76-year-old retired thoracic surgeon

• 6-week h/o painful, purpuric acral lesions which occurred 2

weeks after receiving an influenza vaccination

• PMH –ASHD, hepatitis (resolved), GERD, hyperlipidemia,

tinea pedis & onychomycosis

• Medications – esomeprazole, clopidogrel, dutasteride,

alfuzosin, rosuvastatin, CoQ-10, metoprolol, econazole

cream, ciclopirox gel

• Prior oral terbinafine

Laboratory Findings

• 10-26 – Normal – CBC, ANA, U/A, CMP, cold

agglutinins, Anticardiolipin ab, IFE

• 10-26 – ESR = 48, CRP = 5.24, RF = 24 (nl < 20), CH50 =

28 (nl > 80), fibrinogen = 647 (nl < 450), D dimer = 1721

(nl < 230), anti-phosphatidylserine IgG = 19 (nl < 11)

and IgM = 64 (nl < 25)

Course

• The patient was seen by a hematologist

• Cryoglobulin testing was negative

• Treatment with prednisone 20 mg orally was initiated

without appreciable response

• 11-19 – RF = 54, ESR and CRP both normal

Course

• Prednisone was increased and rituximab was initiated

by hematology

• His cutaneous disease on the hands and feet and pain of

the hands and feet continued to progress despite therapy

• Repeat labs in early January revealed a cryoglobulin

Types of Cryoglobulins

• Type I – The presence of isolated monoclonal Ig (typically IgG or IgM, less commonly IgA or free immunoglobulin light chains) – 5 to 25 percent of cases.

– Associated with Waldenström's macroglobulinemia or multiple myeloma

• Type II –A mixture of polyclonal Ig in association with a monoclonal Ig typically IgM or IgA, with RF activity. – 40 to 60 percent of cases.

– Associated with persistent viral infections, particularly hepatitis C virus

• Type III – Mixed CGs consisting of polyclonal Ig without a monoclonal Ig component characterize type III CGs. – 40 to 50 percent of all CG cases

– often secondary to connective tissue diseases.

Cutaneous Manifestations

• Cutaneous manifestations develop in nearly all patients with CG syndromes and may precede extracutaneous manifestations by decades

• Type I CG classically produces signs related to hyperviscosity and/or thrombosis: Raynaud phenomenon, digital ischemia, livedo reticularis, and purpura may occur. In severe cases, without treatment, this may progress to gangrene.

• Mixed CGs (Types II and III) most often produce constitutional nonspecific symptoms, such as arthralgias, fatigue, and myalgias, as well as palpable purpura due to cutaneous vasculitis.

Systemic Manifestations

• Neurologic:

– Due to hyperviscosity: blurring or loss of vision, headache,

vertigo, nystagmus, dizziness, sudden deafness, diplopia,

ataxia, confusion, dementia, disturbances of consciousness,

stroke, or coma

– Peripheral neuropathy

• Renal: glomerulonephritis

• Pulmonary: rare

Diseases/Disorders Associated with cryoglobulinemia

• Idiopathic

• Infections – viral, particularly HCV, bacterial, fungal, parasitic

• Autoimmune/connective tissue diseases – LE, RA, Sjögren syndrome

• Lymphoproliferative disease –lymphoma, myeloma, macroglobulinemia

• Iatrogenic – vaccinations, BCG administration

• Report of utilizing 3 large databases found over 2600 possible

cases of vasculitis as an adverse reaction following various

types of vaccinations

Cryoglobulinemia following Vaccination

• The only documented report linking influenza vaccination

to cryoglobulinemia:

– The patient developed disease 2 weeks following vaccination. At

two months RF and mixed type II cryoglobulin was found which

persisted despite a disappearance of symptoms. A monoclonal

paraprotein of unknown significance was also found

– Review of the literature consisted of cases of vasculitis following

vaccination, none of who had cryoglobulin demonstrated

– Lohse A, et al. Vascular purpura and cryoglobulinemia after influenza vaccination. Case-

report and literature review. Rev Rheum Engl Ed. 1999 Jun;66(6):359-60.

Indications for Therapy of Cryoglobulinemia

• Glomerulonephritis associated with either a rapidly progressive course and/or nephrotic range proteinuria

• Severe digital ischemia threatening amputation

• Gastrointestinal vasculitis associated with abdominal pain and/or gastrointestinal bleeding

• Rapidly progressive neuropathy

• Central nervous system vasculitis that may present as a stroke or acute cognitive impairment

• Pulmonary vasculitis associated with diffuse alveolar hemorrhage or respiratory failure

• Heart failure

Therapy of Cryoglobulinemia

• Rituximab has become the therapy of choice except for

patients with Hepatitis B or HIV infection

• Alternative therapies: corticosteroids,

cyclophosphamide