CRYOGLOBULINEMIA AND CUTANEOUS LEUKOCYTOCLASTIC VASCULITIS WITH HEPATITIS C VIRUS INFECTION

Background. Mixed cryoglobulinemia (MC) is a systemic disorder, characterized by a typical clinical triad: purpura, weakness, and arthralgias, with visceral complications such as liver and renal involvement. The objective was to study the association between hepatitis C virus (HCV) infection and essential mixed cryoglobulinemia (EMC). Patients and Methods. Markers of HCV infection in 11 patients with cryoglobulinemia were examined and hepatitis C virus (HCV) was detected in eight of them. These patients were included in a clinical and histologic study. Anti-HCV antibodies were determined by a second-generation enzyme-linked immunosorbent assay (ELISA-2) in sera and cryoprecipitates. Studies on HCV-RNA were performed by a two-stage polymerase chain reaction (PCR) in the serum. A control group, consisting of 28 patients with other cutaneous disorders, was studied for HCV infection using ELISA-2 and PCR. Results. All patients had liver dysfunction, arthralgias, and purpura. Three patients had involvement of the peripheral nervous system, two had renal involvement, and one patient had Sjögren's syndrome. Cryocrits ranged from 3% to 20%. Six patients had type III cryoglobulinemia and the remaining two had type II. Markers for hepatitis B virus (HBV) were negative in all serum samples. Anti-HCV antibodies and HCV-RNA were positive in the serum of all the cases with MC. Anti-HCV antibodies were positive in all cases except for one of the cryoprecipitates tested. Four patients received recombinant interferon alfa. In two of them, serum aminotransferases became normal and cryoglobulins disappeared. Conclusions. The results strongly suggest that HCV infection is responsible for the cryoglobulinemia and vasculitis in patients with MC and that treatment with interferon alfa is presently the treatment of choice for such patients.     

Clinical Analysis of Recurrent Hypergammaglobulinemic Purpura Associated with Sjögren Syndrome

Recurrent purpuric lesions are occasionally seen in patients with Sjögren syndrome. Hypergammaglobulinemia is one of the underlying precipitating factors of this condition. Clinical and histopathological analyses were performed on 5 cases of hypergammaglobulinemic purpura associated with Sjögren's syndrome, and the effects of immunomodulatory therapy were evaluated with regards to these conditions. Three out of 5 cases were successfully treated with oral gold compound (Auranofin) and one case with a low dose of cyclophosphamide. Episodic purpura subsided two months after initiation of therapy with improved serum IgG levels. Salivary flow and serum amylase levels also improved in some cases. Immunomodulatory therapy may be useful in managing recurrent purpura based on hypergammaglobulinemia associated with Sjögren syndrome.     

Leucocytoclastic vasculitis associated with mixed cryoglobulinaemia and hepatitis C virus infection

Mixed cryoglobulinaemia is frequently associated with chronic hepatitis. We report a patient with mixed cryoglobulinaemia, hepatitis C virus (HCV) infection and palpable purpura. The skin manifestations were diagnosed as leucocytoclastic vasculitis in view of both the clinical appearance and the histological findings. In this study, we demonstrated the presence of IgG–class anti–HCV–antibody. HCV–RNA and IgA–class rheumatoid factor in the cryoprecipitate. These results suggest that the cryoglobulinaemia in this case was caused by aggregation of an immune complex comprised of HCV and anti–HCV antibody with IgA–type–rheumatoid factor, and that this led to a cutaneous vasculitis.     

Dermatological manifestations in hepatitis B surface antigen carriers in east region of Turkey

BACKGROUND AND DESIGN: Various cutaneous disorders associated with hepatitis B virus infection have been reported so far. Almost all of them were some peculiar eruptions or some disorders mainly based on immune complex reaction. OBJECTIVE: The aim of this study was to compare the frequency of all dermatological disorders other than genetic ones in hepatitis B surface antigen (HBsAg) carrier patients and controls in our geographical area. METHODS: Examinations were made on 88 hepatitis B carriers and 84 control patients, including entire skin surface, and oral and anogenital mucosa, and all the manifestations that could be seen were noted down. RESULTS: While the number of HBsAg carrier patients with dermatological disorders was 62 (70.75%), it was only 24 (28.57%) in control patients. This seems statistically important: Yates' corrected chi-square test = 28.5; P = 0.0000001; odds ratio = 6.0 (2.94 < odds ratio < 12.2). The prevalence of oral lichen planus and pitted keratolysis in HBsAg carrier group was significantly higher than that of controls. We found the duration of positivity was not important statistically in the development of the dermatological disorders. CONCLUSIONS: HBsAg positivity may induce or cause proneness to oral lichen planus and pitted keratolysis with some mechanism that needs to be elucidated.     

A comparative study of liver function tests in patients of chronic liver disorders with and without cutaneous manifestations

Forty six cases of chronic liver disorders with and without cutaneous manifestations were studied for abnormalities of liver function tests. 27 cases were associated with cutaneous manifestations and 19 cases without cutaneous manifestations. A higher serum bilirubin level was seen in all cases with cutaneous manifestations. Serum bilirubin was significantly high (P<0.05) in patients of chronic active hepatitis with cutaneous manifestations. Serum alkaline phosphatase and serum glutamic pyruvic transaminase (SGPT) levels were significantly high in chronic active hepatitis and alcoholic liver disease without cutaneous manifestations respectively.     

Sj?gren's syndrome. Association of cutaneous vasculitis with central nervous system disease

We describe a group of patients with Sj?gren's syndrome, who commonly present to dermatologists with cutaneous manifestations of vasculitis. Two specific clinically recognizable forms of cutaneous vasculitis predominate: palpable purpura of the lower extremities (Waldenstr?m's benign hypergammaglobulinemic purpura) and urticarialike vasculitis. Two pathologic types of cutaneous vasculopathy are demonstrated, one leukocytoclastic and the other mononuclear. The leukocytoclastic vasculopathy is associated with high titers of Ro(SS-A) and La(SS-B) autoantibodies (detected by gel double-diffusion techniques) and general serohyperreactivity. In marked contrast, the mononuclear vasculopathy is associated with low titers of Ro(SS-A) and La(SS-B) autoantibodies (detected by enzyme-linked immunosorbent assay but not gel double-diffusion techniques) and general serohyporeactivity. Approximately 70% of patients with Sj?gren's syndrome and cutaneous vasculitis have also developed peripheral and/or central nervous system disease. The pathogenesis of the nervous system disease is unknown, but preliminary data suggest a vasculopathy.     

Oral lichen planus and HCV infection: a clinical evaluation of 263 cases

Background Hepatitis C virus (HCV) infection induces variable dermatologic manifestations. Our purpose was to determine whether there is an association between HCV infection and oral lichen planus (OLP). Methods Antibodies to HCV were determined in patients with OLP (263 patients; 156 women and 107 men, with a mean age of 55.5 years) and in a control population. Results Seventy six cases (28.8%) were positive for HCV antibodies with the second-generation enzyme-linked immunosorbent assay (ELISA II) test. All of these cases were confirmed with the second-generation recombinant immunoblot assay (RIBA II) test. In 61 cases (23.1%), high levels of serum transaminase were found. Positivity for hepatitis B virus (HBV) markers was found in 31 patients (11.7%) and for hepatitis A virus (HAV) markers in 43 patients (16.3%). None had positivity for hepatitis D virus (HDV) markers. As a control group, we used 100 patients (58 women and 42 men, with a mean age of 55.3 years) referred to the School of Dentistry of the University of Naples “Federico II,” and treated for general dental caries. In the control group, HCV antibody positivity was found in three cases. Conclusions The high prevalence of HCV antibody in this group of patients with OLP, higher than in the healthy population, suggests a link (p = 1.423 × 10^–7, chi-squared test) between these two diseases. These findings stress the importance of liver examination in OLP patients, and the need for other studies on the high susceptibility to hepatitis viruses in the population in the southern part of Europe.     

Etanercept in the treatment of psoriasis and psoriatic arthritis with concomitant hepatitis C virus infection: clinical and virological study in three patients

Treatment of patients with psoriasis and concomitant hepatitis-C virus (HCV) infection poses a therapeutic challenge because most systemic drugs are associated with potential hepatotoxicity, either due to direct liver damage or to immunosuppression. Among newly available drugs for the treatment of psoriasis and psoriatic arthritis, studies investigating the effect of anti-tumour necrosis factor-α in such patients are still limited. We describe three psoriatic patients with HCV, one with concomitant alcoholic hepatitis, who were treated with etanercept monotherapy for six months. We obtained good clinical responses for both psoriasis and arthritis in all three patients. While no significant changes in viral load and transaminases were observed in two patients, alanine aminotrasferase and gamma-glutamyltransferase levels were raised during treatment in the patient with concomitant alcoholic hepatitis. At baseline, one patient was negative and two were positive for mixed-type cryoglobulins. During treatment, none of the patients developed cryoglobulinemia-related clinical symptoms, and one of the two patients positive at baseline was negative for cryoglobulins at the end of follow-up. Our results add to accumulating data suggesting that etanercept represents a valuable therapeutic option for treatment of HCV-positive psoriatic patients, with an acceptable safety profile in the short-term. However, etanercept treatment of HCV cases with concomitant alcoholic hepatitis must be undertaken with caution.     

Afectación cutánea en la crioglobulinemia tipo II. Asociación con la infección por el virus C de la hepatitis

—Introduction. Cryoglobulins (CG) are abnormal proteins that precipitate from cooled serum. Several reports of mixed cryoglobulinemia (MC) associated with chronic hepatitis C have been published. On the clinical spectrum of MC it has been proved that purpura is the most frequent cutaneous manifestation, mainly in women. The aim of our study was to analyse the relationship between the patients with CM and VHC infection, cutaneous lesions and systemic affectation.Patients and methods. We evaluated a group of 62 patients diagnosed of MC during the period between January 1993 and December 2000 (29 women and 33 men), aged from 33 to 81 years old (mean 60 years).Results. Purpura was the most frequent cutaneous manifestation (27 out of 62: 43 %) mainly in women. The group of patients with purpura presented a high level of CG, hypocomplementemia and renal dysfunction. It was present in 27 patients (43 %). The IgMk CG type was related more commonly with purpura, renal dysfunction and hypocomplementemia if compared with IgGK. 72 % of patients with CG were VHC infected. No differences of CG have been found in HCV infected patients.Conclusions. Our results confirm the high frequency of VHC infection in patients with CG. Purpura was the most frequent clinical manifestation related with a high level of CG and more frequency of hypocomplementemia and renal dysfunction.     

Nail changes in patients with liver disease

Background Liver cirrhosis, hepatitis C virus (HCV) and hepatitis B (HBV) virus infections are known to be associated with different skin disorders. Nail changes are additional important criteria, which would help in identification of these systemic diseases. Objective To record the nail abnormalities in patients with liver disease which were not reported before, especially those with HCV and HBV infection. Patients and methods The study comprised 100 patients with HCV, HBV and liver cell failure, and 100 normal healthy controls. Both groups underwent full history taking and thorough general examination, complete blood picture, hepatitis B antigen, hepatitis C antibody, liver function tests, abdominal ultrasonography and PCR were performed in patients with liver disease. Full nail examination was performed. Results Nail changes were more prevalent in patient group (68%) than in the control group (35%). The nail infection, onychomycosis, was the most common finding in 18% of patients and that in controls was 10% followed by in a descending order, longitudinal striations, brittle nails, onychorrhexis, clubbing of fingers, dystrophic nails, leukonychia and longitudinal melanonychia. Conclusion Nail changes are observed with not only liver cirrhosis but also with HCV and HBV infection, and this will add additional clinical criteria for general practitioners and dermatologists to help them with diagnosis of these common systemic infections.     

Skin diseases associated with hepatitis C virus infection

Hepatitis C virus (HCV) is a bloodborne agent transmitted by apparent and inapparent parenteral procedures representing a frequent cause of liver disease world-wide. Both acute and chronic HCV infection may affect the liver as well as various non-hepatic tissues. Numerous extrahepatic disorders have been recognised in association with HCV infection among which dermatological diseases occupy a central part. Cutaneous necrotising vasculitis, mixed cryoglobulinemia, porphyria cutanea tarda and lichen planus are the major skin diseases frequently associated with HCV infection, but other skin disorders, such as Adamantiadis-BehQet syndrome, erythema multiforme and nodosum, malacoplakia, urticaria and pruritus, may also be linked to hepatitis C. Further studies are necessary to establish or refute an aetiopathogenetic role of HCV in these conditions. Skin manifestations are also part of the clinical picture of other extrahepatic disorders associated with HCV infection, such as thyroid dysfunction and HCV-related thrombocytopenia. The response to interferon alpha (a-IFN) therapy in skin diseases is unpredictable with some patients ameliorating, others remaining stationary and others deteriorating.     

HLA in systemic scleroderma (PSS) and familial scleroderma

HLA in systemic scleroderma (PSS), including three familial cases, is reported. Three families in which one sister developed PSS and another sister suffered from either PSS (family 1), mixed connective tissue disease (MCTD) (family 2), or Sjögren's syndrome (SjS) (family 3) were described. The elder sister in family 1 died of respiratory insufficiency caused by scleroderma lung. The sisters in family 2 both had SjS, anti SS-A antibodies, and HLA A2-Bw55-Cwl-DRw8 haplotype in common. The elder sister with PSS in family 3 also had SjS and Hashimoto's thyroiditis. HLA in 28 PSS patients including these 3 familial cases were analyzed with 4 MCTD and 4 generalized morphea patients. HLA A2, Bw46, DR2, DRw8, DRw6 and DQw1 antigens were more frequently found in the PSS patients than in the controls. HLA DRw6 was the only antigen that was positive in common in the 3 familial cases. In those patients with anti topoisomerase I antibodies, HLA DR2 antigen was found more frequently than in the controls. Some, but not all, of these results were similar to the previous reports on HLA in PSS. Further investigations on more patients and the other members of these families would be necessary to clarify the significance of these results.     

The cutaneous manifestations of cholesterol crystal embolization

In an effort to provide a greater understanding of the cutaneous features of cholesterol crystal embolization (CCE), we reviewed the clinical features of all histologically proved cases reported in the English-language literature, exclusive of cases in which there was only central nervous system or cardiac involvement. We found that the skin is involved in 35% of patients with CCE. Livedo reticularis is the most common skin manifestation (49%), followed by gangrene (35%), cyanosis (28%), ulceration (17%), nodules (10%), and purpura (9%). Cholesterol crystal embolization was most common in older men and was frequently associated with anticoagulant therapy (36%) or vascular procedures (31%). Because of its protean systemic manifestations, CCE was often mistaken for vasculitis (16%) and periarteritis nodosa (12%). Mortality was very high (72%). Histologic confirmation of cutaneous CCE was possible in 92% of cases where a skin biopsy specimen was obtained. We conclude that the diagnosis of cutaneous CCE should be suggested and easily confirmed histologically in the appropriate clinical setting.     

Mondor's disease

BACKGROUND: Mondor's disease is a rare entity characterized by thrombophlebitis of the subcutaneous veins of the anterolateral thoraco-abdominal wall. The most common clinical manifestations are a painful subcutaneous cord, sensation of tension, and skin retraction. This condition is usually a benign and self-limited process, although it has been associated with breast cancer. METHODS: We describe four new cases, two men and two women, and comment on the clinical signs and possible etiopathogenic features. General physical examination, radiologic and ecographic studies, laboratory analysis including tumor markers, and exhaustive coagulation study were carried out on all patients. RESULTS: No cases were associated with malignant disease and/or hypercoagulability stage. With conservative treatment, the evolution proved favorable in all patients. CONCLUSIONS: Mondor's disease is usually a benign and self-limited process, but we recommend laboratory studies and physical examination, including mammography in women, in order to rule out the presence of systemic disorders, especially breast cancer.     

Cutaneous findings associated with chronic natural killer cell lymphocytosis

BACKGROUND: Chronic Natural Killer Cell Lymphocytosis (CNKL) is a recently described rare proliferative disorder. We noted an association of cutaneous disorders with CNKL in our clinical experience. METHODS: We reviewed the medical records of all known patients with CNKL at our institution. RESULTS: Five of 14 patients (36%) with CNKL had associated chronic cutaneous disease: two had livedoid vasculopathy; one, urticarial vasculitis; one, peripheral T-cell lymphoma; and one had complex recurrent aphthous stomatitis. In each case, except the one with lymphoma, the cutaneous disease was present before CNKL was diagnosed and CNKL persisted for the duration of the cutaneous disease. All five patients had increased numbers of large granular lymphocytes on a peripheral blood smear and three or four in the bone marrow (one patient did not undergo bone marrow biopsy). CONCLUSIONS: Although CNKL and the reported skin diseases have occurred in the same patients, a causal link cannot yet be established. With CNKL, dermatologists must recognize associated cutaneous diseases, monitor patients for systemic disorders and cytopenias, and appropriately refer patients to a hematologist.     

Tumour necrosis factor-α antagonists in patients with concurrent psoriasis and hepatitis B or hepatitis C: a retrospective analysis of 17 patients

Introduction Tumour necrosis factor (TNF)‐α antagonists are effective for the treatment of plaque‐type psoriasis and psoriatic arthritis, but concerns remain about the safety of these agents in the presence of chronic infections, including past hepatitis B (HBV) and chronic hepatitis C virus (HCV) infections. Objective To assess the safety of TNF‐α therapy in patients with plaque‐type psoriasis and concurrent past HBV or chronic HCV. Methods Data were collected retrospectively from patients in the PsoCare Centre, Division of Dermatology II, Florence University. Patients with plaque‐type psoriasis who were receiving anti‐TNF‐α therapy were retrospectively reviewed for the presence of HBV or HCV by a serological evaluation. Results Seventeen patients (13 men and four women, age 36–74 years) with plaque‐type psoriasis associated with hepatitis infections (11 with past HBV infection, five with chronic HCV infection and one affected by both HBV and HCV) were identified. Fourteen patients had received etanercept, two adalimumab and one adalimumab as a second biologic treatment after an unsuccessful trial of etanercept. In none of the cases were changes in serum aminotransferases or viral load reported. Conclusions In our analysis, the use of anti‐TNF‐α therapy appears to be safe as it did not affect serum aminotransferases or viral load. However, repeated monitoring is necessary throughout the treatment period. Systematic, large‐scale studies are also needed to assess the risks and benefits of TNF‐α antagonists in these patients.     

Mucocutaneous manifestations in Japanese HIV-positive hemophiliacs

BACKGROUND: Although various mucocutaneous manifestations have been reported in patients infected with HIV by sexual transmission or intravenous drug use, the prevalence and characteristics of skin disorders in HIV-positive hemophiliacs coinfected with hepatitis C virus (HCV) have rarely been described. OBJECTIVE: The purpose of this study was to clarify the characteristics of skin disorders in HIV-positive hemophiliacs and to identify differences in comparison with other HIV-positive groups. METHODS: A prospective study of the prevalence of mucocutaneous manifestations in 110 Japanese hemophiliacs (53 HIV-positive hemophiliacs including 24 AIDS and 57 HIV-negative hemophiliacs) was performed from July 1997 to July 1998. RESULT: None of the hemophiliacs developed Kaposi's sarcoma or sexually transmitted skin diseases. Eosinophilic folliculitis was observed in 3 AIDS patients. The incidence of folliculitis, common warts, seborrheic dermatitis, generalized eczema, oral candidiasis and herpes zoster was higher in HIV-positive than in HIV-negative hemophiliacs (p < 0.05). Although anti-HCV antibody was positive in all HIV-positive hemophiliacs, HCV-related dermatoses such as lichen planus and porphyria cutanea tarda were not observed. CONCLUSION: Although Kaposi's sarcoma and sexually transmitted skin diseases such as molluscum contagiosum, condyloma, and scabies are frequently associated with HIV, they were not found in the HIV-positive hemophiliacs in our study. HIV infection-related mucocutaneous manifestations are influenced not only by the presence of HIV but also by other factors such as the mode of transmission and sexual habit.     

Hepatitis C virus and its cutaneous manifestations: treatment in the direct‐acting antiviral era

New all‐oral direct‐acting antivirals (DAA) have changed the hepatitis C virus (HCV) treatment landscape. Given that dermatologists frequently encounter HCV‐infected patients, knowledge of the current treatment options and their utility in treating HCV‐associated dermatologic disorders is important. In addition to highlighting the new treatment options, we review four classically HCV‐associated dermatologic disorders – mixed cryoglobulinaemia (MC), lichen planus (LP), porphyria cutanea tarda (PCT) and necrolytic acral erythema (NAE) – and examine the role for all‐oral direct‐acting antiviral (DAA) regimens in their treatment. A literature search of English‐language publications was conducted of the PubMed and EMBASE databases using search terms including ‘hepatitis C’, ‘direct acting antivirals’, ‘cutaneous’, ‘mixed cryoglobulinemia’, ‘necrolytic acral erythema’, ‘lichen planus’, ‘porphyria cutanea tarda’, ‘rash’, as well as specific drug names, related terms and abbreviations. Currently, limited data exist on the use of DAAs in HCV‐infected patients with cutaneous side‐effects, although treatment of the underlying HCV is now recommended for nearly all patients, with the new drugs offering much‐improved dosage schedules and side‐effect profiles. The most data exist for MC, in which several studies suggest that DAAs and achievement of sustained virologic response (SVR) improve cutaneous symptoms. Studies of both older and newer regimens are limited by their small size, retrospective nature, lack of appropriate controls and wide variability in study protocols. Given the strong association, screening for HCV should be considered in patients with MC, LP, PCT and NAE.     

Granulomatous vasculitides and the skin

Wegener's granulomatosis, lymphomatoid granulomatosis, and Churg-Strauss granulomatosis may all have cutaneous involvement. The morphology of cutaneous lesions in these disorders varies from macular erythema to frank gangrenous ulceration. Most often lesions are located on the extremities; however, truncal or facial involvement has been reported, the latter especially in Wegener's granulomatosis. A common histologic finding in these cutaneous lesions is necrotizing vasculitis. However, it is also possible to see Churg-Strauss extravascular granulomas and even periarteritis. Cutaneous involvement with these three forms of systemic granulomatosis generally parallels the systemic course. The treatment for the cutaneous lesions is dictated by the treatment for the systemic vasculitis. It is important to recognize that the cutaneous extravascular granuloma and cutaneous granulomatous vasculitis can be associated with other disorders in addition to systemic granulomatosis. These disorders include most importantly lymphoproliferative diseases, inflammatory disorders such as arthritis, autoimmune diseases, and other inflammatory disorders such as sarcoidosis. Cutaneous involvement with giant cell or temporal arteritis is not common, but ulcerative temporal-parietal scalp lesions are distinctive. Although not common in the United States, Takayasu's arteritis may have several cutaneous manifestations, including erythema nodosum-like lesions. Granulomatous vasculitides have a myriad of cutaneous manifestations. Knowledge of these manifestations may allow for prompt diagnosis in many cases and increased surveillance in other cases for associated systemic illnesses.