Curr Infect Dis Rep (2015) 17:7 DOI 10.1007/s11908-014-0452-7
SKIN, SOFT TISSUE, BONE AND JOINT INFECTIOUS DISEASES (N SAFDAR, SECTION EDITOR)
Cutaneous Manifestations of Viral Hepatitis Ahmed Akhter & Adnan Said
# Springer Science+Business Media New York (outside the USA) 2015
Abstract There are several extrahepatic cutaneous manifestations associated with hepatitis B and hepatitis C virus infection. Serum sickness and polyarteritis nodosa are predominantly associated with hepatitis B infection, whereas mixed cryoglobulinemia associated vasculitis and porphyria cutanea tarda are more frequently seen in hepatitis C infection. The clinico-pathogenic associations of these skin conditions are not completely defined but appear to involve activation of the host immune system including the complement system. Management of the aforementioned cutaneous manifestations of viral hepatitis is often similar to that done in cases without viral hepatitis, with control of immune activation being a key strategy. In cases associated with hepatitis B and C, control of viral replication with specific antiviral therapy is also important and associated with improvement in most of the associated clinical manifestations.
Keywords Extrahepatic manifestations . Hepatitis B . Hepatitis C . Serum sickness . Polyarteritis nodosa . Gianotti-Crosti syndrome . Mixed cryoglobulinemia . Porphyria cutanea tarda . Lichen planus . Oral lichen planus
This article is part of the Topical Collection on Skin, Soft Tissue, Bone and Joint Infectious Diseases A. Said (*) Division of Gastroenterology and Hepatology, University of Wisconsin School of Medicine and Public Health, 4223 MFCB, 1685 Highland Avenue, Madison, WI 53705, USA e-mail: [email protected] A. Akhter (*) : A. Said Department of Medicine, University of Wisconsin School of Medicine and Public Health, 600 Highland Avenue, Madison, WI 53792, USA e-mail: [email protected]
Introduction Viral hepatitis, specifically hepatitis B (HBV) and hepatitis C (HCV), not only cause liver disease but also can present with extrahepatic manifestations including cutaneous lesions. The spectrum of these cutaneous manifestations can be varied in the acute and chronic phase of viral hepatitis. Although immune complex-mediated reactions result in most of the associated manifestations, clinico-pathogenic correlations are a dynamic area of research. In this review, we will focus on the cutaneous manifestations of HBV and HCV that will include discussion of the clinical presentation, pathogenesis, and treatment strategies. Hepatitis B-Related Cutaneous Manifestations Hepatitis B is spread via the parenteral route, either vertically at birth from infected mothers or from sexual exposure and intravenous drug use. Chronic infection develops in 5 to 10 % of individuals exposed to hepatitis B as adults and in 99 % of children exposed at birth. In the majority of patients with chronic hepatitis B infection, the disease may remain subclinical and thus undetected in two thirds of cases [1]. However, up to 30 % of adult patients may develop icteric hepatitis in the acute phase [2]. Extrahepatic cutaneous manifestations of HBV can occur in 1 to 10 % of HBV-infected patients and include serum sicknesslike syndrome and polyarteritis nodosa [3, 4]. Serum Sickness-Like Syndrome The prodromal pre-icteric phase of acute hepatitis B often manifests as a serum sickness-like syndrome including constitutional symptoms of fatigue, nausea, myalgias, fevers, and anorexia. It is estimated that 10 to 20 % of patients with acute HBV develop this transient syndrome [5]. During the
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prodromal phase, diffuse polyarthralgias involving the spine and neck as well as urticarial rashes may develop and may be the only physical signs of acute hepatitis B [4]. Histology of urticarial lesions demonstrates leukotaxic urticaria with a perivascular infiltrate of polymorphonuclear cells (PMNs) and fibrinoid occlusion and hemorrhage in small vessels [6]. Occasionally, the constellations of symptoms may be indistinguishable from rheumatoid arthritis (RA) given the propensity to involve small symmetric joints as well as joint edema. Unlike RA, however, there is no evidence of erosive arthritis. A discrete or diffuse skin rash that may be tender or nontender in nature with petechial, nodular, or palpable purpura features can also be present, which often resolves as hepatitis progresses—specifically with the onset of icterus. Erythema multiforme (target-like skin lesions) and lichenoid dermatitis (a group of cutaneous disorders similar to lichen planus-like skin lesions) can also be a manifestation of acute hepatitis B [7]. The duration of the serum sickness-like syndrome often corresponds to the level of viremia. The earliest viral serum markers indicative for acute hepatitis B is HBV DNA followed by HBsAg and HBeAg [8]. Serum alanine and aspartate aminotransferases rise and jaundice may appear as the disease progresses. The icteric phase can last from 1 to 2 weeks up to 2 to 6 months and aforementioned constitutional symptoms can last for weeks to months even after icterus has resolved. It is thought the development of circulating immune complexes, which consist of HBsAg, anti-HBs, immunoglobulins, and complement proteins, result in deposition in the skin leading to the maculopapular lesions observed [4]. It has been proposed that these immune complexes may produce the cutaneous lesions observed via production of anaphylatoxins C3a and C5a [6].
Curr Infect Dis Rep (2015) 17:7
and orchiepididymitis are more often associated with HBVrelated PAN than PAN alone [12, 13]. PAN with or without HBV can be associated with arthralgias, proteinuria, hematuria, pericarditis, congestive heart failure, mononeuritis, and cutaneous vasculitic lesions [8]. Cutaneous manifestations of PAN include palpable purpura, nodules, and erythematous rashes (Fig. 1) which occur 10 to 15 % of the time in patients with PAN [6]. A triad of painful subcutaneous nodules along the arteries of the lower extremities, livedo reticularis, and ulceration can be seen along with acral gangrene [14]. The pathogenesis of HBV-related PAN is a dynamic area of research with the most recent theory related to immune complex deposition in the setting of antigen excess. It is suspected the same pathologic changes occur as in non-HBV-associated PAN, including the deposition of immune complexes and HBsAg (3 million kDa) in the laminae of affected arteries. However, HbeAg (19 kDa) may be the predominant player in these immune complexes given its smaller size as compared to HBsAg. Experimental studies have shown that complexes of only 1 million kDa can result in vasculitic lesions [4]. As opposed to non-HBV-related PAN, serum anti-neutrophilic cytoplasmic antibodies (ANCA) are rarely found in HBVrelated PAN [15, 16]. Histologically, cutaneous lesions are often characterized by involvement of medium-sized vessels in the deep dermis with fibrinoid necrosis consisting of neutrophils, eosinophils, and lymphocytes. Occasionally, even thrombi or aneurysmal change may be present which can lead to necrosis of the overlying epithelium [17]. The immunological process associated with PAN usually begins within 6 months of initial HBV infection [4]. An autoimmune mechanism is thought to be unlikely given antiviral therapy results
Polyarteritis Nodosa Polyarteritis nodosa (PAN) is considered one of the more serious syndromes associated with chronic HBV. In the 1970s, Trepo and Thivolet recognized that hepatitis B was significantly associated with PAN [9]. The ability of a virus to cause a systemic vasculitis was a remarkable discovery, and HBV-related PAN is considered the most typical form of PAN [4]. It has been observed that 30 to 50 % of patients with PAN are hepatitis B carriers [10]. However, PAN only occurs in about 1 to 5 % of patients with chronic HBV [11]. PAN is also referred to as generalized necrotizing vasculitis and is a very appropriate moniker given it is a systemic vasculitis involving large, medium, and small vessels. The symptomatology of HBV-related PAN and PAN in general includes vague constitutional symptoms such as weight loss, malaise, and weakness. Multiorgan damage is also often present, but gastrointestinal manifestations including ulcer-related bleeding and perforation as well as malignant hypertension
Fig. 1 PAN. These nodules are located just below the skin’s surface (subcutaneous), are barely felt when pressing on the skin (palpable), and are tender. The skin is typically red (erythematous). Accessed June 1, 2014. http://www.nlm.nih.gov/medlineplus/ency/imagepages/2440.htm
Curr Infect Dis Rep (2015) 17:7
in eradication of the disease and correlates with cessation of viral replication [18]. HBV-related PAN has a mortality rate of 30 to 50 % within 5 years if not treated [19]. Initially, corticosteroids were used in combination with immunosuppressive medications, mainly cyclophosphamide; however, in HBV-related PAN, this is not an effective long-term solution given viral persistence. Currently, antiviral therapy for HBV including interferon alpha and particularly direct-acting antiviral agents including nucleos(t)ide analog reverse transcriptase inhibitors are used for 6 to 12 months or until documented absence of HBV DNA and HBeAg seroconversion. Symptoms have been shown to improve within 1 month with antiviral therapy and signify the importance of treating the combined entity of HBV-related PAN as opposed to PAN alone. Gianotti-Crosti Syndrome Gianotti-Crosti syndrome was formerly known as papular acrodermatitis of childhood and manifests in patient with acute HBV infection and possibly also hepatitis A and Epstein-Barr virus (EBV) [20]. Usually, this syndrome affects infants and children and rarely does it present in children older than 10 years old. It has cutaneous manifestations of nonpruritic, 2 to 3-mm flat-topped papular or papulovesicular erythematous lesions present primarily on the face and distal extremities. Histologically, these lesions represent superficial perivascular lymphophagocytic infiltrate with mild endothelial swelling [6]. There may also be associated lymphadenopathy in the inguinal or axillary areas. Fortunately, it is a selflimited condition that can last for up to 15 to 20 days either prior to or after the onset of jaundice in patients with acute HBV infection. Hepatitis C-Related Cutaneous Manifestations Since the discovery of the hepatitis C viral genome in 1989, it has been implicated in several extrahepatic diseases including cutaneous diseases, renal disease, neuropathy, and even an association with diabetes. One report estimates that 40 to 75 % of patients with chronic HCV infection have at least one extrahepatic clinical manifestation of HCV [21, 22]. It has been proposed that both the host immune response to the hepatitis C virus results in the extrahepatic manifestations along with direct viral cytopathic effects. Elimination of HCV from the host may not resolve all extrahepatic manifestations, but improvement with antiviral therapy is often used as a parameter of correlation between the extrahepatic manifestation and the HCV. We will discuss the cutaneous manifestations that have pathological associations with and known increased prevalence in HCV patients compared to controls, including mixed cryoglobulinemia, porphyria cutanea tarda, and lichen planus.
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Mixed Cryoglobulinemia The most well-known extrahepatic manifestation of chronic HCV is mixed cryoglobulinemia (MC)-associated vasculitis. More than half of patients with HCV are found to have MC, although only 10 % develop symptoms and vasculitis [23, 24]. MC is a B cell lymphoproliferative disorder with three different pathological entities. Type I cryoglobulinemia has monoclonal immunoglobulins (Igs) associated with the HCV antigens usually in the presence of an indolent B cell lymphoma such as Waldenstrom macroglobulinemia or monoclonal gammopathy with undetermined significance. Type II cryoglobulinemia consists of the presence of monoclonal IgM (rheumatoid factor) and polyclonal IgG. Type III cryoglobulinemia is composed of polyclonal IgG and IgM [25]. Type II cryoglobulinemia is the most common type found in HCV-related MC; however, it has been proposed that there may exist a continuous transition of pure polyclonal forms to partial monoclonal forms due to continuous clonal selection [26]. These Igs can reversibly precipitate at temperatures less than 37 °C and form immune complexes with complement proteins, viral antigens, and HCV-RNA in small- and medium-sized blood vessels (arterioles, capillaries, and venules). In contrast to PAN, MC does not affect arteries. Symptomatic MC includes arthralgias, weakness, and palpable purpura as well as peripheral neuropathy. Renal failure can be associated with the development of a GN from immune complex deposition. Clinical manifestations of MC particularly renal failure may portend a worse prognosis, and approximately 10 % of patients may develop a B cell malignancy especially non-Hodgkin lymphoma [24, 27–29]. Cutaneous manifestations of MC in HCV infection occur in 24 to 30 % of patients with identifiable cryoglobulins [21, 26] (Fig. 2). Given the ability of Igs to precipitate in the cold, these cutaneous findings may be more prevalent during the winter months. Palpable purpura is the most common presenting feature and usually involves the lower extremities and less often spreads toward the trunk (where the temperature is higher) and upper extremities. There is a reported association between these findings and erythrocyanosis as well as Raynaud’s syndrome [31] and peripheral neuropathy due to immune complex deposition in the vasa nervorum of the lower extremities. The purpura can last for 3 to 10 days with residual brown pigmentation. Histology demonstrates leukocytoclastic vasculitis of small vessels secondary to deposition of immune complexes. Therapy for HCV-related MC includes a three-pronged attack including elimination of HCV, decreasing lymphocyte proliferation, and managing cutaneous vasculitis. Current evidence for antiviral therapy includes pegylated interferon (IFN) with ribavirin in patients with mild to moderate HCVrelated MC [32]. However, direct-acting antiviral agents (polymerase, protease, and nucleotide inhibitors) will likely
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Fig. 2 Clinical findings of leukocytoclastic vasculitis in cryoglobulinemia and porphyria cutanea tarda: a cryoglobulinassociated vasculitis and b characteristic changes of porphyria cutanea tarda. (with permission from [30])
supersede the current regimen seen in HCV-related MC given their superior efficacy and tolerability in treating HCV [33]. Given the role of B cells in HCV-related MC, rituximab (RTX) (monoclonal antibody against protein CD20 found on the surface of B cells) has been used in patients with severe vasculitis with or without skin ulcers and glomerulonephritis [34•]. Combined therapy with pegylated IFN, ribavarin, and RTX has demonstrated a complete response of 54.5 % compared to 33.3 % in those with pegylated IFN and ribavirin alone (P
SKIN, SOFT TISSUE, BONE AND JOINT INFECTIOUS DISEASES (N SAFDAR, SECTION EDITOR)
Cutaneous Manifestations of Viral Hepatitis Ahmed Akhter & Adnan Said
# Springer Science+Business Media New York (outside the USA) 2015
Abstract There are several extrahepatic cutaneous manifestations associated with hepatitis B and hepatitis C virus infection. Serum sickness and polyarteritis nodosa are predominantly associated with hepatitis B infection, whereas mixed cryoglobulinemia associated vasculitis and porphyria cutanea tarda are more frequently seen in hepatitis C infection. The clinico-pathogenic associations of these skin conditions are not completely defined but appear to involve activation of the host immune system including the complement system. Management of the aforementioned cutaneous manifestations of viral hepatitis is often similar to that done in cases without viral hepatitis, with control of immune activation being a key strategy. In cases associated with hepatitis B and C, control of viral replication with specific antiviral therapy is also important and associated with improvement in most of the associated clinical manifestations.
Keywords Extrahepatic manifestations . Hepatitis B . Hepatitis C . Serum sickness . Polyarteritis nodosa . Gianotti-Crosti syndrome . Mixed cryoglobulinemia . Porphyria cutanea tarda . Lichen planus . Oral lichen planus
This article is part of the Topical Collection on Skin, Soft Tissue, Bone and Joint Infectious Diseases A. Said (*) Division of Gastroenterology and Hepatology, University of Wisconsin School of Medicine and Public Health, 4223 MFCB, 1685 Highland Avenue, Madison, WI 53705, USA e-mail: [email protected] A. Akhter (*) : A. Said Department of Medicine, University of Wisconsin School of Medicine and Public Health, 600 Highland Avenue, Madison, WI 53792, USA e-mail: [email protected]
Introduction Viral hepatitis, specifically hepatitis B (HBV) and hepatitis C (HCV), not only cause liver disease but also can present with extrahepatic manifestations including cutaneous lesions. The spectrum of these cutaneous manifestations can be varied in the acute and chronic phase of viral hepatitis. Although immune complex-mediated reactions result in most of the associated manifestations, clinico-pathogenic correlations are a dynamic area of research. In this review, we will focus on the cutaneous manifestations of HBV and HCV that will include discussion of the clinical presentation, pathogenesis, and treatment strategies. Hepatitis B-Related Cutaneous Manifestations Hepatitis B is spread via the parenteral route, either vertically at birth from infected mothers or from sexual exposure and intravenous drug use. Chronic infection develops in 5 to 10 % of individuals exposed to hepatitis B as adults and in 99 % of children exposed at birth. In the majority of patients with chronic hepatitis B infection, the disease may remain subclinical and thus undetected in two thirds of cases [1]. However, up to 30 % of adult patients may develop icteric hepatitis in the acute phase [2]. Extrahepatic cutaneous manifestations of HBV can occur in 1 to 10 % of HBV-infected patients and include serum sicknesslike syndrome and polyarteritis nodosa [3, 4]. Serum Sickness-Like Syndrome The prodromal pre-icteric phase of acute hepatitis B often manifests as a serum sickness-like syndrome including constitutional symptoms of fatigue, nausea, myalgias, fevers, and anorexia. It is estimated that 10 to 20 % of patients with acute HBV develop this transient syndrome [5]. During the
7
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prodromal phase, diffuse polyarthralgias involving the spine and neck as well as urticarial rashes may develop and may be the only physical signs of acute hepatitis B [4]. Histology of urticarial lesions demonstrates leukotaxic urticaria with a perivascular infiltrate of polymorphonuclear cells (PMNs) and fibrinoid occlusion and hemorrhage in small vessels [6]. Occasionally, the constellations of symptoms may be indistinguishable from rheumatoid arthritis (RA) given the propensity to involve small symmetric joints as well as joint edema. Unlike RA, however, there is no evidence of erosive arthritis. A discrete or diffuse skin rash that may be tender or nontender in nature with petechial, nodular, or palpable purpura features can also be present, which often resolves as hepatitis progresses—specifically with the onset of icterus. Erythema multiforme (target-like skin lesions) and lichenoid dermatitis (a group of cutaneous disorders similar to lichen planus-like skin lesions) can also be a manifestation of acute hepatitis B [7]. The duration of the serum sickness-like syndrome often corresponds to the level of viremia. The earliest viral serum markers indicative for acute hepatitis B is HBV DNA followed by HBsAg and HBeAg [8]. Serum alanine and aspartate aminotransferases rise and jaundice may appear as the disease progresses. The icteric phase can last from 1 to 2 weeks up to 2 to 6 months and aforementioned constitutional symptoms can last for weeks to months even after icterus has resolved. It is thought the development of circulating immune complexes, which consist of HBsAg, anti-HBs, immunoglobulins, and complement proteins, result in deposition in the skin leading to the maculopapular lesions observed [4]. It has been proposed that these immune complexes may produce the cutaneous lesions observed via production of anaphylatoxins C3a and C5a [6].
Curr Infect Dis Rep (2015) 17:7
and orchiepididymitis are more often associated with HBVrelated PAN than PAN alone [12, 13]. PAN with or without HBV can be associated with arthralgias, proteinuria, hematuria, pericarditis, congestive heart failure, mononeuritis, and cutaneous vasculitic lesions [8]. Cutaneous manifestations of PAN include palpable purpura, nodules, and erythematous rashes (Fig. 1) which occur 10 to 15 % of the time in patients with PAN [6]. A triad of painful subcutaneous nodules along the arteries of the lower extremities, livedo reticularis, and ulceration can be seen along with acral gangrene [14]. The pathogenesis of HBV-related PAN is a dynamic area of research with the most recent theory related to immune complex deposition in the setting of antigen excess. It is suspected the same pathologic changes occur as in non-HBV-associated PAN, including the deposition of immune complexes and HBsAg (3 million kDa) in the laminae of affected arteries. However, HbeAg (19 kDa) may be the predominant player in these immune complexes given its smaller size as compared to HBsAg. Experimental studies have shown that complexes of only 1 million kDa can result in vasculitic lesions [4]. As opposed to non-HBV-related PAN, serum anti-neutrophilic cytoplasmic antibodies (ANCA) are rarely found in HBVrelated PAN [15, 16]. Histologically, cutaneous lesions are often characterized by involvement of medium-sized vessels in the deep dermis with fibrinoid necrosis consisting of neutrophils, eosinophils, and lymphocytes. Occasionally, even thrombi or aneurysmal change may be present which can lead to necrosis of the overlying epithelium [17]. The immunological process associated with PAN usually begins within 6 months of initial HBV infection [4]. An autoimmune mechanism is thought to be unlikely given antiviral therapy results
Polyarteritis Nodosa Polyarteritis nodosa (PAN) is considered one of the more serious syndromes associated with chronic HBV. In the 1970s, Trepo and Thivolet recognized that hepatitis B was significantly associated with PAN [9]. The ability of a virus to cause a systemic vasculitis was a remarkable discovery, and HBV-related PAN is considered the most typical form of PAN [4]. It has been observed that 30 to 50 % of patients with PAN are hepatitis B carriers [10]. However, PAN only occurs in about 1 to 5 % of patients with chronic HBV [11]. PAN is also referred to as generalized necrotizing vasculitis and is a very appropriate moniker given it is a systemic vasculitis involving large, medium, and small vessels. The symptomatology of HBV-related PAN and PAN in general includes vague constitutional symptoms such as weight loss, malaise, and weakness. Multiorgan damage is also often present, but gastrointestinal manifestations including ulcer-related bleeding and perforation as well as malignant hypertension
Fig. 1 PAN. These nodules are located just below the skin’s surface (subcutaneous), are barely felt when pressing on the skin (palpable), and are tender. The skin is typically red (erythematous). Accessed June 1, 2014. http://www.nlm.nih.gov/medlineplus/ency/imagepages/2440.htm
Curr Infect Dis Rep (2015) 17:7
in eradication of the disease and correlates with cessation of viral replication [18]. HBV-related PAN has a mortality rate of 30 to 50 % within 5 years if not treated [19]. Initially, corticosteroids were used in combination with immunosuppressive medications, mainly cyclophosphamide; however, in HBV-related PAN, this is not an effective long-term solution given viral persistence. Currently, antiviral therapy for HBV including interferon alpha and particularly direct-acting antiviral agents including nucleos(t)ide analog reverse transcriptase inhibitors are used for 6 to 12 months or until documented absence of HBV DNA and HBeAg seroconversion. Symptoms have been shown to improve within 1 month with antiviral therapy and signify the importance of treating the combined entity of HBV-related PAN as opposed to PAN alone. Gianotti-Crosti Syndrome Gianotti-Crosti syndrome was formerly known as papular acrodermatitis of childhood and manifests in patient with acute HBV infection and possibly also hepatitis A and Epstein-Barr virus (EBV) [20]. Usually, this syndrome affects infants and children and rarely does it present in children older than 10 years old. It has cutaneous manifestations of nonpruritic, 2 to 3-mm flat-topped papular or papulovesicular erythematous lesions present primarily on the face and distal extremities. Histologically, these lesions represent superficial perivascular lymphophagocytic infiltrate with mild endothelial swelling [6]. There may also be associated lymphadenopathy in the inguinal or axillary areas. Fortunately, it is a selflimited condition that can last for up to 15 to 20 days either prior to or after the onset of jaundice in patients with acute HBV infection. Hepatitis C-Related Cutaneous Manifestations Since the discovery of the hepatitis C viral genome in 1989, it has been implicated in several extrahepatic diseases including cutaneous diseases, renal disease, neuropathy, and even an association with diabetes. One report estimates that 40 to 75 % of patients with chronic HCV infection have at least one extrahepatic clinical manifestation of HCV [21, 22]. It has been proposed that both the host immune response to the hepatitis C virus results in the extrahepatic manifestations along with direct viral cytopathic effects. Elimination of HCV from the host may not resolve all extrahepatic manifestations, but improvement with antiviral therapy is often used as a parameter of correlation between the extrahepatic manifestation and the HCV. We will discuss the cutaneous manifestations that have pathological associations with and known increased prevalence in HCV patients compared to controls, including mixed cryoglobulinemia, porphyria cutanea tarda, and lichen planus.
Page 3 of 8 7
Mixed Cryoglobulinemia The most well-known extrahepatic manifestation of chronic HCV is mixed cryoglobulinemia (MC)-associated vasculitis. More than half of patients with HCV are found to have MC, although only 10 % develop symptoms and vasculitis [23, 24]. MC is a B cell lymphoproliferative disorder with three different pathological entities. Type I cryoglobulinemia has monoclonal immunoglobulins (Igs) associated with the HCV antigens usually in the presence of an indolent B cell lymphoma such as Waldenstrom macroglobulinemia or monoclonal gammopathy with undetermined significance. Type II cryoglobulinemia consists of the presence of monoclonal IgM (rheumatoid factor) and polyclonal IgG. Type III cryoglobulinemia is composed of polyclonal IgG and IgM [25]. Type II cryoglobulinemia is the most common type found in HCV-related MC; however, it has been proposed that there may exist a continuous transition of pure polyclonal forms to partial monoclonal forms due to continuous clonal selection [26]. These Igs can reversibly precipitate at temperatures less than 37 °C and form immune complexes with complement proteins, viral antigens, and HCV-RNA in small- and medium-sized blood vessels (arterioles, capillaries, and venules). In contrast to PAN, MC does not affect arteries. Symptomatic MC includes arthralgias, weakness, and palpable purpura as well as peripheral neuropathy. Renal failure can be associated with the development of a GN from immune complex deposition. Clinical manifestations of MC particularly renal failure may portend a worse prognosis, and approximately 10 % of patients may develop a B cell malignancy especially non-Hodgkin lymphoma [24, 27–29]. Cutaneous manifestations of MC in HCV infection occur in 24 to 30 % of patients with identifiable cryoglobulins [21, 26] (Fig. 2). Given the ability of Igs to precipitate in the cold, these cutaneous findings may be more prevalent during the winter months. Palpable purpura is the most common presenting feature and usually involves the lower extremities and less often spreads toward the trunk (where the temperature is higher) and upper extremities. There is a reported association between these findings and erythrocyanosis as well as Raynaud’s syndrome [31] and peripheral neuropathy due to immune complex deposition in the vasa nervorum of the lower extremities. The purpura can last for 3 to 10 days with residual brown pigmentation. Histology demonstrates leukocytoclastic vasculitis of small vessels secondary to deposition of immune complexes. Therapy for HCV-related MC includes a three-pronged attack including elimination of HCV, decreasing lymphocyte proliferation, and managing cutaneous vasculitis. Current evidence for antiviral therapy includes pegylated interferon (IFN) with ribavirin in patients with mild to moderate HCVrelated MC [32]. However, direct-acting antiviral agents (polymerase, protease, and nucleotide inhibitors) will likely
7
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Fig. 2 Clinical findings of leukocytoclastic vasculitis in cryoglobulinemia and porphyria cutanea tarda: a cryoglobulinassociated vasculitis and b characteristic changes of porphyria cutanea tarda. (with permission from [30])
supersede the current regimen seen in HCV-related MC given their superior efficacy and tolerability in treating HCV [33]. Given the role of B cells in HCV-related MC, rituximab (RTX) (monoclonal antibody against protein CD20 found on the surface of B cells) has been used in patients with severe vasculitis with or without skin ulcers and glomerulonephritis [34•]. Combined therapy with pegylated IFN, ribavarin, and RTX has demonstrated a complete response of 54.5 % compared to 33.3 % in those with pegylated IFN and ribavirin alone (P
