Ntatsaki E, Carruthers D, Chakravarty K, et al; BSR and BHPR Standards, Guidelines and Audit Working Group. BSR and BHPR guideline for the management of adults with ANCA-associated vasculitis. Rheumatology (Oxford). 2014 Dec;53(12):2306-9. doi: 10.1093/rheumatology/ket445. Epub 2014 Apr 11. PubMed PMID: 24729399.
Jennette JC, Falk RJ, Bacon PA, et al. 2012 revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides. Arthritis Rheum. 2013 Jan;65(1):1-11. doi: 10.1002/art.37715. PubMed PMID: 23045170.
Mukhtyar C, Guillevin L, Cid MC, et al; European Vasculitis Study Group. EULAR recommendations for the management of primary small and medium vessel vasculitis. Ann Rheum Dis. 2009 Mar;68(3):310-7. doi: 10.1136/ard.2008.088096. Epub 2008 Apr 15. PubMed PMID: 18413444.
Cryoglobulinemic vasculitis (CV) is characterized by cryoglobulin deposits that affect small vessels (mainly capillaries, venules, or arterioles) and circulate in the blood. Cryoglobulin deposits are monoclonal and polyclonal anti-IgG immunoglobulins of IgM class. They precipitate at low temperatures, can block blood vessels, and may eventually lead to gangrenous extremities. CV may be classified as idiopathic if the etiology is unknown or as secondary to other conditions. Most commonly CV is associated with hepatitis C virus (HCV) infection (~80% of patients) but can also be associated with lymphoproliferative or autoimmune diseases.
Clinical Features and Natural HistoryTop
1) General symptoms include fatigue and low-grade fever.
2) Cutaneous manifestations: Palpable purpura in 90% of patients, usually on the lower extremities (cold triggers the appearance of new lesions), Raynaud phenomenon.
3) Renal manifestations associated with glomerulonephritis: Mainly peripheral edema and hypertension.
4) Nervous system manifestations: Peripheral polyneuropathy, cranial nerve involvement, central nervous system vasculitis.
5) Other manifestations: Arthralgia, myalgia. Less frequently, lymphadenopathy, hepatosplenomegaly, gastrointestinal symptoms.
In secondary CV features of the underlying condition may be observed. CV is frequently associated with exacerbations lasting 1 to 2 weeks followed by remissions lasting several days to months. With time, renal failure develops; renal involvement is associated with a less favorable prognosis. The most frequent cause of death is infection.
Diagnosis is based on the clinical manifestations and presence of cryoglobulins in the blood. Frequently, levels of complement component C4 (in 90% of patients) and total hemolytic activity of the complement complex (CH50) are markedly decreased. Rheumatoid factor is present in >70% of patients. The erythrocyte sedimentation rate may also be elevated. Histology results of skin biopsy specimens reveal features of leukocytoclastic angiitis, whereas renal biopsy shows proliferative membranous glomerulonephritis.
In HCV-associated cryoglobulinemic vasculitis treatment with antiviral therapy is recommended.Evidence 1Strong recommendation (benefits clearly outweigh downsides; right action for all or almost all patients). High Quality of Evidence (high confidence that we know true effects of the intervention). Misiani R, Bellavita P, Fenili D, et al. Interferon alfa-2a therapy in cryoglobulinemia associated with hepatitis C virus. N Engl J Med. 1994 Mar 17;330(11):751-6. PubMed PMID: 8107741. Mazzaro C, Colle R, Baracetti S, Nascimben F, Zorat F, Pozzato G. Effectiveness of leukocyte interferon in patients affected by HCV-positive mixed cryoglobulinemia resistant to recombinant alpha-interferon. Clin Exp Rheumatol. 2002 Jan-Feb;20(1):27-34. PubMed PMID: 11892704. Traditionally, this is done with interferon alpha, although combination therapy with ribavirin may be superior and new interferon-free treatments for hepatitis C are also promising (such as sofosbuvir with or without ledipasvir; see Chronic Hepatitis C).Evidence 2Weak recommendation (benefits likely outweigh downsides, but the balance is close or uncertain; an alternative course of action may be better for some patients). Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to the open-label study design and indirectness (no comparison to placebo). Quality of Evidence lowered for sofosbuvir/ledipasvir due to indirectness to cryoglobulinemic vasculitis (the only available studies so far are for hepatitis C). Saadoun D, Resche-Rigon M, Thibault V, Piette JC, Cacoub P. Antiviral therapy for hepatitis C virus--associated mixed cryoglobulinemia vasculitis: a long-term followup study. Arthritis Rheum. 2006 Nov;54(11):3696-706. PubMed PMID: 17075881. Mazzaro C, Zorat F, Comar C, et al. Interferon plus ribavirin in patients with hepatitis C virus positive mixed cryoglobulinemia resistant to interferon. J Rheumatol. 2003 Aug;30(8):1775-81. PubMed PMID: 12913934. Lawitz E, Gane EJ. Sofosbuvir for previously untreated chronic hepatitis C infection. N Engl J Med. 2013 Aug 15;369(7):678-9. doi: 10.1056/NEJMc1307641. PubMed PMID: 23944316. Rituximab may also be of benefit in viral and nonviral cryoglobulinemic vasculitis.Evidence 3Weak recommendation (benefits likely outweigh downsides, but the balance is close or uncertain; an alternative course of action may be better for some patients). Moderate Quality of Evidence (moderate confidence that we know true effects of the intervention). Quality of Evidence lowered due to imprecision. Sneller MC, Hu Z, Langford CA. A randomized controlled trial of rituximab following failure of antiviral therapy for hepatitis C virus-associated cryoglobulinemic vasculitis. Arthritis Rheum. 2012 Mar;64(3):835-42. doi: 10.1002/art.34322. PubMed PMID: 22147444; PubMed Central PMCID: PMC3243106. De Vita S, Quartuccio L, Isola M, et al. A randomized controlled trial of rituximab for the treatment of severe cryoglobulinemic vasculitis. Arthritis Rheum. 2012 Mar;64(3):843-53. doi: 10.1002/art.34331. PubMed PMID: 22147661. In patients with idiopathic CV treatment as in other small-vessel vasculitides is recommendedEvidence 4Weak recommendation (benefits likely outweigh downsides, but the balance is close or uncertain; an alternative course of action may be better for some patients). Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to indirectness and sparse data. There have been no randomized controlled trials to assess treatment of idiopathic CV; the only available evidence is for other small vessel vasculitides. Zaja F, De Vita S, Mazzaro C, et al. Efficacy and safety of rituximab in type II mixed cryoglobulinemia. Blood. 2003 May 15;101(10):3827-34. Epub 2003 Jan 30. PubMed PMID: 12560225. (see Granulomatosis with Polyangiitis).
Five-year survival rates in HCV-related and noninfectious vasculitis are similar (≥75%); in the former group, end-stage liver disease and infections are the most frequent causes of death, while in the latter, it is primarily infections. The main prognostic factors are severe liver fibrosis in HCV-related vasculitis, age >65 years, male sex, gastrointestinal and pulmonary involvement, and renal impairment in noninfectious vasculitis.