Anemia of chronic disease and thrombocytopenia are amongst the commonly reported hematololgical abnormalities in HCV-patients with cryoglobulinemia. The proposed pathological mechanisms in HCV related thrombocytopenia involved; platelet sequestration and destruction in the spleen**,** along with low thrombopoetin production and direct viral infection of the megakariocytes with immune mediated platelet destruction. (De Almeida et al., 2004, Doi et al., 2002, Giannini et al., 2002, Jiang et al., 2002). Autoimmune hemolytic anemia has been reported in female patients with cryoglobulinemic syndrome **(8),** Leukocytosis, an elevated erythrocyte sedimentation rate (ESR) and an elevated C-reactive protein level are common findings in most types of vasculitis. The auto-antibodies seen in patients with HCV infection resemble those seen in chronic viral infections - the autoantibody titers are low, frequently found during the clinical course of cryoglobulinemia, however, not essentially associated with typical autoimmune disease. Serological abnormalities in HCV-MC involve positive antinuclear antibodies (ANA), antismooth muscle antibodies (ASMA), anti-neutrophil cytoplasmic antibodies (ANCA), and anti-

of cirrhosis in patients with chronic hepatitis C**.** Splenomegaly might coexist. (Kayali et al.,

Patterns of cardiovascular involvement in HCV-MC include: mitral valvular damage with mitral regurge, coronary vasculitis complicated by myocardial infarction, pericarditis, congestive heart failure and hypertrophic cardiomyopathy. Arterial thrombosis reported in

Retinopathy with cotton-wool spots, hemorrhages and arteriolar occlusion on fundus examination can occur in HCV patients with cryoglobulinemia, but rather a frequent complication of interferon therapy than HCV related small vessel vasculitis, uveitis is rare. Mooren's ulcer is a rapidly progressive, painful ulceration of the cornea that might occur. The diagnosis of Mooren's ulcer is a diagnosis of exclusion. (Remoroza and Bonkovsky, 2003)

Some endocrinological disorders are significantly more frequent in HCV-MC patients compared to the general population. The most common endocrinal disorders are the thyroid disorders including; autoimmune thyroiditis, subclinical hypothyroidism, thyroid cancer with high prevalence of anti-thyroperioxidase antibody and antithyroglobulin antibody. Hyperthyroidism is less frequent, generally as reversible complication of interferon treatment. Type 2 diabetes is another frequent endocrinal disorder in cryoglobulin-positive than in cryoglobulin-negative patients. The raised prevalence of type 2 diabetes in HCVpatients with mixed cryoglobulinemia is attributed to an immune-mediated mechanism **(127)**. Insulin resistance mediated by proinflammatory cytokines, rather than a deficit in insulin secretion, is propably the primary pathogenic mechanism involved in the development of type 2 diabetes in HCV infection. Erectile dysfunction is another disorder in male patients with HCV-MC attributable to hormonal and/or neuro-vascular alterations.

Anemia of chronic disease and thrombocytopenia are amongst the commonly reported hematololgical abnormalities in HCV-patients with cryoglobulinemia. The proposed pathological mechanisms in HCV related thrombocytopenia involved; platelet sequestration and destruction in the spleen**,** along with low thrombopoetin production and direct viral infection of the megakariocytes with immune mediated platelet destruction. (De Almeida et al., 2004, Doi et al., 2002, Giannini et al., 2002, Jiang et al., 2002). Autoimmune hemolytic anemia has been reported in female patients with cryoglobulinemic syndrome **(8),** Leukocytosis, an elevated erythrocyte sedimentation rate (ESR) and an elevated C-reactive protein level are common findings in most types of vasculitis. The auto-antibodies seen in patients with HCV infection resemble those seen in chronic viral infections - the autoantibody titers are low, frequently found during the clinical course of cryoglobulinemia, however, not essentially associated with typical autoimmune disease. Serological abnormalities in HCV-MC involve positive antinuclear antibodies (ANA), antismooth muscle antibodies (ASMA), anti-neutrophil cytoplasmic antibodies (ANCA), and anti-

2003, Remoroza and Bonkovsky, 2003)

**4.4.8 Cardiovascular involvement**

1%. **(Antonelli et al., 2009)**

**4.4.10 Endocrine system**

(Antonelli et al., 2004 a&b, Ferri et al., 2002,b)

**4.4.11 Hematological abnormalities**

**4.4.9 Ocular**

cardiolipin autoantibodies. The prevalence of ANA and ASMA ranges from 4.4% to 41% and 7% to 66% respectively usually with low titre ≤ 1/160. HCV core particles concentrated in the cryoprecipitate provoke an interaction between the cryoglobulins, endothelial cells and neutrophil granulocytes. A positive ANCA has been found in <5-10% of patients with HCV-associated mixed cryoglobulinemia with proteinase 3 and dihydrolipoamine dehydrogenase as the main anti-neutrophil cytoplasmic antigens in patients with HCV-MC. HCV patients with ANCA had a higher prevalence of skin involvement, anemia, abnormal liver function tests and elevated alpha feto-protein levels**.** Anti-cardiolipin antibodies occur in 3.3% to 22% of HCV patients, with higher frequency in patients with HCV-associated cryoglobulinemia yet insignificant being anti-b2-glicoprotein independent. (Cacoub et al., 1997, Lamprecht et al., 2003, Ordi-Ros et al., 2000, Yee et al., 2004, Wu et al., 2002 )

## **4.4.12 Neoplastic disorders**

Mixed cryoglobulinemia syndrome is considered as a pre-neopastic syndrome that features a cross road between virus related autoimmune syndromes and virus associated malignancies (B cell lymphoma, hepatocellular carcinoma). B-cell lymphoma is the most frequent neoplastic manifestation complicating mixed cryoglobulinemia that presents late in the course of the disease. **(Cacoub et al., 2000)** Neoplasia is attributed to sustained peripheral B-lymphocyte expansion with significantly persistent lymphoid infiltrates that remain unmodified for years in the liver and bone marrow of MC patients**.** Such infiltrates are considered as "early lymphomas", and are given the nomenoclature "monotypic lymphoproliferative disorder of undetermined significance (MLDUS)". Type II MC-related MLDUS has the highest incidence in the same geographic areas with high prevalence of HCV infection. The onset of malignant lymphoma is usually 5-10 years after disease diagnosis, with a reported incidence of less than 10% in some patients to as high as 40% in others. **O**vert lymphoid tumors develop in about 10% of cases. A sudden decrease or disappearance of serum cryoglobulins and RF with abnormally high levels of C4, are presenting symptoms of complicating B-cell malignancy**.** Other neoplastic manifestations, i.e. hepatocellular carcinoma or papillary thyroid cancer, are less frequently observed (Ferri et al., 2002, Matsuo et al., 2004, Quartuccio et al., 2007).

## **4.4.13 Other disease related features**

Constitutional symptoms like fever, fatigue, anorexia, weight loss, amongst other immune mediated HCV related extra-hepatic manifestations including: Porphyria cutanea tarda, Lichen planus, pancreatitis, aplastic anaemia, systemic lupus erythematosus, CREST syndrome, and waldenstrom's macroglobulinemia might exist. (Ferri et al., 2002 a, Ferri et al., 2000)

## **5. HCV and polyarteritis nodosa PAN (medium sized vessel vasculitis)**

Despite that polyarteritis nodosa is more commonly reported in patients with hepatitis B viremia, yet medium sized vessels inflammation can occur in patients with chronic HCV infection featuring a polyarthritis nodosa pattern of vasculitis. PAN can occur in cryoglobulinemic as well as non cryoglobulinemic HCV patients. HCV related PAN displays a more severe and acute clinical presentation with more frequent fever and weight loss, severe hypertension, gastrointestinal tract involvement, severe acute sensory-motor

Hepatitis C Related Vasculitides 317

For the diagnosis of HCV, hepatitis C antibody testing is crucial, regarding the response to treatment quantitative assessment of viral load HCV-RT-PCR as well as the viral genotyping are important prognostic markers. Sustained negative results for HCV-RT-PCR with treatment signifies a sustained viral response. Rheumatoid factor and serum anti-cyclic citrullinated C peptide antibodies (markers for rheumatoid arthritis)are useful diagnostic tools in arthritis patients. Complement 3 (C3) and complement 4 (C4) and CH50 are usually consumed in patients with renal disease. Anti-neutrophil cytoplasmic antibodies (P-ANCA might be found in patients with small to medium sized vessel vasculitis). Anti SSA and anti-SSB (in up to 20%) and thyroid specific antibodies (up t0 22.1%) are amongst associating serological abnormalities (Ghany et al., 2009, Ferri, 2008,

Chest x ray and high resolution computerized tomography for diagnosis of pulmonary involvement, echocardiography and electrocardiogram (ECG) for cardiac disease,

Histopathological evidences of vasculitis remain the gold standard for the diagnosis of vasculitis. Biopsy from clinically involved sites (cutaneous lesions, nerve biopsy, renal biopsy) is a cornerstone in establishing the diagnosis. Bone marrow biopsy should be done to demonstrate polyclonal B cell proliferation and in suspected cases with lympho-

A frequent clinico-pathological overlap exists between HCV-related cryoglobulinemic syndrome and some autoimmune diseases including; small and medium sized vessel vasculitides, infectious vasculitides (Bacterial vasculitis e.g., Neisserial, mycobacterial vasculitis e.g., Tuberculous, spirochetal vasculitis e.g., Syphilitic, rickettsial vasculitis e.g., Rocky Mountain Spotted Fever, fungal vasculitis e.g., Aspergillosis, viral vasculitis e.g., Herpes zoster, HIV), primary S-jogren's syndrome, secondary types of vasculitis (rheumatoid arthritis, systemic lupus erythematosus, seronegative arthritides), membranous glomerulonephritis, immune mediated thyroiditis, type II diabetes, autoimmune hepatitis, and myelo-proliferative disorders (lymphomas, leukemias and Plasma cell dyscrasias).

Clinical improvement of HCV related vasculitides proved to correlate with virological response. Introducing anti-viral therapy namely interferon alpha with or without ribavirin remains the cornerstone in the management of HCV-MC. Antiviral therapy has been shown to reverse bone marrow monoclonal B-cell expansion in patients with HCV-MC. (Davis et

abdominal ultrasound for hepatic and renal disease. (Ferri, 2008)

proliferative disorders (Mukhtyar et al., 2009).

(Ghany et al., 2009, Jennette et al., 1994)

**7. Treatment of HCV related vasculitides**

al., 2002, Mukhtyar et al., 2009, NIDDK, 2010)

**6.3 Serological tests**

Antonelli et al., 2009)

**6.4 Imaging studies**

**6.6 Differential diagnosis**

**7.1 Treatment of HCV**

**6.5 Biopsy**

multifocal mononeuropathy, kidney and liver microaneurysms and elevated acute phase reactants levels. Cases of mesenteric vasculitis with stenosis and narrowing of the superior mesenteric vessels and reno-vascular micro-aneurysm with renal cortical infarcts have been described in HCV patients having purpuric eruptions, hypertension and abdominal pain. Such lesions resolved with antiviral therapy and prednisolone, supporting the possible etiopathogenic role of chronic HCV infection. Another case with vasculitic mucosal colonic ulceration with massive hematochezia, purpura, abdominal discomfort, pulmonary infilterate and acute renal failure was described in a female patient with chronic HCV infection and negative for cryoglobulinemia, colonic biopsy showed evidence of fibrinoid necrotizing arteritis diagnosing a case of HCV related PAN with no evidence of leukocytoclastic vasculitis. (Costedoat-Chalumeau et al., 2002, Elias et al., 1998, Saadoun et al., 2010a)

## **6. Diagnosis of HCV- mixed cryoglobulinemia**

## **6.1 Cryoglobulin detection**

The detection of serum cryoglobulins is fundamental for the diagnosis of mixed cryoglobulinemia. (Ferri et al., 2002 a, Ferri et al., 2008) Due to their thermal instability, the measurement of cryoglobulin level in the blood should be performed immediately after sampling. For a correct evaluation of serum cryoglobulins it is necessary to avoid falsenegative results due to Ig cold precipitation at room temperature, blood sampling, clotting, and serum separation by centrifugation is carried out at 37°C and the cryocrit determination and cryoglobulin characterization at 4°C (after 7 days). Cryocrit determinations (percentage of packed cryoglobulins referred to total serum after centrifugation at +4°C) should be done on blood samples without anticoagulation to avoid false-positive results due to cryofibrinogen. The analysis of cryoprecipitates is generally carried out by means of immunoelectrophoresis or immunofixation, other more sensitive methodologies include; immunoblotting or two-dimensional polyacrylamide gel electrophoresis. Type II MC shows a microheterogeneous composition. Type II-III mixed cryoglobulinemia represents an intermediate, evolutive state from type III to type II**.** The absence of detectable serum cryoglobulins despite the presence of the clinical syndrome is described to be a transient phenomenon due to the wide variability of the percentage of cryoprecipitable immunecomplex during the natural history of the disease or, less frequently, to a switching from 'benign' B-cell lymphoproliferation to malignant lymphoma. The levels of serum cryoglobulins usually do not correlate with the severity and prognosis of the disease. (Ferri et al., 2002 a, Ferri et al., 2000)

## **6.2 Laboratory tests**

Laboratory workup includes complete blood cell count with evidences of anemia of chronic disease, thrombocytopenia or autoimmune hemolytic anemia. Erthrocyte sedimentation rate is almost always elevated in all types of vasculitis, but a normal ESR does not rule out systemic vasculitis. Blood urea nitrogen, creatinine for renal involvement, proteinuria and hematuria on urinalysis, a fresh-spun urine sample should be evaluated for red blood cell casts or dysmorphic red cells to diagnose glomerulonephritis. Up to 40 % of patients with chronic hepatitis C have normal serum ALT levels, even when tested on multiple occasions. (Ferri, 2008, Ghany et al., 2009)

## **6.3 Serological tests**

316 Advances in the Etiology, Pathogenesis and Pathology of Vasculitis

multifocal mononeuropathy, kidney and liver microaneurysms and elevated acute phase reactants levels. Cases of mesenteric vasculitis with stenosis and narrowing of the superior mesenteric vessels and reno-vascular micro-aneurysm with renal cortical infarcts have been described in HCV patients having purpuric eruptions, hypertension and abdominal pain. Such lesions resolved with antiviral therapy and prednisolone, supporting the possible etiopathogenic role of chronic HCV infection. Another case with vasculitic mucosal colonic ulceration with massive hematochezia, purpura, abdominal discomfort, pulmonary infilterate and acute renal failure was described in a female patient with chronic HCV infection and negative for cryoglobulinemia, colonic biopsy showed evidence of fibrinoid necrotizing arteritis diagnosing a case of HCV related PAN with no evidence of leukocytoclastic vasculitis. (Costedoat-Chalumeau et al., 2002, Elias et al., 1998, Saadoun et

The detection of serum cryoglobulins is fundamental for the diagnosis of mixed cryoglobulinemia. (Ferri et al., 2002 a, Ferri et al., 2008) Due to their thermal instability, the measurement of cryoglobulin level in the blood should be performed immediately after sampling. For a correct evaluation of serum cryoglobulins it is necessary to avoid falsenegative results due to Ig cold precipitation at room temperature, blood sampling, clotting, and serum separation by centrifugation is carried out at 37°C and the cryocrit determination and cryoglobulin characterization at 4°C (after 7 days). Cryocrit determinations (percentage of packed cryoglobulins referred to total serum after centrifugation at +4°C) should be done on blood samples without anticoagulation to avoid false-positive results due to cryofibrinogen. The analysis of cryoprecipitates is generally carried out by means of immunoelectrophoresis or immunofixation, other more sensitive methodologies include; immunoblotting or two-dimensional polyacrylamide gel electrophoresis. Type II MC shows a microheterogeneous composition. Type II-III mixed cryoglobulinemia represents an intermediate, evolutive state from type III to type II**.** The absence of detectable serum cryoglobulins despite the presence of the clinical syndrome is described to be a transient phenomenon due to the wide variability of the percentage of cryoprecipitable immunecomplex during the natural history of the disease or, less frequently, to a switching from 'benign' B-cell lymphoproliferation to malignant lymphoma. The levels of serum cryoglobulins usually do not correlate with the severity and prognosis of the disease. (Ferri

Laboratory workup includes complete blood cell count with evidences of anemia of chronic disease, thrombocytopenia or autoimmune hemolytic anemia. Erthrocyte sedimentation rate is almost always elevated in all types of vasculitis, but a normal ESR does not rule out systemic vasculitis. Blood urea nitrogen, creatinine for renal involvement, proteinuria and hematuria on urinalysis, a fresh-spun urine sample should be evaluated for red blood cell casts or dysmorphic red cells to diagnose glomerulonephritis. Up to 40 % of patients with chronic hepatitis C have normal serum ALT levels, even when tested on multiple occasions.

al., 2010a)

**6.1 Cryoglobulin detection**

et al., 2002 a, Ferri et al., 2000)

(Ferri, 2008, Ghany et al., 2009)

**6.2 Laboratory tests**

**6. Diagnosis of HCV- mixed cryoglobulinemia**

For the diagnosis of HCV, hepatitis C antibody testing is crucial, regarding the response to treatment quantitative assessment of viral load HCV-RT-PCR as well as the viral genotyping are important prognostic markers. Sustained negative results for HCV-RT-PCR with treatment signifies a sustained viral response. Rheumatoid factor and serum anti-cyclic citrullinated C peptide antibodies (markers for rheumatoid arthritis)are useful diagnostic tools in arthritis patients. Complement 3 (C3) and complement 4 (C4) and CH50 are usually consumed in patients with renal disease. Anti-neutrophil cytoplasmic antibodies (P-ANCA might be found in patients with small to medium sized vessel vasculitis). Anti SSA and anti-SSB (in up to 20%) and thyroid specific antibodies (up t0 22.1%) are amongst associating serological abnormalities (Ghany et al., 2009, Ferri, 2008, Antonelli et al., 2009)

## **6.4 Imaging studies**

Chest x ray and high resolution computerized tomography for diagnosis of pulmonary involvement, echocardiography and electrocardiogram (ECG) for cardiac disease, abdominal ultrasound for hepatic and renal disease. (Ferri, 2008)

### **6.5 Biopsy**

Histopathological evidences of vasculitis remain the gold standard for the diagnosis of vasculitis. Biopsy from clinically involved sites (cutaneous lesions, nerve biopsy, renal biopsy) is a cornerstone in establishing the diagnosis. Bone marrow biopsy should be done to demonstrate polyclonal B cell proliferation and in suspected cases with lymphoproliferative disorders (Mukhtyar et al., 2009).

## **6.6 Differential diagnosis**

A frequent clinico-pathological overlap exists between HCV-related cryoglobulinemic syndrome and some autoimmune diseases including; small and medium sized vessel vasculitides, infectious vasculitides (Bacterial vasculitis e.g., Neisserial, mycobacterial vasculitis e.g., Tuberculous, spirochetal vasculitis e.g., Syphilitic, rickettsial vasculitis e.g., Rocky Mountain Spotted Fever, fungal vasculitis e.g., Aspergillosis, viral vasculitis e.g., Herpes zoster, HIV), primary S-jogren's syndrome, secondary types of vasculitis (rheumatoid arthritis, systemic lupus erythematosus, seronegative arthritides), membranous glomerulonephritis, immune mediated thyroiditis, type II diabetes, autoimmune hepatitis, and myelo-proliferative disorders (lymphomas, leukemias and Plasma cell dyscrasias). (Ghany et al., 2009, Jennette et al., 1994)

## **7. Treatment of HCV related vasculitides**

## **7.1 Treatment of HCV**

Clinical improvement of HCV related vasculitides proved to correlate with virological response. Introducing anti-viral therapy namely interferon alpha with or without ribavirin remains the cornerstone in the management of HCV-MC. Antiviral therapy has been shown to reverse bone marrow monoclonal B-cell expansion in patients with HCV-MC. (Davis et al., 2002, Mukhtyar et al., 2009, NIDDK, 2010)

Hepatitis C Related Vasculitides 319

The standard initial therapy used to be recombinant interferon alfa-2b at a dose of 3 x 106 units administered subcutaneously 3 times per week for 6 weeks. Recombinant forms of alpha interferon are being currently replaced by pegylated interferon (peginterferon). Peginterferon is alpha interferon modified chemically by the addition of a large inert molecule of polyethylene glycol prolonging its half-life. Peg-Interferon being with better efficacy and easier administration replaced standard interferon both as monotherapy and as combination therapy for hepatitis C viremia. Peg-interferon is more active than standard interferon in inhibiting HCV and yields higher sustained response rates with equivalent side effects. Two forms of peg-interferon are available: peg-interferon alfa-2a and peg-interferon alfa-2b, roughly equivalent in efficacy and safety, with different dosing regimen. Peginterferon alfa-2a is given subcutaneously in a fixed dose of 180 micrograms (mcg) per week, while peginterferon alfa-2b is given subcutaneously weekly in a weight-based dose of

The goal of interferon treatment is suppression of active disease by achieving a sustained viral response (sustained decrease or negative HCV-RT PCR). **Table 4** Interferon alpha monotherapy is effective in purpuric skin lesions, thrombocytopenias, but less effective with neural or renal involvement. IFN-alpha monotherapy is associated with a relatively poor response and a high virologic relapse rate, detectable viremia with active liver disease can occur with normal alanine transferase. Higher initial doses and longer duration of therapy help to increase the interval before relapse and escalation of the dose might help to achieve

 Peg-interferon therapy has bone marrow suppressive effects or cytopenias, therapy might be associated with immune mediated side effects including in about 2% of patients (particularly if high titers of antinuclear or antithyroid antibodies); peripheral sensorymotor neuropathy, nephropathy, retinopathy and micro-hemorrhages, thyroiditis, Sjogren's syndrome, rheumatoid like polyarthritis, psoriasis, fever, chills, headache, lethargy, somnolence, myalgia and fatigue, anorexia, hearing loss and tinnitus and serious CNS complications might occur during therapy. Rare side effects include; acute congestive heart failure, renal failure, vision loss, pulmonary fibrosis or pneumonitis, sepsis, acute myocardial infarction, stroke, suicide, and sepsis. Paradoxical worsening of hepatic disease provoking a form of autoimmune hepatitis that requires corticosteroid therapy is rare. Peginterferon therapy is contraindicated in severe depression or other neuropsychiatric syndromes, active substance or alcohol abuse, uncontrolled autoimmune disease (such as rheumatoid arthritis, lupus erythematosus, or psoriasis), bone marrow compromise, and inability to practice birth control measures. (Casato et al., 1997, Ferri et al., 1993, Iga et al.,

Ribavirin is a broad spectrum antiviral nucleoside analog which acts through enhancement of host T-cell–mediated immunity against viral infection through switching the T-cell phenotype from type 2 to type 1, inhibition of the host enzyme inosine monophosphate dehydrogenase (IMPDH), direct inhibition of HCV, including NS5B-encoded RNAdependent RNA polymerase (RdRp) and being an RNA mutagen it drives a rapidly mutating RNA virus over the threshold to "error catastrophe". Ribavirin is an oral drug,

1.5 mcg per kilogram per week in the range of 75 to 150 mcg per week.

**7.1.1 Interferon-alpha therapy**

response in some non-responders.

2005, Lidove et al., 1999).

**7.1.2 Ribavirin**

Fig. 4. Therapeutic strategies for hepatitis C mixed cryoglobulinemia.

Fig. 5. Treatment of HCV cryoglobulinemic renal disease. The management of renal disease in HCV mixed cryoglobulinemia depends upon the severity of renal disease.The standard regimen is a combination of immunosuppressive drugs, antiviral agents in addition to symptomatic therapy. In refractory cases rituximab will be the drug of choice. (Alric et al., 2004, Kidney International, Guideline 5, 2008)

Fig. 4. Therapeutic strategies for hepatitis C mixed cryoglobulinemia.

Fig. 5. Treatment of HCV cryoglobulinemic renal disease. The management of renal disease in HCV mixed cryoglobulinemia depends upon the severity of renal disease.The standard regimen is a combination of immunosuppressive drugs, antiviral agents in addition to symptomatic therapy. In refractory cases rituximab will be the drug of choice. (Alric et al.,

2004, Kidney International, Guideline 5, 2008)

#### **7.1.1 Interferon-alpha therapy**

The standard initial therapy used to be recombinant interferon alfa-2b at a dose of 3 x 106 units administered subcutaneously 3 times per week for 6 weeks. Recombinant forms of alpha interferon are being currently replaced by pegylated interferon (peginterferon). Peginterferon is alpha interferon modified chemically by the addition of a large inert molecule of polyethylene glycol prolonging its half-life. Peg-Interferon being with better efficacy and easier administration replaced standard interferon both as monotherapy and as combination therapy for hepatitis C viremia. Peg-interferon is more active than standard interferon in inhibiting HCV and yields higher sustained response rates with equivalent side effects. Two forms of peg-interferon are available: peg-interferon alfa-2a and peg-interferon alfa-2b, roughly equivalent in efficacy and safety, with different dosing regimen. Peginterferon alfa-2a is given subcutaneously in a fixed dose of 180 micrograms (mcg) per week, while peginterferon alfa-2b is given subcutaneously weekly in a weight-based dose of 1.5 mcg per kilogram per week in the range of 75 to 150 mcg per week.

The goal of interferon treatment is suppression of active disease by achieving a sustained viral response (sustained decrease or negative HCV-RT PCR). **Table 4** Interferon alpha monotherapy is effective in purpuric skin lesions, thrombocytopenias, but less effective with neural or renal involvement. IFN-alpha monotherapy is associated with a relatively poor response and a high virologic relapse rate, detectable viremia with active liver disease can occur with normal alanine transferase. Higher initial doses and longer duration of therapy help to increase the interval before relapse and escalation of the dose might help to achieve response in some non-responders.

 Peg-interferon therapy has bone marrow suppressive effects or cytopenias, therapy might be associated with immune mediated side effects including in about 2% of patients (particularly if high titers of antinuclear or antithyroid antibodies); peripheral sensorymotor neuropathy, nephropathy, retinopathy and micro-hemorrhages, thyroiditis, Sjogren's syndrome, rheumatoid like polyarthritis, psoriasis, fever, chills, headache, lethargy, somnolence, myalgia and fatigue, anorexia, hearing loss and tinnitus and serious CNS complications might occur during therapy. Rare side effects include; acute congestive heart failure, renal failure, vision loss, pulmonary fibrosis or pneumonitis, sepsis, acute myocardial infarction, stroke, suicide, and sepsis. Paradoxical worsening of hepatic disease provoking a form of autoimmune hepatitis that requires corticosteroid therapy is rare. Peginterferon therapy is contraindicated in severe depression or other neuropsychiatric syndromes, active substance or alcohol abuse, uncontrolled autoimmune disease (such as rheumatoid arthritis, lupus erythematosus, or psoriasis), bone marrow compromise, and inability to practice birth control measures. (Casato et al., 1997, Ferri et al., 1993, Iga et al., 2005, Lidove et al., 1999).

#### **7.1.2 Ribavirin**

Ribavirin is a broad spectrum antiviral nucleoside analog which acts through enhancement of host T-cell–mediated immunity against viral infection through switching the T-cell phenotype from type 2 to type 1, inhibition of the host enzyme inosine monophosphate dehydrogenase (IMPDH), direct inhibition of HCV, including NS5B-encoded RNAdependent RNA polymerase (RdRp) and being an RNA mutagen it drives a rapidly mutating RNA virus over the threshold to "error catastrophe". Ribavirin is an oral drug,

Hepatitis C Related Vasculitides 321

vascular disease should not receive ribavirin, as the anemia caused by treatment can trigger significant ischemia. Fatal myocardial infarctions and strokes are amongst reported side

Ribavirin is excreted largely by the kidneys. Patients with renal disease can develop hemolysis that is severe and even life threatening. With serum creatinine above 2.0 mg per deciliter (dL) patients should not be treated with ribavirin. Ribavirin causes birth defects in animal studies and should not be used in women or men without contraception. Peginterferon has direct antigrowth and anti-proliferative effects so it is contraindicated during pregnancy. Combination therapy should therefore be used with caution. Contraindications to ribavirin include marked anemia, renal dysfunction, and coronary artery or cerebrovascular disease, and inability to practice birth control. The newly emerging directacting antiviral (DAA) drugs are at the preclinical developmental stage and several are in clinical development. Initial clinical trials using some of these inhibitors, either alone or in combination with pegylated IFN-alpha and ribavirin, have yielded encouraging results. (Cacoub et al., 2002, Mazzaro et al., 2003, Pawlotsky, 2011) **Table 5.** Recently nucleotide polymorphism upstream of IL-28B gene has been found to be associated with response to PEG-IFN and ribavirin and spontaneous clearance of HCV infection in addition, genetic variants of inosine triphosphate (ITPA) have been correlated with protection against

**7.2 Corticosteroids, standard Immunosuppression and plasma exchange therapy**  The treatment of cryoglobulinemic vasculitis depends upon the severity of the acute manifestations and the extent of organ involvement. In asymptomatic MC monitoring without treatment is recommended. In patients with mild to moderate cryoglobulinemic symptoms (purpura, arthralgias, peripheral sensory neuropathy) first-line immnosuprression usually consists of low-dose corticosteroids. Patients with severe manifestations (cryoglobulinemic nephropathy, skin ulcers, sensory motor neuropathy, wide spread vasculitis) should promptly receive high-dose steroids and immunosuppressive therapy. Use of high dose intravenous corticosteroids might be useful for controlling life threatening organ involvement. Immunosuppressive drugs (e.g., Cyclophosphamide, Chlorambucil, and Azathioprine) can be used to suppress antibody and cryoglobulin production. The most effective and commonly used cytotoxic drug is Cyclophosphamide (750-1000mg intravenous pulse or orally at doses of 2 mg/kg per day). Recently; Mycophenolate Mofetil (1 g twice a day) is used as an alternative to Cyclophosphamide for the induction of remission in MC vasculitis. Mycophenolic Acid is more selective than Cyclophosphamide in inhibiting lymphocyte proliferation and functions, the drug was found to reduce viremia in HCV-infected renal or heart-transplant recipients due to its ability to inhibit inosine monophosphate dehydrogenase, the target

Plasma exchange therapy permits rapid control of life threatening symptoms of vasculitis by removal of circulating immune complexes with or without using high dose intravenous corticosteroids or immunosuppressive treatments, particularly in active cryoglobulinemic nephropathy. Oral cyclophosphamide (50-100 mg/day for 2-6 weeks) during the tapering of

effects during combination therapy with alpha interferon and ribavirin.

ribavirin induced hemolytic anemia (Fellay 2010)

enzyme inhibited by ribavirin. (Cacoub et al., 2005)

**7.3 Plasma exchange**

given twice a day in 200-mg capsules for a total daily dose based upon body weight (1,000 mg< 75 kg or 165 pounds and 1,200 mg for those >75 kg). Combination of ribavirin and interferon increases the sustained response rate by 2- to 3-fold with rapid improvements in serum ALT levels and disappearance of detectable HCV RNA in up to 70 percent of patients. The optimal therapeutic dose of ribavirin and the optimal duration varies depending upon viral genotype (genotype I, rare genotypes 4, 5, 6 require the maximum therapeutic dose/body weight, and longer duration). Considering the variable responses to treatment, testing for HCV genotype is clinically useful before starting combination therapy**.**  A response is considered "sustained" if HCV RNA remains undetectable for 6 months or more after stopping therapy.Some patients relapse by the end of treatment, the relapse rate is lower with combination therapy (55% sustained response with combination therapy for 48 weeks compared 35% with monotherapy)

Table 5. Combined Treatment Interferon plus Ribavirin in HCV-related

Cryoglobulinemia.CR = Complete remission; HCV = Hepatits C virus; NA = Not applicable; PR = Partial remission; Riba = Ribavirin.

Ribavirin therapy causes anemia, fatigue and irritability, itching, skin rash, nasal stuffiness, sinusitis, and cough, red cell hemolysis to a variable degree in almost all patients. Patients with a pre-existing hemolysis or anemia (hemoglobin < 11 grams or hematocrit < 33 percent) should not receive ribavirin. Similarly, patients who have significant coronary or cerebral

given twice a day in 200-mg capsules for a total daily dose based upon body weight (1,000 mg< 75 kg or 165 pounds and 1,200 mg for those >75 kg). Combination of ribavirin and interferon increases the sustained response rate by 2- to 3-fold with rapid improvements in serum ALT levels and disappearance of detectable HCV RNA in up to 70 percent of patients. The optimal therapeutic dose of ribavirin and the optimal duration varies depending upon viral genotype (genotype I, rare genotypes 4, 5, 6 require the maximum therapeutic dose/body weight, and longer duration). Considering the variable responses to treatment, testing for HCV genotype is clinically useful before starting combination therapy**.**  A response is considered "sustained" if HCV RNA remains undetectable for 6 months or more after stopping therapy.Some patients relapse by the end of treatment, the relapse rate is lower with combination therapy (55% sustained response with combination therapy for 48

**Treatment Responses**

**week + Riba 1200 mg/day × 1 year**

**week + Riba 15 mg/kg/day × 6 months.**

**week × 3 months, 3 MU × 3 per week × 3 months + Riba 15 mg/kg/day × 6**

**week + Riba 1200 mg/day × 1 year**

**months**

Cryoglobulinemia.CR = Complete remission; HCV = Hepatits C virus; NA = Not applicable;

Ribavirin therapy causes anemia, fatigue and irritability, itching, skin rash, nasal stuffiness, sinusitis, and cough, red cell hemolysis to a variable degree in almost all patients. Patients with a pre-existing hemolysis or anemia (hemoglobin < 11 grams or hematocrit < 33 percent) should not receive ribavirin. Similarly, patients who have significant coronary or cerebral

**(%) (genotype unrelated)**  **Follow up**

**65 22% relapse rate**

**85 55% relapse**

**CR+PR: 85 70% early**

**year**

**rate within 1**

**relapse; 22% long-term clinical and virological response**

**100 NA**

weeks compared 35% with monotherapy)

**TYPE OF STUDY**

**13 Prospective IFN 3 MU × 3 per**

**9 Prospective IFN 3 MU × 3 per**

**17 Prospective IFN 6 MU × 3 per**

**27 Prospective IFN 3 MU × 3 per**

Table 5. Combined Treatment Interferon plus Ribavirin in HCV-related

PR = Partial remission; Riba = Ribavirin.

**(no)**

**Study Patients**

**Calleja et al., 1999 (13)**

**Zuckerman et al., 2000 (114)**

**Donado et al., 1998 (28)**

**Mazzaro et al., 2003 (68)**  vascular disease should not receive ribavirin, as the anemia caused by treatment can trigger significant ischemia. Fatal myocardial infarctions and strokes are amongst reported side effects during combination therapy with alpha interferon and ribavirin.

Ribavirin is excreted largely by the kidneys. Patients with renal disease can develop hemolysis that is severe and even life threatening. With serum creatinine above 2.0 mg per deciliter (dL) patients should not be treated with ribavirin. Ribavirin causes birth defects in animal studies and should not be used in women or men without contraception. Peginterferon has direct antigrowth and anti-proliferative effects so it is contraindicated during pregnancy. Combination therapy should therefore be used with caution. Contraindications to ribavirin include marked anemia, renal dysfunction, and coronary artery or cerebrovascular disease, and inability to practice birth control. The newly emerging directacting antiviral (DAA) drugs are at the preclinical developmental stage and several are in clinical development. Initial clinical trials using some of these inhibitors, either alone or in combination with pegylated IFN-alpha and ribavirin, have yielded encouraging results. (Cacoub et al., 2002, Mazzaro et al., 2003, Pawlotsky, 2011) **Table 5.** Recently nucleotide polymorphism upstream of IL-28B gene has been found to be associated with response to PEG-IFN and ribavirin and spontaneous clearance of HCV infection in addition, genetic variants of inosine triphosphate (ITPA) have been correlated with protection against ribavirin induced hemolytic anemia (Fellay 2010)

#### **7.2 Corticosteroids, standard Immunosuppression and plasma exchange therapy**

The treatment of cryoglobulinemic vasculitis depends upon the severity of the acute manifestations and the extent of organ involvement. In asymptomatic MC monitoring without treatment is recommended. In patients with mild to moderate cryoglobulinemic symptoms (purpura, arthralgias, peripheral sensory neuropathy) first-line immnosuprression usually consists of low-dose corticosteroids. Patients with severe manifestations (cryoglobulinemic nephropathy, skin ulcers, sensory motor neuropathy, wide spread vasculitis) should promptly receive high-dose steroids and immunosuppressive therapy. Use of high dose intravenous corticosteroids might be useful for controlling life threatening organ involvement. Immunosuppressive drugs (e.g., Cyclophosphamide, Chlorambucil, and Azathioprine) can be used to suppress antibody and cryoglobulin production. The most effective and commonly used cytotoxic drug is Cyclophosphamide (750-1000mg intravenous pulse or orally at doses of 2 mg/kg per day). Recently; Mycophenolate Mofetil (1 g twice a day) is used as an alternative to Cyclophosphamide for the induction of remission in MC vasculitis. Mycophenolic Acid is more selective than Cyclophosphamide in inhibiting lymphocyte proliferation and functions, the drug was found to reduce viremia in HCV-infected renal or heart-transplant recipients due to its ability to inhibit inosine monophosphate dehydrogenase, the target enzyme inhibited by ribavirin. (Cacoub et al., 2005)

#### **7.3 Plasma exchange**

Plasma exchange therapy permits rapid control of life threatening symptoms of vasculitis by removal of circulating immune complexes with or without using high dose intravenous corticosteroids or immunosuppressive treatments, particularly in active cryoglobulinemic nephropathy. Oral cyclophosphamide (50-100 mg/day for 2-6 weeks) during the tapering of

Hepatitis C Related Vasculitides 323

Table 6. Rituximab treatment in Patients with HCV cryoglobulinemic vascultis.CNI = Calcineurin inhibitor; HCV = Hepatitis C virus; HSV = Herpes simplex virus; MMF = Mycophenolate mofetil; NR = Not reported; S = Steroids.↑: Increase; ↓: Decrease; =: No

LAC-diet is a particular dietetic treatment that can improve the clearance of circulating immune-complexes by restoring the activity of the reticulo-endothelial system, overloaded

change.

**7.5 Low antigen diet (LAC-diet)**

aphaeretic sessions can reinforce the beneficial effect of plasma exchange; and prevent the rebound phenomenon that may be observed after the aphaeresis discontinuation. Plasma The use of INF- alpha after each plasma exchange session doesn't modify the viral response (Hausfaster et al., 2002, Khattab et al., 2010, Morra, 2010)

## **7.4 Biologic agents**

#### **7.4.1 Anti-CD20 therapy -Rituximab**

Rituximab is a humanized anti- CD-20 monoclonal antibody that was primarily successfully employed for the treatment of B-cell lymphomas and other chronic lymphoproliferative diseases. The drug has proven efficacy in autoimmune disorders including vasculitis and refractory systemic lupus with nephritis. Recently, rituximab showed efficacy in cases of HCV-mixed cryoglobulinemia. The drug was successfully used in combination with antiviral agents as well as monotherapy in HCV cryoglobulinemic vasculitis. Rituximab combined with Peg-IFN-α/ribavirin delete both virus-dependent and -independent B-cell clones. Antiviral therapy alone decreased the memory B cells; whereas in association with rituximab, naive B cells are the main depleted population. This fact accounts for the delayed B-cell reconstitution after rituximab plus Peg-IFN-α/ribavirin and stresses the synergistic action of rituximab and antiviral therapy at the immunologic level. Rituximab shortens the therapeutic interval required for achieving a complete clinical reponse. Clonal expansion of marginal zone– like IgM+ CD27+ B cells (VH1-69 clonal B) has been recently observed in certain HCV-MC patients. Rituximab with Peg-IFN and ribavirin exerts a synergistic effect on polclonal B lymphocyte expansion. Rituximab plus Peg-IFN-α/ribavirin was more efficient to suppress both memory and VH1-69 clonal B cells compared with Peg-IFN-α/ribavirin alone. (Zaga et al., 2003, Sansonno et al., 2003, Roccatello et al., 2008) A standard therapeutic dose of 375 mg/m2 weekly for 4 weeks is effective, well tolerated and induces a significant and rapid improvement of clinical signs (purpura, arthralgia, peripheral neuropathy) with a decline of cryocrit in most patients with mixed cryoglobulinemia even in cases resistant to IFN therapy.

Rituximab trials emphasized the benefit of the drug in inducing remission in cutaneous vasculitis, cryoglobulinemic nephropathy, cryoglobulinemic neuropathy and in underlying malignant lymphoproliferative disorder. Relapse of cryoglobulinemic vasculitis might occur. Complete clinical remission was associated with a significant reduction of RF activity and anti-HCV antibody titers. (Saadoun et al., 2008) An increase of viremia might be observed in responders, with insignificant variation of transaminases or deterioration of liver disease. Rituximab infusions proved effective on cryoglobulinemic vasculitis, with a Recent studies showed a relapse in 36.1% of patients within a few days to 19 months after the last rituximab infusion**.** Complete immunologic response was higher with the combination of rituximab plus Peg-IFN-α/ribavirin. Recently, rituximab treatment of a renal-transplant patient with de novo HCV-related type III cryoglobulinemic MPGN resulted in clearance of cryoglobulinemia, a decrease in proteinuria yet without a change in serum creatinine or HCV RNA. Rituximab, the drug can cause serum sickness, serum sickness like disease, neutropenia and increased risk of infections, pneumopathy, varicella zoster infection, erysipelas and as monotherapy increases HCV viremia. (Saadoun et al., 2010, Pereira et al., 2010) **Table 6**

aphaeretic sessions can reinforce the beneficial effect of plasma exchange; and prevent the rebound phenomenon that may be observed after the aphaeresis discontinuation. Plasma The use of INF- alpha after each plasma exchange session doesn't modify the viral response

Rituximab is a humanized anti- CD-20 monoclonal antibody that was primarily successfully employed for the treatment of B-cell lymphomas and other chronic lymphoproliferative diseases. The drug has proven efficacy in autoimmune disorders including vasculitis and refractory systemic lupus with nephritis. Recently, rituximab showed efficacy in cases of HCV-mixed cryoglobulinemia. The drug was successfully used in combination with antiviral agents as well as monotherapy in HCV cryoglobulinemic vasculitis. Rituximab combined with Peg-IFN-α/ribavirin delete both virus-dependent and -independent B-cell clones. Antiviral therapy alone decreased the memory B cells; whereas in association with rituximab, naive B cells are the main depleted population. This fact accounts for the delayed B-cell reconstitution after rituximab plus Peg-IFN-α/ribavirin and stresses the synergistic action of rituximab and antiviral therapy at the immunologic level. Rituximab shortens the therapeutic interval required for achieving a complete clinical reponse. Clonal expansion of marginal zone– like IgM+ CD27+ B cells (VH1-69 clonal B) has been recently observed in certain HCV-MC patients. Rituximab with Peg-IFN and ribavirin exerts a synergistic effect on polclonal B lymphocyte expansion. Rituximab plus Peg-IFN-α/ribavirin was more efficient to suppress both memory and VH1-69 clonal B cells compared with Peg-IFN-α/ribavirin alone. (Zaga et al., 2003, Sansonno et al., 2003, Roccatello et al., 2008) A standard therapeutic dose of 375 mg/m2 weekly for 4 weeks is effective, well tolerated and induces a significant and rapid improvement of clinical signs (purpura, arthralgia, peripheral neuropathy) with a decline of cryocrit in most patients with mixed cryoglobulinemia even

Rituximab trials emphasized the benefit of the drug in inducing remission in cutaneous vasculitis, cryoglobulinemic nephropathy, cryoglobulinemic neuropathy and in underlying malignant lymphoproliferative disorder. Relapse of cryoglobulinemic vasculitis might occur. Complete clinical remission was associated with a significant reduction of RF activity and anti-HCV antibody titers. (Saadoun et al., 2008) An increase of viremia might be observed in responders, with insignificant variation of transaminases or deterioration of liver disease. Rituximab infusions proved effective on cryoglobulinemic vasculitis, with a Recent studies showed a relapse in 36.1% of patients within a few days to 19 months after the last rituximab infusion**.** Complete immunologic response was higher with the combination of rituximab plus Peg-IFN-α/ribavirin. Recently, rituximab treatment of a renal-transplant patient with de novo HCV-related type III cryoglobulinemic MPGN resulted in clearance of cryoglobulinemia, a decrease in proteinuria yet without a change in serum creatinine or HCV RNA. Rituximab, the drug can cause serum sickness, serum sickness like disease, neutropenia and increased risk of infections, pneumopathy, varicella zoster infection, erysipelas and as monotherapy increases HCV viremia.  Rituximab treatment in Patients with HCV cryoglobulinemic vascultis.CNI = Calcineurin inhibitor; HCV = Hepatitis C virus; HSV = Herpes simplex virus; MMF = Mycophenolate mofetil; NR = Not reported; S = Steroids.↑: Increase; ↓: Decrease; =: No change.

## **7.5 Low antigen diet (LAC-diet)**

LAC-diet is a particular dietetic treatment that can improve the clearance of circulating immune-complexes by restoring the activity of the reticulo-endothelial system, overloaded

Hepatitis C Related Vasculitides 325

(cryoglobulinemic vasculitis), and management of neoplastic complications. The prognosis of the disease depends largely upon the extent and severity of organ

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[3] Alric L, Plaisier E, Thebault S, et al. (2004) Influence of antiviral therapy in hepatitis C virus-associated cryoglobulinemic MPGN. Am J Kidney Dis 2004;43:617-23. [4] Antonelli A, Ferri C, Fallahi P, et al. (2004, a) Thyroid involvement in patients with overt

[5] Antonelli A, Ferri C, Fallahi P, et al. (2004, b): Type 2 diabetes in hepatitis C-related mixed cryoglobulinaemia patients. Rheumatology (Oxford) 2004, 43:238-40. [6] Antonelli A, Ferri C, Ferrari S M, et al., (2009). Serum levels of proinflammatory

[7] Authier FJ, Bassez G, Payan C et al. (2003) Detectio n of genomic viral RNA in nerve and muscle of patients with HCV neuropathy. Neurology 2003; 60:808–12. [8] Basse G, Ribes D, Kamar N et al. (2005) Rituximab therapy for de novo mixed

[9] Cacoub P, Musset L, Amoura Z, et al. (1997) Anticardiolipin, anti-beta2- glycoprotein I,

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[13] Calleja JL, Albillos A, Moreno-Otero R et al. (1999) Sustained response to interferon-α or

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**10. References**

pages 3841–3847.

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by large amounts of circulating cryoglobulins. LAC-diet can be used for controlling mild disease manifestations**.** (Ferri et al., 1989, Morra, 2010)

## **7.6 Symptomatic therapy**

Controlling blood pressure: diuretics, renin–angiotensin system blockade, the treatment of hyperlipidemia, are of proven benefit in prognosis of renal disease**.** Colchicine, an antiinflammatory agent has been proposed for MC patients with mild to moderate levels of the disease**.** (Khattab et al., 2010)

## **7.7 Treatment of HCV-related vasculitis relapses**

Clinical relapses are usually associated with relapsing HCV viremia (detectable HCV-RT-PCR). The use of combination therapy for in escalating doses for longer duration (18-24 months) effective in limiting relapses particularly in cases with renal involvement or peripheral neuropathy. A relapsing cryoglobulinemic vasculitis without HCV viral relapse might occur and in such conditions the possibility of an underlying malignant lymphoma (B cell Non-Hodgkin's Lymphoma) should be considered. Relapses can be successfully treated with a second trial of combination antiviral therapy with immunosuppression or anti CD-20 monoclonal antibody rituximab. (Fois et al., 2003, Saadoun et al., 2010) New direct acting antiviral drug combinations are under trial, the evolution of these drugs might expand the therapeutic benefit of combination therapy in HCV infection as well as extrahepatic disease. (Franciscus, 2011)

## **8. Prognosis**

The prognosis of HCV-MC depends upon the extent and severity of organ involvement and the response to treatment (viral load and clinical manifestations). The overall prognosis is worse in persons with concomitant renal disease or lympho-proliferative disease (B cell non Hodgkin lymphoma or malignant lymphoma). Mean survival is approximately 50% at 10 years after diagnosis. Survival rates reported among patients with cryoglobulinemic renal involvement varies from greater than 60% at 5 years of follow-up, up to 30% at 7 years of follow-up. Infection, cardiovascular disease and hepatic failue are amongst causes of morbidity. (Morra, 2010, Saadoun et al., 2010)

## **9. Conclusion**

Mixed cryoglobulinemia represents a form of leukocytoclastic vasculitis, which is considered to be a relatively rare disorder. Given its clinical polymorphism, a correct diagnosis might be delayed in addition the actual prevalence of disease is probably underestimated. Establishing the diagnosis of HCV-MC requires careful patient evaluation, biopsy from involved sites is the gold standard for diagnosing leukocytoclastic vasculitis. Owing to its' complex etio-pathogenesis and clinical polymorphism, the treatment of mixed cryoglobulinemia and cryoglobulinemic vasculitis remains challenging. The initial therapeutic step must target hepatitis C viremia being the chronic trigger for sustained immune-stimulation and autoantibody production. The second therapeutic target is to control downstream B cell clonal expansion thereby controlling the autoimmune manifestations related to cryoglobulinemia (cryoglobulinemic vasculitis), and management of neoplastic complications. The prognosis of the disease depends largely upon the extent and severity of organ involvement and adequate therapeutic intervention.

## **10. References**

324 Advances in the Etiology, Pathogenesis and Pathology of Vasculitis

by large amounts of circulating cryoglobulins. LAC-diet can be used for controlling mild

Controlling blood pressure: diuretics, renin–angiotensin system blockade, the treatment of hyperlipidemia, are of proven benefit in prognosis of renal disease**.** Colchicine, an antiinflammatory agent has been proposed for MC patients with mild to moderate levels of the

Clinical relapses are usually associated with relapsing HCV viremia (detectable HCV-RT-PCR). The use of combination therapy for in escalating doses for longer duration (18-24 months) effective in limiting relapses particularly in cases with renal involvement or peripheral neuropathy. A relapsing cryoglobulinemic vasculitis without HCV viral relapse might occur and in such conditions the possibility of an underlying malignant lymphoma (B cell Non-Hodgkin's Lymphoma) should be considered. Relapses can be successfully treated with a second trial of combination antiviral therapy with immunosuppression or anti CD-20 monoclonal antibody rituximab. (Fois et al., 2003, Saadoun et al., 2010) New direct acting antiviral drug combinations are under trial, the evolution of these drugs might expand the therapeutic benefit of combination therapy in HCV infection as well as extrahepatic disease.

The prognosis of HCV-MC depends upon the extent and severity of organ involvement and the response to treatment (viral load and clinical manifestations). The overall prognosis is worse in persons with concomitant renal disease or lympho-proliferative disease (B cell non Hodgkin lymphoma or malignant lymphoma). Mean survival is approximately 50% at 10 years after diagnosis. Survival rates reported among patients with cryoglobulinemic renal involvement varies from greater than 60% at 5 years of follow-up, up to 30% at 7 years of follow-up. Infection, cardiovascular disease and hepatic failue are amongst causes of

Mixed cryoglobulinemia represents a form of leukocytoclastic vasculitis, which is considered to be a relatively rare disorder. Given its clinical polymorphism, a correct diagnosis might be delayed in addition the actual prevalence of disease is probably underestimated. Establishing the diagnosis of HCV-MC requires careful patient evaluation, biopsy from involved sites is the gold standard for diagnosing leukocytoclastic vasculitis. Owing to its' complex etio-pathogenesis and clinical polymorphism, the treatment of mixed cryoglobulinemia and cryoglobulinemic vasculitis remains challenging. The initial therapeutic step must target hepatitis C viremia being the chronic trigger for sustained immune-stimulation and autoantibody production. The second therapeutic target is to control downstream B cell clonal expansion thereby controlling the autoimmune manifestations related to cryoglobulinemia

disease manifestations**.** (Ferri et al., 1989, Morra, 2010)

**7.7 Treatment of HCV-related vasculitis relapses**

morbidity. (Morra, 2010, Saadoun et al., 2010)

**7.6 Symptomatic therapy**

disease**.** (Khattab et al., 2010)

(Franciscus, 2011)

**8. Prognosis**

**9. Conclusion**

Hepatitis C Related Vasculitides 327

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**Part 4**

**Selected Issues in Vasculitis**

## **Part 4**

**Selected Issues in Vasculitis**

332 Advances in the Etiology, Pathogenesis and Pathology of Vasculitis

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**17**

*Spain*

 *IFIMAV, Santander,*

**Audiovestibular Manifestations in**

Juan Carlos Amor-Dorado1 and Miguel Angel Gonzalez-Gay2

The term systemic vasculitis encompasses a group of diseases that were considered rare years ago. However, as knowledge of them has been expanded, there have become increasingly important in the differential diagnosis of patients with varied manifestations, not only rheumatological, but also with sensory and visceral affectation in diverse locations,

This is a heterogeneous group of diseases that often overlap each other, with various etiologies and clinical manifestations. The common feature among them is the inflammation of the lining of blood vessels, which causes ischemic events and tissue necrosis, as well as the occlusion of the lumen of vessels and, consequently, impaired function of the affected

Any blood vessel can be affected by the vasculitic phenomenon. Moreover, the extent and site of affectation of the vessels varies depending on the type of vasculitis; in general, they tend to be irregular and segmental. In severe forms, lesions spread throughout the body. In mild forms, it can be located in a single region of the body; for example, limited to the skin in patients with cutaneous leukocytoclastic vasculitis. Others, however, cause lesions in several distant organs such as kidneys or lungs in patients with microscopic polyangiitis and Wegener's granulomatosis. Some types of vasculitis manifest with lesions in the same stage of development, as in the case of cutaneous lesions that appear with an outbreak of Henoch- Schönlein purpura. In others, such as polyarteritis nodosa, lesions that are at different stages of development in different organs. Some forms of vasculitis may have an acute course, mainly those with a predominantly skin involvement. In contrast, others such

as Takayasu's arteritis have shown varying degrees of activity for over 20 years [1].

The inner ear may be involved in organ-specific autoimmune diseases such as the autoimmune inner ear disease described by McCabe in 1979 and it may be the target organ in various non-organ specific systemic diseases. Among these, some are the result of direct autoimmune lesion and others of vascular damage which, in turn, can be primary or

**2. Audiovestibular manifestations in systemic vasculitis**

**1. Introduction**

extent and severity.

organ [1].

*2Rheumatology Division, Hospital Universitario Marques de Valdecilla,*

**Systemic Vasculitis: An Update**

*1Otolaryngology Division, Hospital Lucus Augusti, Lugo,*

## **Audiovestibular Manifestations in Systemic Vasculitis: An Update**

Juan Carlos Amor-Dorado1 and Miguel Angel Gonzalez-Gay2 *1Otolaryngology Division, Hospital Lucus Augusti, Lugo, 2Rheumatology Division, Hospital Universitario Marques de Valdecilla, IFIMAV, Santander, Spain*

## **1. Introduction**

The term systemic vasculitis encompasses a group of diseases that were considered rare years ago. However, as knowledge of them has been expanded, there have become increasingly important in the differential diagnosis of patients with varied manifestations, not only rheumatological, but also with sensory and visceral affectation in diverse locations, extent and severity.

This is a heterogeneous group of diseases that often overlap each other, with various etiologies and clinical manifestations. The common feature among them is the inflammation of the lining of blood vessels, which causes ischemic events and tissue necrosis, as well as the occlusion of the lumen of vessels and, consequently, impaired function of the affected organ [1].

Any blood vessel can be affected by the vasculitic phenomenon. Moreover, the extent and site of affectation of the vessels varies depending on the type of vasculitis; in general, they tend to be irregular and segmental. In severe forms, lesions spread throughout the body. In mild forms, it can be located in a single region of the body; for example, limited to the skin in patients with cutaneous leukocytoclastic vasculitis. Others, however, cause lesions in several distant organs such as kidneys or lungs in patients with microscopic polyangiitis and Wegener's granulomatosis. Some types of vasculitis manifest with lesions in the same stage of development, as in the case of cutaneous lesions that appear with an outbreak of Henoch- Schönlein purpura. In others, such as polyarteritis nodosa, lesions that are at different stages of development in different organs. Some forms of vasculitis may have an acute course, mainly those with a predominantly skin involvement. In contrast, others such as Takayasu's arteritis have shown varying degrees of activity for over 20 years [1].

## **2. Audiovestibular manifestations in systemic vasculitis**

The inner ear may be involved in organ-specific autoimmune diseases such as the autoimmune inner ear disease described by McCabe in 1979 and it may be the target organ in various non-organ specific systemic diseases. Among these, some are the result of direct autoimmune lesion and others of vascular damage which, in turn, can be primary or

Audiovestibular Manifestations in Systemic Vasculitis: An Update 337

BPPV: benign paroxysmal positional vertigo; HSC: horizontal semicircular canal; PSC: posterior semicircular canal; PAN: panarteritis nudosa; CTSIB: Clinical Test for Sensory Interaction and Balance.

Interestingly, regardless of the etiology of the various diseases affecting the inner ear, pathological findings are identical. They include degeneration and destruction of the peripheral receptor; segmental and diffuse infiltration of lymphocytes, plasma cells, and

Table 1. Audiovestibular manifestations in systemic vasculitis

secondary to infections or collagen diseases. The systemic vasculitis forms belong to the group of diseases that have vascular damage as the main pathogenic factor [2, 3].

secondary to infections or collagen diseases. The systemic vasculitis forms belong to the

group of diseases that have vascular damage as the main pathogenic factor [2, 3].

BPPV: benign paroxysmal positional vertigo; HSC: horizontal semicircular canal; PSC: posterior semicircular canal; PAN: panarteritis nudosa; CTSIB: Clinical Test for Sensory Interaction and Balance.

Table 1. Audiovestibular manifestations in systemic vasculitis

Interestingly, regardless of the etiology of the various diseases affecting the inner ear, pathological findings are identical. They include degeneration and destruction of the peripheral receptor; segmental and diffuse infiltration of lymphocytes, plasma cells, and

Audiovestibular Manifestations in Systemic Vasculitis: An Update 339

In our series, the audiometric tests at the time of diagnosis showed a remarkable auditory dysfunction in GCA patients. Another point to be considered from our study was the presence of a frequent asymmetrical auditory dysfunction that it is in keeping with the asymmetrical cranial manifestations reported in many patients with GCA. During follow-up improvement in auditory function was observed within the first 3 months after the onset of therapy. However, such an improvement was only found in 27% of the cases. In addition, despite corticosteroid therapy, further deterioration in auditory function after 3 months of treatment was detected in 3 patients. Moreover, no additional improvement in hearing function was observed after another 3 months of treatment. These data suggest that the possible improvement in hearing function may be achieved generally early during the first months after the onset of therapy [16]. In summary, our results support the presence of both auditory and vestibular dysfunction closely related to the vasculitic process in GCA

**Polymyalgia rheumatica** is characterized by pain in the scapulae and proximal aspects of the shoulders, pelvis and proximal aspects of the lower extremities and the cervical region, together with morning stiffness of more than 1 h; it may be present in about 40% of patients with GCA [5]. However, polymyalgia rheumatica may be a separate entity [6] or the initial form of a GCA that does not initially show cranial condition data or other ischemic symptoms suggesting a GCA [18]. Therefore, the presence of audiovestibular abnormalities in one of our patients who initially showed only clinical symptoms of polymyalgia rheumatica was of particular importance. The patient did not initially present the ischemic vascular disease typical of GCA, but at follow-up showed the typical manifestations attributable to it. The presence of vestibular dysfunction may be an alarm sign to consider the possibility of having a "silent and subclinical" GCA in those patients presenting with PMR symptoms. In this regard, the presence of vestibular dysfunction, probably related to ischemic manifestations, may be considered as an early and reversible sign in the course of the disease. Thus, the knowledge of these manifestations as alert signs for a possible underlying GCA is of main importance in elderly people as early corticosteroid treatment reduces significantly the risk of blindness due to GCA. This fact is even more important in GCA whose presenting manifestation is PMR only, as in these cases low dose prednisone does not prevent the development of blindness. The presence of abnormal vestibular tests in patients presenting with PMR without cranial manifestations of GCA may be considered as

**Takayasu's arteritis** is a chronic vasculitis of unknown etiology that affects the aorta, its major branches, the pulmonary artery and the coronary arteries; it causes headache, absence of arterial pulses, heart failure, renovascular hypertension and ocular and cerebral ischemia. In contrast to GCA, Takayasu's arteritis primarily affects young people, especially women between 15 and 25, more commonly in Asian or Central-American populations [19]. In this vasculitis affecting large vessels, a patient has been described who presented sudden deafness and decreased pulse in the radial artery. The hearing condition worsened upon withdrawal of parenterally administered steroids and improved when they were reintroduced [20]. Histopathological studies of the temporal bone are of great interest in patients with systemic vasculitis. Among them, those published for patients diagnosed with **polyarteritis nodosa (PAN)** should be highlighted. In a patient whose first manifestation of the disease was sudden unilateral deafness and vertigo, the temporal bone histopathological study showed bilateral cochlear condition in the form of loss of the organ of Corti in various portions of the cochlea, the absence of the tectorial membrane and atrophy of the stria

a red flag to raise the suspicion of an underlying GCA [16].

patients.

macrophages; proliferation of fibrous tissue, and varying degrees of ossification of the inner ear [4].

Next, we discuss the studies to date that have disclosed an association of vasculitis involvement with auditory and vestibular manifestations. Table 1 presents an update of the different audiovestibular manifestations described according to the classification of vasculitis.

## **3. Primary vasculitis**

**Giant cell arteritis (GCA)** is a multisystemic vasculitis of elderly people. It mainly involves large and medium-sized blood vessels with predisposition to the cranial arteries. GCA constitutes the most common systemic vasculitis in Western countries. Some cranial ischemic manifestations, in particular permanent visual loss, have been widely described in patients with this vasculitis. However, audiovestibular manifestations in GCA patients, such as hearing loss, vertigo, or tinnitus, have been less commonly reported. It is also characterized by granulomatous affectation of the aorta and its major branches, with a predisposition towards the cranial area, both in the arterial branches arising from the external carotid (explaining the topical headaches) and the internal carotid artery, leading to the feared blindness, either by affectation of the posterior ciliary arteries or the central retinal artery. GCA is often present with temporoparietal pulsating headaches, different from the usual, which often accompanied by polymyalgia rheumatica and, to a lesser extent, jaw claudication, amaurosis fugax, blindness, or stroke predominantly in the vertebrobasilar territory [5-8]. The definitive diagnosis is obtained by a temporal artery biopsy demonstrating disruption of the internal elastic lamina with lymphocytic inflammatory infiltration and multinucleated giant cells in 50% of cases [9].

The last 4 decades have witnessed a significant increase in the number of diagnosed cases of GCA. This increase has not only been found in areas where GCA is common [10] but also here the incidence was low [11-13]. This fact can be explained by a greater awareness of the disease. In our population in Lugo of individuals older than 50, the incidence of GCA adjusted for age and gender is 10/100 000 inhabitants/year, but it reaches 23/100 000 inhabitants/year in the group of patients between 70 and 79 [14,15].

In a prospective study of 44 patients with GCA and 10 with isolated polymyalgia rheumatica from our Lugo population, in 39 (89%) of the 44 GCA patients only exhibited abnormalities in the vestibular tests when these were performed in the first four days at the onset of diagnosis and parenterally corticosteroid therapy. Our data suggest that the vestibule is very sensitive to the ischemic effects of the GCA. Also, they suggest that the vestibular damage may be reversible in some cases. With respect to this, only 13 (30%) of the 44 after 3 months of treatment and 1 patient after 6 months of follow-up had persistent vestibular impairment, coinciding with the start of treatment with steroids. The most significant vestibular finding observed at 3 months was paretic horizontal nystagmus in the head shaking nystagmus test. Moreover, although in our study a Dix-Hallpike test was found to be positive in 7% of the control population, this test yielded positive results in 21% of the biopsy-negative GCA and 33% of biopsy-positive GCA patients. This finding in GCA patients seems to be extremely high. It may suggest that in some cases the benign paroxysmal positional vertigo (BPPV) may be related to a vasculitic inflammatory disorder. Furthermore, we found a close relationship between GCA and benign paroxysmal positional vertigo of the posterior semicircular canal in our population [16,17].

macrophages; proliferation of fibrous tissue, and varying degrees of ossification of the inner

Next, we discuss the studies to date that have disclosed an association of vasculitis involvement with auditory and vestibular manifestations. Table 1 presents an update of the different audiovestibular manifestations described according to the classification of

**Giant cell arteritis (GCA)** is a multisystemic vasculitis of elderly people. It mainly involves large and medium-sized blood vessels with predisposition to the cranial arteries. GCA constitutes the most common systemic vasculitis in Western countries. Some cranial ischemic manifestations, in particular permanent visual loss, have been widely described in patients with this vasculitis. However, audiovestibular manifestations in GCA patients, such as hearing loss, vertigo, or tinnitus, have been less commonly reported. It is also characterized by granulomatous affectation of the aorta and its major branches, with a predisposition towards the cranial area, both in the arterial branches arising from the external carotid (explaining the topical headaches) and the internal carotid artery, leading to the feared blindness, either by affectation of the posterior ciliary arteries or the central retinal artery. GCA is often present with temporoparietal pulsating headaches, different from the usual, which often accompanied by polymyalgia rheumatica and, to a lesser extent, jaw claudication, amaurosis fugax, blindness, or stroke predominantly in the vertebrobasilar territory [5-8]. The definitive diagnosis is obtained by a temporal artery biopsy demonstrating disruption of the internal elastic lamina with lymphocytic inflammatory

The last 4 decades have witnessed a significant increase in the number of diagnosed cases of GCA. This increase has not only been found in areas where GCA is common [10] but also here the incidence was low [11-13]. This fact can be explained by a greater awareness of the disease. In our population in Lugo of individuals older than 50, the incidence of GCA adjusted for age and gender is 10/100 000 inhabitants/year, but it reaches 23/100 000

In a prospective study of 44 patients with GCA and 10 with isolated polymyalgia rheumatica from our Lugo population, in 39 (89%) of the 44 GCA patients only exhibited abnormalities in the vestibular tests when these were performed in the first four days at the onset of diagnosis and parenterally corticosteroid therapy. Our data suggest that the vestibule is very sensitive to the ischemic effects of the GCA. Also, they suggest that the vestibular damage may be reversible in some cases. With respect to this, only 13 (30%) of the 44 after 3 months of treatment and 1 patient after 6 months of follow-up had persistent vestibular impairment, coinciding with the start of treatment with steroids. The most significant vestibular finding observed at 3 months was paretic horizontal nystagmus in the head shaking nystagmus test. Moreover, although in our study a Dix-Hallpike test was found to be positive in 7% of the control population, this test yielded positive results in 21% of the biopsy-negative GCA and 33% of biopsy-positive GCA patients. This finding in GCA patients seems to be extremely high. It may suggest that in some cases the benign paroxysmal positional vertigo (BPPV) may be related to a vasculitic inflammatory disorder. Furthermore, we found a close relationship between GCA and benign paroxysmal positional

infiltration and multinucleated giant cells in 50% of cases [9].

inhabitants/year in the group of patients between 70 and 79 [14,15].

vertigo of the posterior semicircular canal in our population [16,17].

ear [4].

vasculitis.

**3. Primary vasculitis**

In our series, the audiometric tests at the time of diagnosis showed a remarkable auditory dysfunction in GCA patients. Another point to be considered from our study was the presence of a frequent asymmetrical auditory dysfunction that it is in keeping with the asymmetrical cranial manifestations reported in many patients with GCA. During follow-up improvement in auditory function was observed within the first 3 months after the onset of therapy. However, such an improvement was only found in 27% of the cases. In addition, despite corticosteroid therapy, further deterioration in auditory function after 3 months of treatment was detected in 3 patients. Moreover, no additional improvement in hearing function was observed after another 3 months of treatment. These data suggest that the possible improvement in hearing function may be achieved generally early during the first months after the onset of therapy [16]. In summary, our results support the presence of both auditory and vestibular dysfunction closely related to the vasculitic process in GCA patients.

**Polymyalgia rheumatica** is characterized by pain in the scapulae and proximal aspects of the shoulders, pelvis and proximal aspects of the lower extremities and the cervical region, together with morning stiffness of more than 1 h; it may be present in about 40% of patients with GCA [5]. However, polymyalgia rheumatica may be a separate entity [6] or the initial form of a GCA that does not initially show cranial condition data or other ischemic symptoms suggesting a GCA [18]. Therefore, the presence of audiovestibular abnormalities in one of our patients who initially showed only clinical symptoms of polymyalgia rheumatica was of particular importance. The patient did not initially present the ischemic vascular disease typical of GCA, but at follow-up showed the typical manifestations attributable to it. The presence of vestibular dysfunction may be an alarm sign to consider the possibility of having a "silent and subclinical" GCA in those patients presenting with PMR symptoms. In this regard, the presence of vestibular dysfunction, probably related to ischemic manifestations, may be considered as an early and reversible sign in the course of the disease. Thus, the knowledge of these manifestations as alert signs for a possible underlying GCA is of main importance in elderly people as early corticosteroid treatment reduces significantly the risk of blindness due to GCA. This fact is even more important in GCA whose presenting manifestation is PMR only, as in these cases low dose prednisone does not prevent the development of blindness. The presence of abnormal vestibular tests in patients presenting with PMR without cranial manifestations of GCA may be considered as a red flag to raise the suspicion of an underlying GCA [16].

**Takayasu's arteritis** is a chronic vasculitis of unknown etiology that affects the aorta, its major branches, the pulmonary artery and the coronary arteries; it causes headache, absence of arterial pulses, heart failure, renovascular hypertension and ocular and cerebral ischemia. In contrast to GCA, Takayasu's arteritis primarily affects young people, especially women between 15 and 25, more commonly in Asian or Central-American populations [19]. In this vasculitis affecting large vessels, a patient has been described who presented sudden deafness and decreased pulse in the radial artery. The hearing condition worsened upon withdrawal of parenterally administered steroids and improved when they were reintroduced [20]. Histopathological studies of the temporal bone are of great interest in patients with systemic vasculitis. Among them, those published for patients diagnosed with **polyarteritis nodosa (PAN)** should be highlighted. In a patient whose first manifestation of the disease was sudden unilateral deafness and vertigo, the temporal bone histopathological study showed bilateral cochlear condition in the form of loss of the organ of Corti in various portions of the cochlea, the absence of the tectorial membrane and atrophy of the stria

Audiovestibular Manifestations in Systemic Vasculitis: An Update 341

**Rheumatoid arthritis** is a chronic, multisystemic inflammatory disease characterised by persistent inflammatory synovitis, usually involving peripheral joints in a symmetrical manner, predominantly the wrists, the metacarpophalangeal and proximal interphalangeal joints of the hands, elbows and knees and metatarsal-phalangeal of feet. It is more common in women; although its etiology is unknown, there is a genetic predisposition, as shown by the tendency to familial aggregation, the high concordance with rheumatoid arthritis in monozygotic twins and the association with genes within the major histocompatibility complex, particularly with certain alleles that share a common sequence of amino acids within the hypervariable control region of the HLA-DRB1 chain, called shared epitope [37]. One study has described sudden hearing loss in patients with RA with an underlying

In the Lugo population, as in the Anglo-Saxon, an association of rheumatoid arthritis with HLA-DR4 alleles has been observed, in particular with HLA-DRB1\*0401 and \*0404. These alleles have also been shown as markers of vascular damage in patients with rheumatoid arthritis in Lugo, since patients with these alleles are at increased risk of endothelial vascular dysfunction [39] a marker of early stage of atherosclerosis and an increased risk of

Interestingly, in a series of 33 patients diagnosed with idiopathic sudden hearing loss in our Lugo population, we also observed an association of HLA-DR4 with increased susceptibility to the disease and a worse prognosis for recovery with steroid treatment [41]. Accordingly with this, an increased susceptibility to sensorineural hearing loss has been described in patients with rheumatoid arthritis with respect to a control group. Specifically, in a series of 194 patients diagnosed with rheumatoid arthritis, sensorineural hearing loss was also described in 39% [42]. The coincidence of findings involving HLA-DR4 alleles with increased severity of rheumatoid arthritis [37] and its association with increased risk of vascular damage in this disease [39,40] together with the finding of an increased risk of sudden deafness with worse functional outcome in people presenting HLA-DR4 may indicate that these alleles would be true markers of endothelial vascular damage regardless

**Scleroderma or systemic sclerosis** is included in the collagenosis group. Systemic sclerosis (SSc) is a disease characterized by excessive deposition of connective tissue and extracellular matrix proteins in different organs and tissues, and is more common in women. Its etiology is unknown, but it is known to involve disorders of collagen synthesis as well as vascular and immune system abnormalities. Two clinical forms have been established: the limited and the diffuse variants. The predominate features in the limited form are Raynaud's phenomenon, clinical data defined in the CREST syndrome (calcinosis, Raynaud's phenomenon, sclerodactyly, oesophageal disorders, and telangiectasia), increased risk of pulmonary hypertension and presence of positive antinuclear antibodies anticentromere B positive and distal skin condition in the extremities [43]. In the diffuse form, the predominate features are proximal skin condition and more intense injury to internal organs that leads to increased risk of pulmonary fibrosis and renal scleroderma crisis, typically

Recently, in the population of Lugo, we tried to assess the presence of audiovestibular damage in a homogenous cohort of patients with limited SSc and antibodies against CENB. We were able to observe abnormalities of audiometric and vestibular tests

**4. Secondary vasculitis**

cardiovascular events [40].

of the underlying disease [41].

associating with anti-SCL70 positive antibodies [43].

vasculitic process affecting the eighth cranial nerve [38].

vascularis, whereas no vestibular histopathological changes were observed [21]. In another patient with a diagnosis of PAN and unilateral profound hearing loss and vertigo, the histopathological study found vasculitis in the internal auditory artery, accompanied by ossification of the cochlea and the vestibular system as well as endolymphatic hydrops in the basal ramp of the cochlea [22]. The loss of sensory cells and neurons in the maculae of the semicircular canals, utricle and saccule has also been reported in PAN [23]. Most of the reported cases with a diagnosis of PAN met the criteria of the Chapel Hill Consensus Conference relative to microscopic polyangiitis. Recently, the possibility has been described of obtaining a recovery of hearing through a cochlear implant in a patient diagnosed with PAN by biopsy. This reinforces the impression that the lesion is located at the cochlear level. In this group of patients with PAN and profound bilateral hearing loss, this may be secondary to labyrinthine ischemia by a vascular phenomenon [24].

**Kawasaki disease (KD)** is a diffuse necrotizing vasculitis involving medium-sized vessels, with almost constant injury of the coronary arteries and large non-intraparenchymatous arteries. 85% of patients with KD are children under 5 in whom the disease occurs sporadically or in small outbreaks. It is predominant in males (1.5:1) and, although it is more frequent in Japan, the disease has been diagnosed in more than 40 countries [25]. In a study of 62 patients diagnosed with KD, sensorineural hearing loss was described in the acute phase of the disease in 30% and conductive hearing loss in 9%. On examination of auditory function after the acute phase, neurosensorial hearing loss persisted in 5.5% of patients, so the partially reversible character after treatment with steroids was confirmed [26].

**Wegener's granulomatosis** is defined as a granulomatous inflammation that affects the airways combined with necrotizing vasculitis of small and medium vessels together with glomerulonephritis and positive cANCA [27]. Furthermore to the known hearing loss secondary to obstruction of the Eustachian tube due to granulomas in the nasopharynx, a series of 21 patients described sudden hearing loss and tinnitus [28]. Bilateral sensorineural hearing loss was observed in 12 of 13 patients with auditory symptoms in a series of 19 patients diagnosed with Wegener's disease by biopsy [29]. Some patients also described vestibular manifestations such as vertigo and peripheral nystagmus [30].

**Churg-Strauss allergic granulomatous vasculitis** is characterized by granulomas in the upper airways, with eosinophilic infiltration and systemic vasculitis in medium and small vessels, along with a history of asthma, circulating eosinophilia and high concentrations of circulating IgE [27]. It has been described with otitis media with effusion, acute otitis media and progressive sensorineural hearing loss in 9.5% of patients, who improved or stabilized after administration of steroids and immunosuppressors [31].

**Behcet's disease** is a multisystemic, chronic and recurrent disease that almost always occurs with oral thrush and, in variable frequency, genital sores, uveitis, skin lesions and neurological, vascular and gastrointestinal manifestations with a pathological substrate of leukocytoclastic or lymphocytic vasculitis, preferably from capillaries and venules [32]. Auditory manifestations such as sudden deafness have been described, as well as vertigo during the course of the disease and in relapses [33,34]. Sensorineural hearing loss with a cochlear location was described in 30% of 62 patients diagnosed with Behcet's disease, and central vestibular syndrome in 40% [35].

**Cogan's syndrome** is characterized by fluctuating hearing loss, tinnitus, spontaneous sudden vertigo, and interstitial keratitis. A significant audiovestibular function has also been described. However, the reported damage is so severe that it does not seem to be the result of a true vasculitis, but rather of a primary labyrinthitis [36].

## **4. Secondary vasculitis**

340 Advances in the Etiology, Pathogenesis and Pathology of Vasculitis

vascularis, whereas no vestibular histopathological changes were observed [21]. In another patient with a diagnosis of PAN and unilateral profound hearing loss and vertigo, the histopathological study found vasculitis in the internal auditory artery, accompanied by ossification of the cochlea and the vestibular system as well as endolymphatic hydrops in the basal ramp of the cochlea [22]. The loss of sensory cells and neurons in the maculae of the semicircular canals, utricle and saccule has also been reported in PAN [23]. Most of the reported cases with a diagnosis of PAN met the criteria of the Chapel Hill Consensus Conference relative to microscopic polyangiitis. Recently, the possibility has been described of obtaining a recovery of hearing through a cochlear implant in a patient diagnosed with PAN by biopsy. This reinforces the impression that the lesion is located at the cochlear level. In this group of patients with PAN and profound bilateral hearing loss, this may be

**Kawasaki disease (KD)** is a diffuse necrotizing vasculitis involving medium-sized vessels, with almost constant injury of the coronary arteries and large non-intraparenchymatous arteries. 85% of patients with KD are children under 5 in whom the disease occurs sporadically or in small outbreaks. It is predominant in males (1.5:1) and, although it is more frequent in Japan, the disease has been diagnosed in more than 40 countries [25]. In a study of 62 patients diagnosed with KD, sensorineural hearing loss was described in the acute phase of the disease in 30% and conductive hearing loss in 9%. On examination of auditory function after the acute phase, neurosensorial hearing loss persisted in 5.5% of patients, so

**Wegener's granulomatosis** is defined as a granulomatous inflammation that affects the airways combined with necrotizing vasculitis of small and medium vessels together with glomerulonephritis and positive cANCA [27]. Furthermore to the known hearing loss secondary to obstruction of the Eustachian tube due to granulomas in the nasopharynx, a series of 21 patients described sudden hearing loss and tinnitus [28]. Bilateral sensorineural hearing loss was observed in 12 of 13 patients with auditory symptoms in a series of 19 patients diagnosed with Wegener's disease by biopsy [29]. Some patients also described

**Churg-Strauss allergic granulomatous vasculitis** is characterized by granulomas in the upper airways, with eosinophilic infiltration and systemic vasculitis in medium and small vessels, along with a history of asthma, circulating eosinophilia and high concentrations of circulating IgE [27]. It has been described with otitis media with effusion, acute otitis media and progressive sensorineural hearing loss in 9.5% of patients, who improved or stabilized

**Behcet's disease** is a multisystemic, chronic and recurrent disease that almost always occurs with oral thrush and, in variable frequency, genital sores, uveitis, skin lesions and neurological, vascular and gastrointestinal manifestations with a pathological substrate of leukocytoclastic or lymphocytic vasculitis, preferably from capillaries and venules [32]. Auditory manifestations such as sudden deafness have been described, as well as vertigo during the course of the disease and in relapses [33,34]. Sensorineural hearing loss with a cochlear location was described in 30% of 62 patients diagnosed with Behcet's disease, and

**Cogan's syndrome** is characterized by fluctuating hearing loss, tinnitus, spontaneous sudden vertigo, and interstitial keratitis. A significant audiovestibular function has also been described. However, the reported damage is so severe that it does not seem to be the

the partially reversible character after treatment with steroids was confirmed [26].

vestibular manifestations such as vertigo and peripheral nystagmus [30].

after administration of steroids and immunosuppressors [31].

result of a true vasculitis, but rather of a primary labyrinthitis [36].

central vestibular syndrome in 40% [35].

secondary to labyrinthine ischemia by a vascular phenomenon [24].

**Rheumatoid arthritis** is a chronic, multisystemic inflammatory disease characterised by persistent inflammatory synovitis, usually involving peripheral joints in a symmetrical manner, predominantly the wrists, the metacarpophalangeal and proximal interphalangeal joints of the hands, elbows and knees and metatarsal-phalangeal of feet. It is more common in women; although its etiology is unknown, there is a genetic predisposition, as shown by the tendency to familial aggregation, the high concordance with rheumatoid arthritis in monozygotic twins and the association with genes within the major histocompatibility complex, particularly with certain alleles that share a common sequence of amino acids within the hypervariable control region of the HLA-DRB1 chain, called shared epitope [37]. One study has described sudden hearing loss in patients with RA with an underlying vasculitic process affecting the eighth cranial nerve [38].

In the Lugo population, as in the Anglo-Saxon, an association of rheumatoid arthritis with HLA-DR4 alleles has been observed, in particular with HLA-DRB1\*0401 and \*0404. These alleles have also been shown as markers of vascular damage in patients with rheumatoid arthritis in Lugo, since patients with these alleles are at increased risk of endothelial vascular dysfunction [39] a marker of early stage of atherosclerosis and an increased risk of cardiovascular events [40].

Interestingly, in a series of 33 patients diagnosed with idiopathic sudden hearing loss in our Lugo population, we also observed an association of HLA-DR4 with increased susceptibility to the disease and a worse prognosis for recovery with steroid treatment [41]. Accordingly with this, an increased susceptibility to sensorineural hearing loss has been described in patients with rheumatoid arthritis with respect to a control group. Specifically, in a series of 194 patients diagnosed with rheumatoid arthritis, sensorineural hearing loss was also described in 39% [42]. The coincidence of findings involving HLA-DR4 alleles with increased severity of rheumatoid arthritis [37] and its association with increased risk of vascular damage in this disease [39,40] together with the finding of an increased risk of sudden deafness with worse functional outcome in people presenting HLA-DR4 may indicate that these alleles would be true markers of endothelial vascular damage regardless of the underlying disease [41].

**Scleroderma or systemic sclerosis** is included in the collagenosis group. Systemic sclerosis (SSc) is a disease characterized by excessive deposition of connective tissue and extracellular matrix proteins in different organs and tissues, and is more common in women. Its etiology is unknown, but it is known to involve disorders of collagen synthesis as well as vascular and immune system abnormalities. Two clinical forms have been established: the limited and the diffuse variants. The predominate features in the limited form are Raynaud's phenomenon, clinical data defined in the CREST syndrome (calcinosis, Raynaud's phenomenon, sclerodactyly, oesophageal disorders, and telangiectasia), increased risk of pulmonary hypertension and presence of positive antinuclear antibodies anticentromere B positive and distal skin condition in the extremities [43]. In the diffuse form, the predominate features are proximal skin condition and more intense injury to internal organs that leads to increased risk of pulmonary fibrosis and renal scleroderma crisis, typically associating with anti-SCL70 positive antibodies [43].

Recently, in the population of Lugo, we tried to assess the presence of audiovestibular damage in a homogenous cohort of patients with limited SSc and antibodies against CENB. We were able to observe abnormalities of audiometric and vestibular tests

Audiovestibular Manifestations in Systemic Vasculitis: An Update 343

Hearing loss and vertigo of probable ischemic origin have been described in **relapsing polychondritis**, an autoimmune disease that affects, unilaterally or bilaterally, the cartilage of the ear, nose and trachea. Its pathophysiology has been explained assuming the existence

Another disease involving audiovestibular manifestations and vasculitis is **Sjögren's syndrome**. This is a slowly progressing, chronic auto-immune disease, characterized by lymphocytic infiltration of exocrine glands, as well as hyper-reactivity and proliferation of B cells that end up producing xerostomia and dry eyes. It may be primary or secondary; in the latter case, it is accompanied by another auto-immune disease with systemic clinic, as occurs

Like SLE, Sjögren's syndrome also causes secondary vasculitis [46]. Sensorineural hearing loss concomitant with cardiolipinic antibodies has been described in 14 of 30 patients with Sjögren's syndrome [49]. A sudden hearing loss has also been reported as initial and

**Ankylosing spondylitis (AS)** is a chronic inflammatory disease of unknown origin affecting up to 1% of the population. To further investigate hearing loss in AS we studied a series of 50 consecutive patients that fulfilled the modified New York diagnostic criteria for AS and 44 matched controls from the Lugo region of Northwest Spain. In this study, 29 (58%) of the patients with AS showed abnormal hearing loss in the audiogram compared to only 8 (18%) of the controls. Of interest, the audiogram shape disclosed a predominant pattern of symmetrical high frequency sensorineural hearing loss in AS patients (50%). In our study, individuals with severe extraspinal manifestations had an increased risk of having hypoacusia. Furthermore, the presence of hip involvement, anterior uveitis, and HLA-B27 in patients with AS appears to be a signal for sensorineural hearing loss (SNHL) that deserves further investigation. Besides sensorineural damage, in our series middle ear dysfunction, manifested by an abnormal tympanometry, was found in 8% of patients with a flattened tracing who was considered the most specific sign of abnormal tympanometry in AS patients. This finding could be explained by an increased rigidity of the tympanossicular

Furthermore, our results confirm that the vestibule is also involve in patients with AS. Patients with AS have a marginally increased frequency of abnormal head thrust test and a significantly increased frequency of abnormal head-shaking nystagmus in oculocephalic response study (vestibule-ocular reflex) and disclosed an abnormal vestibular function in

In our series from Lugo, we also founded a significantly increased frequency of abnormal CTSIB results in AS patients (36%). In this regard, increased frequency of abnormal postural control in CTSIB test was of vestibular origin, conditions 5 and 6 of the study, that

All our findings support the presence of a peripheral vestibular lesion in patients with AS. On the other hand, although the difference did not reach statistical significance, BPPV also was found more frequently in patients than in the controls. Therefore, these studies confirm the presence of inner ear compromise and audiovestibular dysfunction in patients with AS that may be the result of vascular involvement or due to a direct immune-mediated injury of the inner ear and it could provide justification for rheumatologists or physicians to screen

correspond to a vestibular pattern of the study in patients with AS.

for inner ear compromise in their AS population. [51,52].

of a vasculitis of the labyrinthine artery and its branches [48].

in 30% of patients. It mainly affects women between 40 and 50.

exceptional presentation in a case of Sjögren's syndrome [50].

system.

caloric testing (canal paresis).

supporting the presence of audiovestibular damage in limited forms of SSc. We also examined the influence of disease duration on the development of audiovestibular abnormalities; however, we found no association between disease duration and the development of abnormalities of audiometric, vestibular, or postural tests. Nevertheless, we found a significantly increased frequency of patients with abnormal hearing loss in the audiogram (77%). Of interest, a high frequency loss in the audiogram was common in our series; the typical pattern of hearing impairment in our patients with limited SSc was a bilateral and symmetrical sensorineural hearing loss with a flat curve in the audiogram. Vasculitis leading to focal strial atrophy or malfunction of the hair cells of the organ of Corti, or both, has been proposed as responsible for sensorineural hearing loss in SSc. Besides sensorineural damage, we also found middle ear dysfunction, manifested by a flattened tracing in tympanometry in 20% of the patients with limited SSc, due to myringosclerosis confirmed by otomycroscopic examination.

Furthermore, our results confirm that the vestibule is also involved in SSc, even in limited forms of the disease. Patients with limited SSc had a significantly increased frequency of abnormal oculo-cephalic response or head thrust test (29%) and head-shaking nystagmus (26%), and a higher frequency of 3 or more abnormal positions when positional nystagmus was assessed by means of videonystagmography and videonystagmoscopy goggles [44]. The static postural study also yielded a significantly increased frequency of abnormal clinical test of sensory interaction and balance (CTSIB) in limited and diffuse SSc patients (46%) compared with controls (12%). Interestingly, vestibular loss was the main pattern of abnormal CTSIB in our patients. All these findings support the presence of a peripheral vestibular lesion, probably due to vascular involvement in patients with SSc.

In our series, almost a fifth of the patients with limited and diffuse SSc showed a benign paroxysmal positioning vertigo (BPPV) that was generally caused by the involvement of the horizontal semicircular canal (HSC). Interestingly, we observed the presence of abnormal caloric test in 43% of SSc patients with associated BPPV. These observations indicate that abnormalities found in our patients with SSc are not the result of an injury in a single semicircular canal of the inner ear. They also suggest that vascular disease in the setting of this connective tissue disease may be responsible for these findings, supporting an ischemic cause as responsible for the functional damage. However, an alternative cause for BPPV could be related to a possible intralabyrinthine autoimmune process [45].

In summary, we have described hearing and vestibular dysfunctions, as well as an abnormal postural control of static balance in systemic sclerosis, both in limited and in diffuse forms. The etiology is probably vasculitic, although a direct autoimmune mechanism in the inner ear cannot be ruled out. In this patient group studied, we highlight symmetrical and bilateral sensorineural hearing loss, vestibular hypofunction on caloric testing and an abnormal response in head shaking nystagmus test and oculocephalic maneuver (head thrust test), all these findings are typically related with peripheral vestibular dysfunction. Furthermore, we also describe a close association with benign paroxysmal positional vertigo (BPPV), predominantly of the horizontal canal [44,45].

**Systemic lupus erythematosus (SLE)** is the prototype of autoimmune disease, which primarily affects women between 15 and 50 and also causes secondary vasculitis [46]. Sensorineural hearing loss has been observed with relative frequency in this group of patients with SLE, and both autoimmune and vasculitic mechanisms have been involved in its pathogenesis [47].

supporting the presence of audiovestibular damage in limited forms of SSc. We also examined the influence of disease duration on the development of audiovestibular abnormalities; however, we found no association between disease duration and the development of abnormalities of audiometric, vestibular, or postural tests. Nevertheless, we found a significantly increased frequency of patients with abnormal hearing loss in the audiogram (77%). Of interest, a high frequency loss in the audiogram was common in our series; the typical pattern of hearing impairment in our patients with limited SSc was a bilateral and symmetrical sensorineural hearing loss with a flat curve in the audiogram. Vasculitis leading to focal strial atrophy or malfunction of the hair cells of the organ of Corti, or both, has been proposed as responsible for sensorineural hearing loss in SSc. Besides sensorineural damage, we also found middle ear dysfunction, manifested by a flattened tracing in tympanometry in 20% of the patients with limited SSc, due to

Furthermore, our results confirm that the vestibule is also involved in SSc, even in limited forms of the disease. Patients with limited SSc had a significantly increased frequency of abnormal oculo-cephalic response or head thrust test (29%) and head-shaking nystagmus (26%), and a higher frequency of 3 or more abnormal positions when positional nystagmus was assessed by means of videonystagmography and videonystagmoscopy goggles [44]. The static postural study also yielded a significantly increased frequency of abnormal clinical test of sensory interaction and balance (CTSIB) in limited and diffuse SSc patients (46%) compared with controls (12%). Interestingly, vestibular loss was the main pattern of abnormal CTSIB in our patients. All these findings support the presence of a peripheral

In our series, almost a fifth of the patients with limited and diffuse SSc showed a benign paroxysmal positioning vertigo (BPPV) that was generally caused by the involvement of the horizontal semicircular canal (HSC). Interestingly, we observed the presence of abnormal caloric test in 43% of SSc patients with associated BPPV. These observations indicate that abnormalities found in our patients with SSc are not the result of an injury in a single semicircular canal of the inner ear. They also suggest that vascular disease in the setting of this connective tissue disease may be responsible for these findings, supporting an ischemic cause as responsible for the functional damage. However, an alternative cause for BPPV

In summary, we have described hearing and vestibular dysfunctions, as well as an abnormal postural control of static balance in systemic sclerosis, both in limited and in diffuse forms. The etiology is probably vasculitic, although a direct autoimmune mechanism in the inner ear cannot be ruled out. In this patient group studied, we highlight symmetrical and bilateral sensorineural hearing loss, vestibular hypofunction on caloric testing and an abnormal response in head shaking nystagmus test and oculocephalic maneuver (head thrust test), all these findings are typically related with peripheral vestibular dysfunction. Furthermore, we also describe a close association with benign paroxysmal positional vertigo

**Systemic lupus erythematosus (SLE)** is the prototype of autoimmune disease, which primarily affects women between 15 and 50 and also causes secondary vasculitis [46]. Sensorineural hearing loss has been observed with relative frequency in this group of patients with SLE, and both autoimmune and vasculitic mechanisms have been involved in

myringosclerosis confirmed by otomycroscopic examination.

vestibular lesion, probably due to vascular involvement in patients with SSc.

could be related to a possible intralabyrinthine autoimmune process [45].

(BPPV), predominantly of the horizontal canal [44,45].

its pathogenesis [47].

Hearing loss and vertigo of probable ischemic origin have been described in **relapsing polychondritis**, an autoimmune disease that affects, unilaterally or bilaterally, the cartilage of the ear, nose and trachea. Its pathophysiology has been explained assuming the existence of a vasculitis of the labyrinthine artery and its branches [48].

Another disease involving audiovestibular manifestations and vasculitis is **Sjögren's syndrome**. This is a slowly progressing, chronic auto-immune disease, characterized by lymphocytic infiltration of exocrine glands, as well as hyper-reactivity and proliferation of B cells that end up producing xerostomia and dry eyes. It may be primary or secondary; in the latter case, it is accompanied by another auto-immune disease with systemic clinic, as occurs in 30% of patients. It mainly affects women between 40 and 50.

Like SLE, Sjögren's syndrome also causes secondary vasculitis [46]. Sensorineural hearing loss concomitant with cardiolipinic antibodies has been described in 14 of 30 patients with Sjögren's syndrome [49]. A sudden hearing loss has also been reported as initial and exceptional presentation in a case of Sjögren's syndrome [50].