  Neurological examination was unremarkable.

Discussion

• Based on a prospective observational study of
  1786 cardiac catheterizations, the rate of
  cholesterol embolization syndrome is estimated to
  be approximately 1.4 (2).
• Major risk factors for cholesterol emboli
  include advanced age, vascular procedures, and
  peripheral vascular disease.
• The prognosis of CCE is poor with a 72 fatality
  rate due to concomitant visceral ischemia.
• Some studies have implicated anticoagulation as
  a precipitant for CCE (3). However, in a study of
  519 patients with severe aortic plaque the rate
  of cholesterol emboli was similar in those
  receiving warfarin as those who were not (1)
  (4).
• Treatment remains supportive. Statins, which
  stabilize and may cause regression of
  atherosclerotic plaques, improve renal and
  overall outcome. Additionally, steroids, iloprost
  and LDL apheresis have been beneficial in small
  numbers of patients.

Differential diagnosis

• Rheumatoid vasculitis
• Typically develops in patients with longstanding
  erosive disease.
• Commonly involves small and medium-sized vessels
  of the skin, digits, peripheral nerves, eyes and
  heart.
• Risk factors include male gender, high-titer
  rheumatoid factor, joint erosions, pleuritis,
  subcutaneous nodules, and presence of nail-fold
  lesions.
• Vasculitis related to TNF-a inhibitor use
• Several reports suggest that TNF-a inhibitors
  induce vasculitis, others have reported a
  successful response of rheumatoid vasculitis to
  these drugs
• Most vasculitis cases (86) involved skin
  lesions including purpura, ulcerative lesions,
  nodules, digital vasculitis, maculopapular rash
  and chilblain lesions (1). Vasculitis appeared
  after a mean of 38 weeks of therapy and in most
  cases resolved with discontinuation. Adalimumab
  was implicated in only 4 of cases in this study,
  and there were no reports of cardiac involvement.
  
• Prothrombotic states
• Both acquired and inherited hypercoagulable
  states should be suspected when unusual,
  migratory, or widespread locations of thrombosis
  are seen at early age of onset with recurrent
  episodes and a strong family history
• Both heterozygous plasminogen activator
  inhibitor-1 mutation, and elevated homocysteine
  level may have contributed to the development of
  the pulmonary embolus but are not typically
  associated with arterial thrombi.

Conclusion
Cholesterol crystal embolism is a well recognized
mimicker of vasculitis and should be considered
in rheumatoid athritis patients presenting with
tissue ischemia following a vascular procedure.
References

• Ramos-Casals M et al. Autoimmune diseases induced
  by TNF-targeted therapies. Best Pract Res Clin
  Rheumatol. 200822(5)847-61.
• Bashore TM, Gehrig T. Cholesterol emboli after
  invasive cardiac procedures. J Am Coll Cardiol.
  200342(2)217-8.
• Hyman BT et al. Warfarin-related purple toes
  syndrome and cholesterol microembolization. Am J
  Med. 198782(6) 1233-7.
• Tunick PA, et al. Effect of treatment on the
  incidence of stroke and other emboli in 519
  patients with severe thoracic aortic plaque. Am J
  Cardiol. 200290(12)1320-5.

Figure 2 Arteriogram of the left lower extremity
showing occlusion of the superficial femoral
artery
Figure1 Gangrenous ulcer on the heel of the
right foot.