**2. ANCA-associated vasculitis**

#### **2.1. Cryoglobulinaemic vasculitis**

Cryoglobulinaemia refers to circulating cryoglobulins. Cryoglobulins are immunoglobulins, which precipitate in temperatures below 37o C and dissolve upon rewarming [2]. Cryoglobu‐ linaemia is classified in 3 types based on clonality and immunoglobulin class. In particular, type I consists of monoclonal IgM or IgG immunoglobulin, type II is a mixture of monoclo‐ nal IgM and polyclonal IgG, while type III is a mixture of polyclonal IgM and IgG. Type II and III are also called "mixed", since both contain a mixture of IgM and IgG immunoglobu‐ lins [3]. The IgM component of type II cryoglobulins has rheumatoid factor activity (can bind to the Fc portion of IgG). All 3 types of cryoglobulinaemia may or may not result from an underlying disorder. In the absence of an identifiable cause cryoglobulinaemia is charac‐ terized as "essential".

Circulating cryoglobulins induce damage through 2 mechanisms: type I monoclonal IgM cryoglobulins, due to the large size of IgM and their high concentration levels – usually as‐

© 2013 Katsiari et al.; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

sociated with Waldenström disease– result in hyperviscosity-induced vascular damage. On the other hand, type II and III mixed cryoglobulins in combination with complement com‐ ponents form immune complexes, which deposit in capillaries and small arterioles leading to vascular inflammation [3]. Patients with symptomatic mixed cryoglobulinaemic vasculitis typically display low serum levels of complement C4, reflecting complement consumption via the classical, immune complexed-mediated activation pathway. Palpable purpura repre‐ sents a typical clinical manifestation. Skin biopsy reveals small vessel leukocytoclastic vas‐ culitis namely inflammation and destruction of the vessel wall along with polymorphonuclear leukocyte nuclear debris. Involvement of internal organs, most com‐ monly peripheral nerves, kidneys and joints will dictate prognosis and treatment decisions. Clinical and laboratory features of cryoglobulinaemia are summarized in Table1.

suspicion of HCV infection is strong further examination of the cryoprecipitate, where both antibodies and RNA are concentrated, should be performed. Management of patients in this

The role of interferon alpha (INFα) in the treatment of cryoglobulinaemic vasculitis has been examined approximately 2 decades ago. In an early study, among 53 patients with HCV – related cryoglobulinaemic vasculitis, only patients who displayed a drop in the virus RNA levels showed clinical improvement. Reduction of RNA levels was restricted to patients who received INFα in addition to conventional treatment [4]. Moreover, vire‐ mia, cryoglobulinaemia and clinical symptoms returned following INFα cessation. Apart from INFα therapeutic potential, this as well as similar studies showed that clinical re‐

Addition of the broad spectrum anti-viral agent rivabirin proved to add therapeutic benefit to INFα monotherapy [5, 6]. More recently, PEGylated INFα combined with ribavirin was shown to have superior efficacy compared to non-pegylated INFα / ribavirin combination [7-9]. PEGylation is a process where polyethylene molecules (PEG) are covalently attached to, in this case, INFα producing a molecule with prolonged pharmacokinetics. A recent up‐ date of recommendations by the American Association for the Study of Liver Diseases is

180 μg PEG-INFα-2a <sup>+</sup> BW<75kg: 1000mg,

There are no definite guidelines regarding duration of treatment. Treatment of HCV infec‐ tion is recommended to last from 24 weeks (for virus genotypes 2 and 3) to 48 weeks (geno‐ types 1 and 4). The rational behind this recommendation lies on the observation that if viral response has not been achieved within this time frame, it is highly unlikely that prolonga‐ tion of treatment will lead to substantial and sustained viral response [10]. However, in the case of cryoglobulinaemic vasculitis accompanying HCV infection, a less strict approach is endorsed, where besides viral levels, clinical and immunologic features are also taken into account [7, 11]. Prolongation of antiviral therapies may be appropriate in a subset of patients

or

Ribavirin (orally per day)

Treatment of ANCA-Negative Small Vessel Vasculitis

http://dx.doi.org/10.5772/54272

219

BW"/>75kg: 1200mg

BW<65kg: 800mg, BW=65-85kg: 1000mg, BW=85-105kg: 1200mg BW"/>105kg: 1400mg

category should take place in collaboration with a hepatologist

sponse parallels the levels of viremia.

INFα

(SC per week) **plus**

1 – 5 μg PEG-INFα-2b +

SC: subcutaneous, PEG-INFα: PEGylated interferon alpha, BW: body weight

who display clinical benefit and no drug intolerance [3].

**Table 2.** Antiviral combination treatment in HCV-related cryoglobulinaemic vasculitis

shown in Table 2 [10].

Treatment of mixed cryoglobulinaemic syndrome depends essentially on two parameters: First the type and severity of manifestations and second the underlying disease. It is appa‐ rent that the identification and treatment of the underlying cause is of paramount impor‐ tance. Mixed cryoglobulinaemic syndrome is typically divided as hepatitis virus C (HCV) – related or not.


**Table 1.** Clinical and laboratory characteristics of cryoglobulinaemia.

#### **2.2. Treatment of HCV related cryoglobulinaemic vasculitis**

#### *2.2.1. Aiming the virus: Treatment of chronic HCV*

The majority of cases with cryoglobulinaemia are considered to be induced by HCV. Evi‐ dence of HCV infection is usually displayed by serum antibodies against the virus or pres‐ ence of HCV-RNA. It should be noted however that false negative results do occur. If suspicion of HCV infection is strong further examination of the cryoprecipitate, where both antibodies and RNA are concentrated, should be performed. Management of patients in this category should take place in collaboration with a hepatologist

sociated with Waldenström disease– result in hyperviscosity-induced vascular damage. On the other hand, type II and III mixed cryoglobulins in combination with complement com‐ ponents form immune complexes, which deposit in capillaries and small arterioles leading to vascular inflammation [3]. Patients with symptomatic mixed cryoglobulinaemic vasculitis typically display low serum levels of complement C4, reflecting complement consumption via the classical, immune complexed-mediated activation pathway. Palpable purpura repre‐ sents a typical clinical manifestation. Skin biopsy reveals small vessel leukocytoclastic vas‐ culitis namely inflammation and destruction of the vessel wall along with polymorphonuclear leukocyte nuclear debris. Involvement of internal organs, most com‐ monly peripheral nerves, kidneys and joints will dictate prognosis and treatment decisions.

Clinical and laboratory features of cryoglobulinaemia are summarized in Table1.

related or not.

TYPE I monoclonal IgM or IgG

218 Updates in the Diagnosis and Treatment of Vasculitis

HYPER – VISCOSITY Raynaud's Digital ischemia Hyperviscosity syndrome

Waldenström Myeloma Lymphoma

**Table 1.** Clinical and laboratory characteristics of cryoglobulinaemia.

*2.2.1. Aiming the virus: Treatment of chronic HCV*

**2.2. Treatment of HCV related cryoglobulinaemic vasculitis**

Treatment of mixed cryoglobulinaemic syndrome depends essentially on two parameters: First the type and severity of manifestations and second the underlying disease. It is appa‐ rent that the identification and treatment of the underlying cause is of paramount impor‐ tance. Mixed cryoglobulinaemic syndrome is typically divided as hepatitis virus C (HCV) –

**CRYOGLOBULINAEMIA**

TYPE III polyclonal IgM + polyclonal IgG

> Autoimmune diseases Chronic Inflammatory diseases

TYPE II monoclonal IgM + polyclonal IgG

**Essential Secondary Essential Secondary Essential Secondary**

**CLINICAL SYNDROME**

The majority of cases with cryoglobulinaemia are considered to be induced by HCV. Evi‐ dence of HCV infection is usually displayed by serum antibodies against the virus or pres‐ ence of HCV-RNA. It should be noted however that false negative results do occur. If

HCV Myeloma Lymphoma Autoimmune diseases

> CRYOGLOBULINAEMIC VASCULITIS Purpura, Arthritis, Raynaud's, Renal disease, Neuropathy

The role of interferon alpha (INFα) in the treatment of cryoglobulinaemic vasculitis has been examined approximately 2 decades ago. In an early study, among 53 patients with HCV – related cryoglobulinaemic vasculitis, only patients who displayed a drop in the virus RNA levels showed clinical improvement. Reduction of RNA levels was restricted to patients who received INFα in addition to conventional treatment [4]. Moreover, vire‐ mia, cryoglobulinaemia and clinical symptoms returned following INFα cessation. Apart from INFα therapeutic potential, this as well as similar studies showed that clinical re‐ sponse parallels the levels of viremia.

Addition of the broad spectrum anti-viral agent rivabirin proved to add therapeutic benefit to INFα monotherapy [5, 6]. More recently, PEGylated INFα combined with ribavirin was shown to have superior efficacy compared to non-pegylated INFα / ribavirin combination [7-9]. PEGylation is a process where polyethylene molecules (PEG) are covalently attached to, in this case, INFα producing a molecule with prolonged pharmacokinetics. A recent up‐ date of recommendations by the American Association for the Study of Liver Diseases is shown in Table 2 [10].


SC: subcutaneous, PEG-INFα: PEGylated interferon alpha, BW: body weight

**Table 2.** Antiviral combination treatment in HCV-related cryoglobulinaemic vasculitis

There are no definite guidelines regarding duration of treatment. Treatment of HCV infec‐ tion is recommended to last from 24 weeks (for virus genotypes 2 and 3) to 48 weeks (geno‐ types 1 and 4). The rational behind this recommendation lies on the observation that if viral response has not been achieved within this time frame, it is highly unlikely that prolonga‐ tion of treatment will lead to substantial and sustained viral response [10]. However, in the case of cryoglobulinaemic vasculitis accompanying HCV infection, a less strict approach is endorsed, where besides viral levels, clinical and immunologic features are also taken into account [7, 11]. Prolongation of antiviral therapies may be appropriate in a subset of patients who display clinical benefit and no drug intolerance [3].

#### *2.2.2. Downregulation of cryoglobulins: Rituximab*

Although many patients achieve virological response using INFα and ribavirin, several con‐ siderations still exist: only 50% patients carrying genotype 1, which is the most common genotype in Europe and Americas, respond. Also, pegylated form of INFα as well as ribavir‐ in are contraindicated in patients with compromised renal function, which may prove puz‐ zling when treating patients with severe renal involvement.

have not been assessed in controlled clinical trials. Consequently, therapeutic decisions are usually taken on an individual basis according to clinical response, personal history, comor‐

Antiviral treatment is usually avoided until acute flare has been controlled [21, 22]. Exac‐ erbation of the underlying vasculitis due to INFα and restrictions regarding ribavirin ad‐ ministration in patients with impaired renal function remain the main considerations. The same may apply to rituximab where monotherapy rather than combination with an‐ tiviral therapy is recommended by some authorities during the treatment of a severe dis‐ ease [23]. Following remission of severe inflammatory phenomena, antiviral treatment

**Mild-to-moderate disease.** Manifestations, such as purpura, arthralgias/arthritis, mild pro‐ teinuria/hematuria with normal serum creatinine or peripheral sensory neuropathy repre‐ sent mild-to-moderate disease activity. In cases of HCV-related disease, viral clearance with

Low-dose corticosteroids (<7.5–10 mg/day) can be administered for more efficient control of symptoms (arthritis/arthralgias, persisting purpura, etc.). Sequential or simultaneous ad‐ ministration [16, 24] of corticosteroids with IFNα did not influence the sustained virological response in treated patients. Nevertheless, whenever possible it is prudent to avoid cortico‐ steroids during the initial course of antiviral therapy. Quick tapering of corticosteroids is al‐ so advised since long-term administration does not seem to grant a favorable effect on

The use of immunosuppression in cyoglobulinaemic vasculitis is summarized in Table 3.

**Drug Dosage Comments**

(CyP) for 3-6 pulses Oral CyP (2 mg/Kg/day) can be used

Rituximab IV 375 mg/m2/week for 4 pulses In intolerance to CyP and in young patients

Mycophenolate Mofetil 2 g/day In patients with moderate renal involvement

IV methylprednisolone 500-1,000 mg/day for 3 successive days in critical organ manifestations

Treatment of ANCA-Negative Small Vessel Vasculitis

http://dx.doi.org/10.5772/54272

221

with severe disease

who cannot take CyP

weeks In critical organ manifestations

mg/day at 3 months

combination therapy as described above is the initial treatment of choice.

Prednisolone 60 mg/day for 1 month tapered to 15

Azathioprin 2 mg /kg/ day

**Table 3.** Immunosuppressive treatment for cryoglobulinaemic vasculitis

Plasmapheresis three times weekly for two to three

bidity as well as the centre's experience to treat such patients.

should be administered.

Cyclophosphamide

vasculitis, while can harm the liver function.

Rituximab is an anti-CD20 chimeric monoclonal antibody, which results in prompt deple‐ tion of circulating and tissue B cells. Cryoglobulins are produced by B cells. Hence, B-cell depleting biological therapy using Rituximab, holds theoretical promise of down-regulating the production and circulating levels of cryoglobulins. Following few cohort studies with promising results [12-16], a prospective randomized controlled trial to examine the role of rituximab in the treatment of patients non-responding to antiviral therapy has only recently been presented [17]. Twenty-four non-responders were included and followed for 12 months. Twelve patients were managed according to conventional strategies (maintain or increase immunosuppression) and twelve received rituximab (as administered in vasculitis: 375mg/m2 every week for 4 weeks). Following 6 months, 10 patients (83%) receiving rituxi‐ mab achieved remission compared to 1 patient (8%) in the control group. At this point it ap‐ pears that rituximab could be used in patients who did not respond to conventional treatment. In addition there is no restriction regarding renal function. However, the risk of serious infection remains an important consideration. Of note, in patients with high concen‐ trations of IgM-k cryoglobulins with rheumatoid factor activity, complex formation with rit‐ uximab can occur resulting in severe systemic reactions.

A significant proportion of patients treated with conventional therapy despite sustained vi‐ rological response relapsed during long-term follow-up, posing a significant question re‐ garding the role of HCV on the pathophysiology of the disease [18]. Off label experience with rituximab to date may provide relevant insight: in patients receiving rituximab, relap‐ ses did not parallel virus load but coincided with the recovery of peripheral B cells. It has been proposed that B cell proliferation and thus subsequent cryoglobulin production can be‐ come independent of HCV overtime [3].

#### *2.2.3. Vasculitis treatment: Plasmapheresis and conventional immunosuppression*

**Severe, life-threatening disease.** Plasmapheresis is reserved for patients with acute, serious, life-threatening disease such as progressive renal failure, severe neuropathy, intestinal ische‐ mia, alveolar hemorrhage and digital necrosis [19]. Removing cryoglobulins from the circu‐ lation presumably hinders immune-complex mediated vasculopathy leading to prompt improvement. However, following termination of plasma exchange a rebound overproduc‐ tion of cryoglobulins may occur. Therefore, concomitant treatment aiming to mute cryoglo‐ bulin production is required. High dose glucocorticoids in conjunction with cyclophosphamide (CyP) represent the standard therapeutic regimen. Following the para‐ digm of ANCA-associated vasculitis, azathioprine and mycophenolate mofetil (MMF) are often used for remission maintenance or in the place of CyP when the disease is less severe (doses are presented in Table 2) [20]. Duration and efficacy of such treatment modalities have not been assessed in controlled clinical trials. Consequently, therapeutic decisions are usually taken on an individual basis according to clinical response, personal history, comor‐ bidity as well as the centre's experience to treat such patients.

*2.2.2. Downregulation of cryoglobulins: Rituximab*

220 Updates in the Diagnosis and Treatment of Vasculitis

zling when treating patients with severe renal involvement.

uximab can occur resulting in severe systemic reactions.

come independent of HCV overtime [3].

Although many patients achieve virological response using INFα and ribavirin, several con‐ siderations still exist: only 50% patients carrying genotype 1, which is the most common genotype in Europe and Americas, respond. Also, pegylated form of INFα as well as ribavir‐ in are contraindicated in patients with compromised renal function, which may prove puz‐

Rituximab is an anti-CD20 chimeric monoclonal antibody, which results in prompt deple‐ tion of circulating and tissue B cells. Cryoglobulins are produced by B cells. Hence, B-cell depleting biological therapy using Rituximab, holds theoretical promise of down-regulating the production and circulating levels of cryoglobulins. Following few cohort studies with promising results [12-16], a prospective randomized controlled trial to examine the role of rituximab in the treatment of patients non-responding to antiviral therapy has only recently been presented [17]. Twenty-four non-responders were included and followed for 12 months. Twelve patients were managed according to conventional strategies (maintain or increase immunosuppression) and twelve received rituximab (as administered in vasculitis: 375mg/m2 every week for 4 weeks). Following 6 months, 10 patients (83%) receiving rituxi‐ mab achieved remission compared to 1 patient (8%) in the control group. At this point it ap‐ pears that rituximab could be used in patients who did not respond to conventional treatment. In addition there is no restriction regarding renal function. However, the risk of serious infection remains an important consideration. Of note, in patients with high concen‐ trations of IgM-k cryoglobulins with rheumatoid factor activity, complex formation with rit‐

A significant proportion of patients treated with conventional therapy despite sustained vi‐ rological response relapsed during long-term follow-up, posing a significant question re‐ garding the role of HCV on the pathophysiology of the disease [18]. Off label experience with rituximab to date may provide relevant insight: in patients receiving rituximab, relap‐ ses did not parallel virus load but coincided with the recovery of peripheral B cells. It has been proposed that B cell proliferation and thus subsequent cryoglobulin production can be‐

**Severe, life-threatening disease.** Plasmapheresis is reserved for patients with acute, serious, life-threatening disease such as progressive renal failure, severe neuropathy, intestinal ische‐ mia, alveolar hemorrhage and digital necrosis [19]. Removing cryoglobulins from the circu‐ lation presumably hinders immune-complex mediated vasculopathy leading to prompt improvement. However, following termination of plasma exchange a rebound overproduc‐ tion of cryoglobulins may occur. Therefore, concomitant treatment aiming to mute cryoglo‐ bulin production is required. High dose glucocorticoids in conjunction with cyclophosphamide (CyP) represent the standard therapeutic regimen. Following the para‐ digm of ANCA-associated vasculitis, azathioprine and mycophenolate mofetil (MMF) are often used for remission maintenance or in the place of CyP when the disease is less severe (doses are presented in Table 2) [20]. Duration and efficacy of such treatment modalities

*2.2.3. Vasculitis treatment: Plasmapheresis and conventional immunosuppression*

Antiviral treatment is usually avoided until acute flare has been controlled [21, 22]. Exac‐ erbation of the underlying vasculitis due to INFα and restrictions regarding ribavirin ad‐ ministration in patients with impaired renal function remain the main considerations. The same may apply to rituximab where monotherapy rather than combination with an‐ tiviral therapy is recommended by some authorities during the treatment of a severe dis‐ ease [23]. Following remission of severe inflammatory phenomena, antiviral treatment should be administered.

**Mild-to-moderate disease.** Manifestations, such as purpura, arthralgias/arthritis, mild pro‐ teinuria/hematuria with normal serum creatinine or peripheral sensory neuropathy repre‐ sent mild-to-moderate disease activity. In cases of HCV-related disease, viral clearance with combination therapy as described above is the initial treatment of choice.

Low-dose corticosteroids (<7.5–10 mg/day) can be administered for more efficient control of symptoms (arthritis/arthralgias, persisting purpura, etc.). Sequential or simultaneous ad‐ ministration [16, 24] of corticosteroids with IFNα did not influence the sustained virological response in treated patients. Nevertheless, whenever possible it is prudent to avoid cortico‐ steroids during the initial course of antiviral therapy. Quick tapering of corticosteroids is al‐ so advised since long-term administration does not seem to grant a favorable effect on vasculitis, while can harm the liver function.


The use of immunosuppression in cyoglobulinaemic vasculitis is summarized in Table 3.

**Table 3.** Immunosuppressive treatment for cryoglobulinaemic vasculitis

#### **2.3. Treatment of non-HCV mixed cryoglobulaenimic syndrome**

According to current EULAR recommendations, patients presenting with mixed cryoglobu‐ linaemic syndrome non-related to HCV or other disorder should be treated as patients with ANCA – associated vasculitis [8].

**3. Henoch-Schonlein Purpura**

posits with affected vessels.

ment is summarized in Table 4.

**3.1. Supportive management**

intestinal bleeding.

**3.2. Targeted treatment**

*3.2.1. Glucocorticosteroids*

susceptions and thus surgical interventions [29-31] .

renal disease is greater in adults with HSP [32]

Henoch-Schönlein purpura (HSP) is the most common vasculitis syndrome of childhood, al‐ though is also well described in adults. Clinical features include palpable non-thrombocyto‐ penic purpura, particularly over the buttocks and lower extremities, arthritis (or arthralgia) affecting primarily large joints, diffuse abdominal pain and renal involvement with micro‐ scopic or gross haematuria, and/or proteinuria. There are also reports on the involvement of other organs, including lungs, brain and testes. Generally, it is a benign disorder that fol‐

Treatment of ANCA-Negative Small Vessel Vasculitis

http://dx.doi.org/10.5772/54272

223

HSP is an immune complex-mediated small vessel vasculitis. Serologic studies document elevated levels of IgA and activation of the alternate pathway of the complement system. The characteristic histopathologic finding of HSP is leukocytoclastic vasculitis with IgA de‐

Although prognosis is excellent in children with HSP, a small minority of patients develop long-term complications, and primarily renal disease. In adults, the risk of significant renal disease is increased. Management of HSP includes supportive care to ameliorate acute symptoms, as well as targeted treatment to decrease the risk of complications (usually due to gastrointestinal complications) and to prevent chronic renal insufficiency. Targeted treat‐

Treatment of HSP is primarily supportive and includes adequate hydration and sympto‐ matic relief of pain. Edema of the lower extremities and buttocks is improved with bed rest and/or elevating the affected area. Acetaminophen and non-steroidal anti-inflamma‐ tory drugs (NSAIDs) help with mild rash and arthritis. However, NSAIDs should be used cautiously in elderly persons due to increased risk of renal impairment and gastro‐

**Oral steroids.** Oral steroids are used in patients with painful cutaneous edema, severe rash, scrotal and testicular involvement, renal involvement and abdominal pain [28]. There is some supportive evidence for the use of corticosteroids in severe abdominal pain. In a sys‐ temic review that included three randomized trials and 12 retrospective studies, predniso‐ lone at a dose of 1 mg/Kg/day for two weeks or 2 mg/Kg/day for one week may decrease the intensity and duration of abdominal pain and may decrease the frequency of bowel intus‐

Renal involvement is a common finding in HSP. Although the prognosis of HSP is excellent in children, persistent renal disease can cause long-term morbidity. This risk of significant

lows an intercurrent illness, usually an upper respiratory tract infection.

Although rare, cases associated to hepatitis B virus (HBV) have been documented. Antiviral therapy with lamivudine or entecavir has led to remission in isolated case reports. Myelo‐ proliferative diseases and most commonly B cell lymphoma may also be the cause of mixed cryoglobulinaemia. Prompt diagnosis and appropriate treatments should be applied. Among autoimmune diseases, Sjogren's syndrome and systemic lupus erythematosus most commonly are associated with cryoglobulinaemia.

#### **2.4. Special considerations**

**Patients with end Stage Renal Disease.** Patients are treated with hemodialysis or peritoneal dialysis. Survival is comparable with with that of end stage renal diseases. Kidney trans‐ plantation can be performed. High rate of relapse has been recorded (up to 70%). However, recurrent disease does not lead to graft loss and thus relapse risk does not forbid transplan‐ tation in patients with end stage renal disease. Another concern in cases of HCV-related dis‐ ease is that robust immunosuppression following transplantation may exacerbate HCV infection. Fortunately, this has proven to be the exception rather than the rule [25].

**Cancer Risk.** B-cell lymphoma has been reported in up to 25% of patients with mixed cryo‐ globulinaemic syndrome. Patients are usually diagnosed within 10 years. Low levels of gamma globulins may predate neoplastic transformation. Standard chemotherapy in combi‐ nation with rituximab is usually required. HCV infection increases the B-cell lymphoma risk by 20-30% and is associated with increased frequency of liver cancer, which is diagnosed in up to 10% of patients [26].

#### **2.5. Prognosis**

Prognosis mainly depends on whether vital organ(s) are involved.

Most studies have examined glomerulonephritis (GN) where 10-year survival rate was re‐ ported to be 30-50%. However, therapeutic progress substantially improved prognosis since 10-year survival has recently been raised to almost 80%. Male gender, HCV infection, high cryocrit, low C3 and raised serum creatinine at baseline are considered bad prognostic fac‐ tors. Intestinal ischaemia and alveolar haemorrhage have high mortality rates (>80%). In pa‐ tients with HCV infection, carriers of genotype 2 and 3 along with early virological response have the best outcome. Of interest, changes of cryocrit level do not seem to correlate with clinical activity. It would be interesting, however, to examine whether the degree of solubili‐ ty at 37°C or a decline in the temperature at which the cryoproteins precipitate might better correlate with response to treatment [27].
