Systemic Vasculitis

Contributor: Peter Valen, MD, FACP

CASE 1

A 50 year old female presents with a six-month history of " painful red spots " on her lower legs. They occur in crops over a period of time and resolve with residual hyperpigmentation. She has no systemic features such as fever or weight loss, and no circulatory, pulmonary, gastrointestinal, or other symptoms. Her past medical history is unremarkable and she is on no medications. There is no family history of bleeding disorders.

Physical examination is unremarkable except for palpable purpura on both lower extremities. Initial laboratory tests include a normal complete blood count, ESR and urinalysis. A biopsy of a skin lesion reveals leukocytoclastic vasculitis (LCV).

What is the differential diagnosis?

LCV resulting in palpable purpura is secondary to another underlying condition in more than 70% of cases.

These include:

  1. Infections
    • Viral: consider hepatitis B and C, HIV, EBV
    • Acute bacterial: consider meningococcemia, GC, gram negative bacteremia
    • Chronic infections: consider SBE, fungal infections
  2. Drugs (hypersensitivity vasculitis)
  3. Para-proteins (cryoglobulins, macroglobulinemia)
  4. Systemic vasculitis: consider ANCA-associated vasculitis (Wegener'sGranulomatosis (GPA), Microscopic Polyangiitis (MPA), Churg-Strauss), Polyarteritis Nodosa (PAN)
  5. Rheumatic diseases: consider Systemic Lupus Erythematosus (SLE), Rheumatoid Arthritis (RA), Polymyositis/Dermatomyositis (PM/DM), Sjogren's syndrome (SS)
  6. Miscellaneous: consider malignancy, inflammatory bowel disease (IBD)

What testing is indicated in this patient's work up?

The following tests can be done to look for systemic causes of LCV:

  • CBC
  • ESR
  • UA
  • ANA
  • RF
  • ANCA
  • Cryoglobulins
  • Serum protein electrophoresis (SPEP)
  • Hepatitis B and C serology
  • C3 and C4 complement levels
  • Echocardiography

All tests were negative or normal.

This patient had LCV of unknown cause, with no evidence of systemic vasculitis, underlying connective tissue disease, or other systemic illness. Treatment in this case often consists of low dose prednisone with a gradual taper. Other medications such as colchicine, anti-histamines and dapsone may be helpful in resistant cases.

CASE 2

A 43 year old man presents with a 2-3 week history of fever, cough and migratory arthralgias. This was preceded by persistent nasal stuffiness and a mildly productive cough that on one occasion included bright red blood. He reports a 5-10 year history of recurrent sinus and ear infections that seem unresponsive to antibiotics and decongestants. Additionally, he reports recent malaise and fatigue, with mild dyspnea on exertion. For the past 4-5 days, he has had a painful, red left eye. He is a non-smoker, with no recent travel or exposures, and he denies cocaine or other drug use.

Physical examination reveals an ill-appearing male, with a blood pressure of 140/90 and a pulse of 102, temperature is 101 degrees F. There is no skin rash or adenopathy. He is tender over the maxillary sinuses, and the left eye is injected and slightly swollen. Chest exam reveals decreased breath sounds with rales in the upper lung fields. A chest X-ray reveals multiple, large pulmonary nodules in both upper lobes with cavitation in several areas. Laboratory studies include a mild anemia and WBC of 12,200 with a slight left shift and no significant eosinophilia. A urinalysis reveals 2+ protein and 20-30 RBCs. Serum creatinine is 1.5. Sinus films show opacification of the left maxillary sinus.

What is the likely diagnosis and what additional tests do you want to obtain to help confirm your diagnosis?

This patient presents with multi-organ system disease, with prominent findings in the upper and lower respiratory tract and kidney. Systemic vasculitis, as well as infection, malignancy, and vasculitis mimics, should be considered.

  • The following tests should be considered in the evaluation a patient with this presentation:
    • CBC with differential, UA, C3 and C4 complement levels, ESR, CRP
    • Hepatitis Serologies and HIV
    • PPD skin testing and sputum for AFB and fungal cultures
    • Urine drug screen if drug use is suspected
    • Serum antibody testing for ANA, RF, anti-GBM (Goodpasture's disease),ANCA (withantigen-specific anti-PR3 and anti-MPO if ANCA is positive)
    • Biopsy of tissue to look for granulomatous inflammation with necrotizing vasculitis- the highest yield is found with lung biopsy (open or video-assisted thoracoscopic surgery)

A PPD skin test was negative; sputum for AFB and fungal cultures were obtained; AFB smears and sputum cytology were negative. Serum antibody tests for ANA, RF, and HIV were negative. Anti-GBM antibodies were negative. ANCA was positive at a titer of 1:1280 with cytoplasmic staining (c-ANCA), and anti-proteinase 3 (PR3) antibodies by ELISA were also positive. Serum C3 and C4 complement levels were normal. Bronchoscopy revealed no obstructing lesions or bloody secretions. An open lung biopsy was performed, and tissue sections revealed granulomatous inflammation, necrotizing vasculitis, and multi-nucleated giant cells.

What is the most likely diagnosis in this patient?

This patient's presentation suggests a pulmonary-renal syndrome, the most common causes of which include Goodpasture's (anti-GBM disease), post-infectious, lupus and other auto-immune diseases, and ANCA-associated vasculitis. Several additional clinical features in this case suggest Granulomatosis with Polyangiitis - Wegener's (GPA) as a likely diagnosis. This condition should be suspected in patients with chronic epistaxis, septal perforation, nasal bridge collapse, chronic sinus and/or ear infections, hearing loss, hoarseness, necrotizing scleritis of the eye, proptosis, hemoptysis and glomerulonephritis. Several conditions may mimic GPA, including cocaine-induced midline destructive lesion (CIMDL), sino-nasal sarcoid, relapsing polychondritis, fungal infections (esp. mucormycosis) and NK/T cell lymphomas. Although c-ANCA and anti-PR3 positivity are highly suggestive, tissue biopsy is recommended in most cases to confirm the diagnosis, and rule out malignancy and infections.

In this case, a diagnosis of Granulomatosis with Polyangiitis-Wegener's was made, based on clinical presentation, test and biopsy results. He was treated with high-dose corticosteroids and oral cyclophosphamide, with trimethoprim-sulfa for pneumocystis prophylaxis Plasmapheresis may be indicated in certain patients with alveolar hemorrhage, rapidly progressive renal failure, or concomitant anti-GBM antibodies. Rituximab has recently been approved to treat this condition and may be an alternative to cyclophosphamide. The treatment plan was to continue cyclophosphamide and tapering doses of steroids for 3-6 months and clinical remission, then switch to methotrexate or azathioprine for maintenance therapy.

Patient Care

  1. Identify common complaints suggestive of vasculitis, including fever, weight loss, fatigue, skin rash, hemoptysis, mononeuritis multiplex, circulatory problems, etc.
  2. Recognize the urgency of confirming a diagnosis and initiating appropriate therapy in patients with organ-threatening disease.
  3. Implement and interpret appropriate clinical laboratory and radiologic testing to suggest, confirm or exclude a diagnosis of vasculitis.
  4. Recognize the risks and benefits of individual treatments/medications for vasculitis.
  5. Describe the management strategies for vasculitis and match the most appropriate strategy to the clinical situation.

Medical Knowledge

  1. Understand the basic pathophysiology and pathogenic mechanisms of vasculitis.
  2. Distinguish the nomenclature and unique pathophysiologic and histologic features of the individual vasculitis syndromes.
  3. Describe the general classification schemes for vasculitis.
  4. Describe a diagnostic approach for a patient with a suspected vasculitis.
  5. Recognize multi-organ system involvement of the individual vasculitis syndromes and discriminate clinical patterns that identify them.
  6. Understand the treatment options for systemic vasculitis, including the risks and benefits of commonly used drugs for the treatment of vasculitis.
  7. Recognize common vasculitis mimics.
    1. Buerger's disease
    2. Cholesterol emboli syndrome
    3. Calciphylaxis
    4. Disseminated intravascular coagulation (DIC)

Interpersonal And Communication Skills

  • Engage the patient and ask probing questions to maximize the value of the clinical history, which is an essential and key part of the evaluation of vasculitis.
  • Recognize the patient's fears in dealing with a potentially life-threatening condition and establish a trusting relationship with the patient and family.
  • Allow the patient and their family to express concerns and openly ask questions about their condition and treatment options.
  • Summarize the information to be provided to a specialist to whom you might refer a patient with suspected vasculitis.
  • Professionalism

    1. Provide compassionate and respectful care.
    2. Take on the role of patient advocate when their medical condition leads to conflicts and issues at home or workplace.
    3. Ensure that medical decision-making is always done with the best interests of the patient at the forefront.

    Practice-Based Learning And Improvement

    1. Identify personal learning goals in the diagnosis and treatment of vasculitis.
    2. Engage in ongoing self-assessment and continuous self-evaluation of learning needs.
    3. Utilize information technology to search for and critically evaluate medical information relevant to the care of patients with vasculitis.

    Systems-Based Practice

    1. Recognize the importance of a multi-disciplinary approach to the diagnosis and treatment of vasculitis.
    2. Identify any system problems that interfere with the timely and efficient care of patients with vasculitis.
    3. Incorporate considerations of cost-effectiveness in the diagnosis and treatment of vasculitis.

    References

    Questions

    (Answer questions 1 - 5 on a piece a paper. Find Answer Key at the bottom on the page.)

    1. A 48-year-old man presents with a 4-month history of a recurring, painful, erythematous papular rash on the upper and lower extremities. A skin biopsy reveals leukocytoclastic vasculitis (LCV). He is otherwise healthy and on no medications.

      Laboratory studies:
      Complete blood count Normal
      Urinalysis Normal
      C3, C4 complement Normal
      ANCA Negative
      Serum protein electrophoresis Normal
      Cryoglobulins positive for Type II cryoglobulins
      ANA Titer of 1:80

    2. The laboratory testing which would be the most appropriate in this patient's evaluation is:

      1. Anti-DNA
      2. Hepatitis serologies
      3. Anti-phospholipid antibodies
      4. Anti-SSA, SSB antibodies

    3. A 76-year-old man presents with a 6-week history of fevers, fatigue, a new temporal headache, and morning stiffness involving the shoulder and hip girdle. Two days prior to his visit, he experienced an episode of transient diplopia.

      On physical examination, he has mild scalp tenderness diffusely, with normal pulses. There is no lymphadenopathy. Musculoskeletal examination reveals mild pain and restricted motion of his hips and shoulders bilaterally. Neurologic examination is unremarkable.

        Laboratory studies:
        Hematocrit 31%
        Leukocyte count 10,500/uL
        Platelet count 401,000/uL
        Erythrocyte sedimentation rate 68 mm/hr

    4. The next best step in management of this patient is:

      1. Refer the patient to an ophthalmologist for a dilated fundiscopic examination
      2. Start prednisone 15mg daily for polymyalgia rheumatica and ask him to return in 7-10 days for a repeat examination
      3. Refer the patient for a temporal artery biopsy with a return appointment after the biopsy to discuss treatment options
      4. Start prednisone 60mg daily and arrange for an urgent temporal artery biopsy

    5. A 47-year-old woman with a history of chronic asthma presents with numbness and tingling in her hands and feet, with right foot "weakness". She has recently noted increased dyspnea without wheezes, as well as PND, orthopnea and ankle swelling.

      On physical exam, she has palpable purpura and papular lesions over her elbow. HEENT exam reveals nasal polyps. On lung exam, she is noted to have bibasilar crackles without wheezes, and an S3 gallop is noted on cardiac auscultation. Lower extremity exam reveals 1+ pitting edema. Neurologic exam reveals decreased sensation in both feet, and reduced dorsi-flexion of right foot.

    6. Laboratory studies:
      Hemoglobin 12.9 g/dL
      Leukocyte count 12,400 /uL (46% neutrophils, 29% eosinophils, 16% lymphocytes, 9% monocytes)
      Serum creatinine 1.0 mg/dL
      Creatinine kinase normal
      p-ANCA negative
      Urinalysis trace protein; 0-3 RBC's/hpf

      Chest radiograph reveals scattered bilateral nodular infiltrates, cardiac enlargement and vascular congestion

      Echocardiogram reveals global hypokinesis with ejection fraction of 4

      The most likely diagnosis is:

      1. Churg-Strauss syndrome (eosinophilic granulomatosis with polyangiitis-EGPA)
      2. Microscopic polyangiitis (MPA)
      3. Henoch-Schonlein purpura (HSP)
      4. Giant cell arteritis
    7. A 68-year-old man with a history of diffuse atherosclerotic vascular disease presents with purplish discoloration of the toes of his right foot. He has noted a low-grade fever and diffuse myalgias. Ten days ago he underwent an arterial catheterization procedure.

      On physical examination he has normal blood pressure, reduced pulses in his lower extremities, and a blotchy rash on both lower legs (livedo reticularis).

    8. Laboratory studies:
      Leukocyte count 11,500 /uL with 18% eosinophils
      Erthrocyte sedimentation rate 68 mm/h
      C3 decreased
      C4 decreased
      Rheumatoid factor negative
      Anti-nuclear antibodies Titer of 1:80
      Creatinine 1.8 mg/dL
      Urinalysis trace protein, 0-3 RBCs/hpf
      Anti-cardiolipin antibodies negative
      Hepatitis serologies negative

      The most likely diagnosis is:

      1. Thromboangiitis obliterans (Buerger's disease)
      2. Cholesterol emboli syndrome
      3. Polyarteritis nodosa
      4. Cryoglobulinemia
    9. A 27-year-old woman presents with the acute onset of a severe headache ("I thought my head was going to explode"), which peaked in 15-20 seconds, lasted several hours, and recurred on the 2ndhospital day. There were no associated neurologic symptoms. She is otherwise healthy and her physical exam was unremarkable.

    10. Laboratory studies:
      Complete blood count normal
      Erythrocyte sedimentation rate normal
      Urine drug screen positive for cocaine
      Spinal fluid analysis normal
      Chest X-ray normal
      Non-contrast head CT normal
      Contrast-enhanced head MRI normal
      Cerebral angiogram suggestive of "vasculitis", with diffuse areas of vascular ectasia and stenosis ("beading")
      Repeat cerebral angiogram 3 weeks later normal

      The most likely diagnosis is:

      1. Primary CNS vasculitis (PACNS)
      2. Neurosarcoidosis
      3. Susac's syndrome
      4. Reversible cerebral vasoconstriction syndrome (RCVS)
      5. Subarachnoid hemorrhage

    Answer Key

    1. The correct answer is B.

      An underlying cause for LCV is found in 60-70% of cases. Hypersensitivity vasculitis is a term used when an offending drug is implicated. Several autoimmune conditions may be associated with LCV, including systemic lupus and Sjogren's syndrome. Although this patient has a weakly positive anti-nuclear antibody (ANA), he has no other symptoms to suggest lupus or Sjogren's syndrome, and testing for antibodies to DNA, SSA and SSB is not likely to be helpful. Anti-phospholipid antibody syndrome may cause a rash, but the most common cutaneous manifestation is livedo reticularis, followed by digital necrosis and splinter hemorrhages. LCV may be related to infection, and the presence of type II cryoglobulins would suggest the possibility of hepatits C or HIV infection, and therefore hepatitis serologies would be the most appropriate test to perform.

    2. The correct answer is D.

      This patient likely has polymyalgia rheumatica and associated temporal arteritis. Diplopia, although seen in only about 10 percent of cases, is quite suggestive of the diagnosis when present. Although 15mg of prednisone daily is appropriate therapy for polymyalgia rheumatica , it is not an appropriate dose for the initial treatment of active temporal arteritis. The risk of delayed therapy is visual loss, and prompt initiation of corticosteroids (1 mg/kg/d of prednisone) is critical. Temporal artery biopsy findings do not change significantly for several weeks, and therefore the best course of action is to promptly start treatment while awaiting the temporal artery biopsy.

    3. The correct answer is A.

      This patient most likely has Churg-Strauss syndrome (CSS). This form of systemic vasculitis often occurs in patients in the setting of a long-standing history of asthma, allergic rhinitis, sinusitis, or atopic disease. Common findings include eosinophilia, pulmonary infiltrates, skin rash (including LCV, and occasionally a characteristic papular rash on the elbows), mononeuritis multiplex, and constitutional symptoms. Although considered an ANCA-associated vasculitis, only about one-half of patients with CSS will have a positive test for ANCA, usually p-ANCA with anti-myeloperoxidase specificity. Patients who are ANCA-negative are more likely to have eosinophilic infiltrative disease such as pneumonitis and eosinophilic cardiomyopathy, a leading cause of mortality in CSS. The presence of neuropathy suggests the patient may be entering a vasculitic phase of the disease, at which point asthma may paradoxically improve. Microscopic polyangiitis (MPA) is a systemic ANCA-associated vasculitis involving the kidney and lungs, and most patients are p-ANCA positive with anti-myeloperoxidase specificity. The absence of both ANCA antibodies and clinical evidence of active glomerulonephritis makes this diagnosis less likely. HSP most often occurs in children, and although it may cause palpable purpura, abdominal pain and hematuria are frequently present. The neurologic and cardiac findings seen in this patient would not be expected. Giant cell arteritis is a large vessel vasculitis usually affecting individuals over the age of 50. Atlhough the aortic arch and major branch vessels may be involved, direct cardio-pulmonary involvement and neuropathy would be unexpected findings.

    4. The correct answer is B.

      This patient likely has cholesterol emboli syndrome, a vasculitis mimic, with risk factors including atherosclerosis and a recent vascular procedure. Although the physical findings, including "purple toes" and livedo reticularis, are related to microvascular ischemia, there may be systemic effects, possibly immune-complex mediated, resulting in elevated acute phase reactants, eosinophilia and hypo-complementemia.

      Thromboangiitis obliterans may cause digital ischemia, but is generally seen in younger male smokers. Patients generally lack evidence of systemic inflammation , and acute phase reactants are generally normal. Polyarteritis nodosa may cause digital ischemia and livedo reticularis, but other common clinical features, such as abdominal pain due to mesenteric ischemia, neuropathy, testicular pain, subcutaneous nodules, hypertension, and evidence of hepatitis B infection, are lacking. Cryoglobulinemic vasculitis generally causes a purpuric rash, and is frequently accompanied by neuropathy, immune complex glomerulonephritis, rheumatoid factor positivity, and evidence of hepatitis C or other chronic viral infection.

    5. The correct answer is D.

      This patient most likely has reversible vasoconstriction syndrome. This is a group of disorders linked by reversible vasoconstriction of cerebral arteries. It is typically associated with severe, acute-onset headache ("thunderclap" headache). It often occurs in defined clinical settings, such as the post-partum state, with a migraine headache, or following ingestion of vasoactive drugs (pseudoephedrine, ergots, cocaine, etc). Spinal fluid findings are usually normal unless there is an associated subarachnoid hemorrhage. Cerebral angiographic findings may be indistinguishable from primary CNS vasculitis, but should be reversible. Primary CNS vasculitis is seen more commonly in males, and is characterized by a long prodromal period, often with diffuse neurologic dysfunction. Spinal fluid findings are abnormal, with elevated protein and pleocytosis, in 80-90% of patients. The combination of normal head MRI and CSF examination makes primary CNS vasculitis unlikely. Cerebral angiography revealing ectatic and stenotic vessels ("beading") in several sites of the cerebral circulation is suggestive, however the relatively poor sensitivity and specificity of these findings make angiographic diagnosis problematic. Brain or leptomeningeal biopsy may be required for diagnosis. About 5% of patients with sarcoidosis develop CNS disease which may mimic CNS vasculitis. Common clinical features include cranial nerve involvement, seizures, cognitive dysfunction. Contrast-enhanced MRI generally reveals meningeal or parenchymal enhancement. Abnormal spinal fluid, with pleocytosis and increased protein, is seen in the majority of patients. Susac's syndrome is a microangiopathy characterized by encephalopathy, sensorineural hearing loss, branch retinal artery occlusions, and characteristic hyperintensities in the corpus callosum on MRI. Subarachnoid hemorrhage is unlikely with a negative head CT and spinal fluid examination.

    Last updated February 2015.