Treatment for hepatitis C virus‐associated cryoglobulinaemic vasculitis
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
This review aims to look at the benefits and harms of the currently available treatment options to treat the HCV‐associated cryoglobulinaemic vasculitis with active manifestations of vasculitis (cutaneous or glomerulonephritis).
Background
Description of the condition
The second most frequent chronic viral infection in the world is hepatitis C virus (HCV) infection. Its estimated prevalence is 3% globally (around 170 million cases). HCV causes chronic liver disease as well as extra‐hepatic symptoms such as lymphoproliferative disorders, kidney disease, or the most common ‐ mixed cryoglobulinaemia. HCV is characterised by two remarkable immunologic characteristics: escape of immune response in more than 80% of infected people and production of monoclonal/polyclonal rheumatoid factor in 20% to 40% (Dammacco 2000).
Immunoglobulins that precipitate at low temperature (below 4ºC) and re‐dissolve after warming to 37ºC are called cryoglobulins ("cryo" comes from the Greek word for cold). Cryoglobulins cause organ damage via two main routes: hyperviscosity syndrome and immune‐mediated mechanisms. Although plasma cryoglobulins are detected in approximately 50% of HCV‐infected patients, only 2% develop mixed cryoglobulinaemia systemic vasculitis (Charles 2009; Lauletta 2012; Saadoun 2008). This vasculitis is the manifestation of an inflammation of small and medium‐sized vessels produced by a pathogenic IgM with rheumatoid factor activity generated by an expansion of B‐cells (Dammacco 2010). The immune complexes formed precipitate mainly in the skin, joints, kidneys or peripheral nerve fibres. Disease manifestations are variable, ranging from moderate clinical symptoms (arthralgias, weakness that is nearly always present, lower limb palpable purpura, Raynaud's phenomenon, livedo reticularis, cutaneous ulcers, urticarial or oedema) or appearance of endocrinologic disorders (autoimmune thyroiditis, subclinical hypothyroidism, thyroid cancer or diabetes) to life threatening complications such as widespread vasculitis, glomerulonephritis or B‐cell lymphoma (Ferri 2004; Matignon 2009; Saadoun 2008; Sansonno 2005; Sansonno 2007).
Mixed cryoglobulinaemia is diagnosed by cryoglobulin testing, laboratory tests for evaluating visceral involvement and histopathological data to demonstrate a particular organ affection. The diagnosis requires demonstration of the presence of cryoglobulins in serum and typical organ involvement (Ramos‐Casals 2012).
The demonstration of the role of HCV as the aetiological factor in more than 90% of mixed cryoglobulinaemia patients has been critical to establish the treatment goals. Current therapeutic approaches are aimed at elimination of HCV infection, deletion of cryoglobulins and also of the B‐cell clonal expansions (Lauletta 2012).
Description of the intervention
The main alternative interventions to treat mixed cryoglobulinaemia are eradicating the HCV infection, the use of different immunosuppressive medications, or extracorporeal therapies (including plasma exchange therapy, cryofiltration or immunoadsorption apheresis) used individually or in combination (Schwartz 2013; Siami 1995; Stefanutti 2009). However, the best strategy to treat this disease is not well defined.
Antiviral therapy against HCV with the combination of interferon‐α or pegylated‐interferon‐α and ribavirin (a nucleoside antimetabolite agent) is the gold standard for the treatment of HCV infection (EASL 2011; Latt 2012). The effectiveness of this strategy is demonstrated by a complete clinical response and sustained virological response (described as undetectable HCV RNA levels for at least 6 months after cessation of therapy) in 78% of HCV‐related mixed cryoglobulinaemia patients (Cacoub 2005). If not achieved, a further therapeutic option may be the use of boceprevir and telaprevir (a new HCV genotype 1 protease inhibitors recently approved by the US Food and Drug Administration) (Liang 2013; Lok 2012; Maasoumy 2013; Myers 2012).
There are also different possibilities of immunosuppressive treatments (corticosteroids or cyclophosphamide); biological therapies such as tumour necrosis factor blockade by infliximab or etanercept (Bartolucci 2002; Chandesris 2004; Josselin 2008); anti‐interleukin‐6 therapy (Cohen 2012); interferon therapy (Kotter 2010); or rituximab (a chimeric monoclonal antibody specifically directed to CD20 antigen) (De Vita 2012; Sneller 2012). These strategies are sometimes ineffective, contraindicated, poorly tolerated, or may be associated with serious side effects (De Vita 2012). Therapeutic apheresis may be a useful option and can have immediate beneficial effects for the treatment of severe vasculitis or for clinical manifestations that are resistant to other treatments (Cacoub 2013; Pietrogrande 2011; Ramunni 2008; Schwartz 2013; Stefanutti 2009). There have been other approaches proposed for mixed cryoglobulinaemia, such as: imatinib (a tyrosine kinase inhibitor), thalidomide (an anti‐angiogenic drug), bortezomib (a proteasome inhibitor) or proleukin (IL‐2 therapy).
How the intervention might work
The principal target of any disease treatment is to remove the aetiologic factor of the disorder. As a result of this assumption, in the case of HCV‐related mixed cryoglobulinaemia, it seems that it is essential to eradicate the virus. However, the extrahepatic clinical manifestations of HCV infection can persist or relapse despite clearance of the HCV virus because they are mainly consequence of B‐cell clonal expansions that can become independent of HCV stimulation. Consequently, B‐cell clonal deletion with immunosuppression therapy may be a required step. The use of therapeutic apheresis is to remove a component of the blood which contributes to a disease state, in this case, cryoglobulins. Nevertheless, the concentration of cryoglobulin does not correlate with clinical severity or with response to therapy. Nowadays, the decision of immediate removal of cryoglobulins by plasma exchange is based on the severity of the disease manifestations, although it is unknown if it may have independent positive effects on survival.
Why it is important to do this review
Different therapeutic approaches in combination or alone have been assessed in several studies. Recent clinical research has been done on the promising role of the biological agents or the therapeutic apheresis. Mixed cryoglobulinaemia involves important use of hospital resources, it entails morbidity and it also affects the quality of life of the HCV patients. The prognosis and natural history of mixed cryoglobulinaemia are variable. It principally depends on the extent of vasculitic lesions and kidney‐associated disease. In fact, the overall five‐year survival ranges from 90% to 50% when kidneys are involved (Terrier 2013). There is presently no evidence‐based strategy to manage mixed cryoglobulinaemia.
Objectives
This review aims to look at the benefits and harms of the currently available treatment options to treat the HCV‐associated cryoglobulinaemic vasculitis with active manifestations of vasculitis (cutaneous or glomerulonephritis).
Methods
Criteria for considering studies for this review
Types of studies
All randomised controlled trials (RCTs) and quasi‐RCTs (RCTs in which allocation to treatment was obtained by alternation, use of alternate medical records, date of birth or other predictable methods) looking at interventions directed at treatment of HCV‐associated cryoglobulinaemic vasculitis with active manifestations of vasculitis (immunosuppressive medications and plasma exchange therapy) will be included. There will be no language restrictions.
Types of participants
Inclusion criteria
All patients with HCV‐associated cryoglobulinaemic vasculitis (male or female), of any age, with or without chronic kidney disease (CKD) with active manifestations of vasculitis (cutaneous, peripheral neuropathy or glomerulonephritis).
The diagnosis of active vasculitis in patients with HCV‐associated cryoglobulinaemic vasculitis could be done following these criteria (Dammacco 2010): detection of serum cryoglobulins associated with purpura, arthralgia, and weakness; anti‐HCV antibodies positivity and polymerase chain reaction‐based assay to detect HCV RNA in serum; liver biopsy showing chronic hepatitis; negativity for hepatitis B surface antigen and human immunodeficiency virus. This review will not be limited by this criteria and will accept any definition described in the study reports.
Exclusion criteria
We will exclude all studies focusing only on cryoglobulinaemic peripheral neuropathy.
Types of interventions
All possible comparisons between possible treatments will be eligible and will be analysed separately as well as in combination. These will include the following.
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Immunosuppressive medications (including rituximab, glucocorticoids, azathioprine, cyclophosphamide)
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Different drug preparations
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Different doses
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Different frequency
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Different duration
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Different routes of administration
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Monotherapy, dual therapy
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Extracorporeal therapies
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Plasma exchange therapy
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Cryofiltration or cryoglobulin apheresis
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Immunoadsorption apheresis
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Treatment for HCV (including interferon, peg‐interferon alfa‐2b, ribavirin, boceprevir, telaprevir and others).
Types of outcome measures
Primary outcomes
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Decreasing clinical manifestations (measured in different time points: 1, 6, 12 and 24 months)
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Nephropathy (serum creatinine, glomerular filtration rate, proteinuria, active urinary sediment, need of dialysis, biopsy with active glomerulonephritis)
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Skin vasculitis (number and diameter of lesions, purpura, cutaneous ulcers or others)
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Musculoskeletal symptoms (weakness (percentage of patients with complete response any time), peripheral joint arthralgias (percentage of patients with complete response any time) and peripheral neuropathies (percentage of patients with complete response any time))
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Liver involvement (serum liver enzymes; echographic, histologic hepatitis or both; hepatocellular carcinoma)
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Interstitial lung involvement characterized by subclinical alveolitis (presence of symptoms with radiologic, pulmonary function test alterations or both)
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Widespread vasculitis involving medium‐small sized arteries, capillaries and venules with multiple organ involvement: skin, kidney, lungs, central nervous system, and gastrointestinal tract (pain simulating an acute abdomen)
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Mortality.
Secondary outcomes
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Duration of the therapy (months)
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Laboratory findings (in different time points): rheumatoid factor activity (IU/mL), quantification of C3, C4 and C1q levels (mg/dL), serum levels of IgA, IgG and IgM (mg/dL), type I, II and III cryoglobulin levels (mg/L), cryocrit percentage (%), B cell clonal expansion (CD20, CD19, CD20/CD5) in circulation (%), anti‐HCV antibody titre (IU/L), serum HCV‐RNA (IU/mL), fast glycaemia, cholesterol (total, LDL, HDL), thyroid function (thyrotropin, free thyroxine and triiodothyronine)
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Adverse effects of medication including: leukopenia (leukocytes/mL), thrombocytopenia (platelets/mL), aspartate aminotransferase (IU/L), total bilirubin (mg/dL), infusion reactions (number), discontinuations of treatment due to adverse drug reactions (number), infections (pneumonia, urosepsis), change in blood pressure, cardiovascular events (angina, myocardial infarction, heart failure), gastrointestinal bleeding, haemorrhagic alveolitis.
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Antiviral therapy failure and not indicated
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B‐cell lymphoma
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Endocrinologic disorders (autoimmune thyroiditis, subclinical hypothyroidism, thyroid cancer or diabetes)
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Economic costs of treatment (including hospitalisation rate).
Search methods for identification of studies
Electronic searches
We will search the Cochrane Renal Group's Specialised Register through contact with the Trials' Search Co‐ordinator using search terms relevant to this review. The Cochrane Renal Group’s Specialised Register contains studies identified from the following sources.
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Monthly searches of the Cochrane Central Register of Controlled Trials CENTRAL
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Weekly searches of MEDLINE OVID SP
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Handsearching of renal‐related journals and the proceedings of major renal conferences
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Searching of the current year of EMBASE OVID SP
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Weekly current awareness alerts for selected renal journals
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Searches of the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov.
Studies contained in the Specialised Register are identified through search strategies for CENTRAL, MEDLINE, and EMBASE based on the scope of the Cochrane Renal Group. Details of these strategies, as well as a list of handsearched journals, conference proceedings and current awareness alerts, are available in the Specialised Register section of information about the Cochrane Renal Group.
See Appendix 1 for search terms.
Searching other resources
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Reference lists of clinical practice guidelines, review articles and relevant studies.
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Letters seeking information about unpublished or incomplete studies to investigators known to be involved in previous studies.
Data collection and analysis
Selection of studies
The search strategy described will be used to obtain titles and abstracts of studies that may be relevant to the review. The titles and abstracts will be screened independently by two authors (NM, CB), who will discard studies that are not applicable, however studies and reviews that might include relevant data or information on studies will be retained initially. Two authors (NM, CB) will independently assess retrieved abstracts and, if necessary the full text, of these studies to determine which studies satisfy the inclusion criteria.
Data extraction and management
Data extraction will be carried out independently by two authors using standard data extraction forms. Studies reported in non‐English language journals will be translated before assessment. Where more than one publication of one study exists, reports will be grouped together and the publication with the most complete data will be used in the analyses. Where relevant outcomes are only published in earlier versions these data will be used. Any discrepancy between published versions will be highlighted.
Assessment of risk of bias in included studies
The following items will be independently assessed by two authors using the risk of bias assessment tool (Higgins 2011) (see Appendix 2).
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Was there adequate sequence generation (selection bias)?
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Was allocation adequately concealed (selection bias)?
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Was knowledge of the allocated interventions adequately prevented during the study (detection bias)?
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Participants and personnel
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Outcome assessors
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Were incomplete outcome data adequately addressed (attrition bias)?
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Are reports of the study free of suggestion of selective outcome reporting (reporting bias)?
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Was the study apparently free of other problems that could put it at a risk of bias?
Measures of treatment effect
For dichotomous outcomes (mortality, adverse effects of medications, active urinary sediment, need of dialysis, antiviral therapy failure) results will be expressed as risk ratio (RR) with 95% confidence intervals (CI). Where continuous scales of measurement are used to assess the effects of treatment (serum creatinine, GFR, proteinuria, economic cost of the treatment, laboratory findings, duration of the therapy), the mean difference (MD) will be used, or the standardised mean difference (SMD) if different scales have been used. In case it is necessary to deal with change scores (decreasing global disease activity, reduction of the number or diameter of skin lesions), the statistical approach will be to include the baseline outcome measurements as a covariate in a regression model or analysis of covariance (ANCOVA) and will be included in the meta‐analysis using the generic inverse‐variance method. We will approach time to event data we will express the intervention effect as a hazard ratio using to analyse it the generic inverse variance method. For counts and rates the results of a study may be expressed as a RR and the (natural) logarithms of the rate ratios may be combined across studies using the generic inverse‐variance method (Higgins 2011).
Unit of analysis issues
Cross‐over studies will not be included. Although it is highly unlikely to find other studies with non‐standard designs, if a cluster‐RCT is included, statistical advice will be asked for determining the most appropriate method to use and if studies with multiple intervention groups are included, they will be analysed combining groups to create a single pair‐wise comparison.
Dealing with missing data
Any further information required from the original author will be requested by written correspondence (e.g. emailing corresponding author) and any relevant information obtained in this manner will be included in the review. Evaluation of important numerical data such as screened, randomised patients as well as intention‐to‐treat, as‐treated and per‐protocol population will be carefully performed. Attrition rates, for example drop‐outs, losses to follow‐up and withdrawals will be investigated. Issues of missing data and imputation methods (for example, last‐observation‐carried‐forward) will be critically appraised (Higgins 2011).
Assessment of heterogeneity
Heterogeneity will be analysed using a Chi² test on N‐1 degrees of freedom, with an alpha of 0.05 used for statistical significance and with the I² test (Higgins 2003). I² values of 25%, 50% and 75% correspond to low, medium and high levels of heterogeneity.
Assessment of reporting biases
If possible, funnel plots will be used to assess for the potential existence of small study bias (Higgins 2011).
Data synthesis
Data will be pooled using the random‐effects model but the fixed‐effect model will also be used to ensure robustness of the model chosen and susceptibility to outliers.
Subgroup analysis and investigation of heterogeneity
Subgroup analysis will be used to explore possible sources of heterogeneity (participants, interventions and study quality). Heterogeneity among participants could be related to the HCV genotype (1 or 2) and efficacy of the antiviral agents therapy for HCV (interferon, ribavirin, boceprevir, telaprevir), age, liver involvement (considering all the possible criteria being used: severe versus non‐severe liver fibrosis, i.e. F3‐F4 vs F0‐F2 in the Metavir scoring system or following a histologic criteria) or presence of chronic kidney disease. Heterogeneity in treatments could be related to prior immunosuppressive agent(s) used and the agent, previous administration of immunosuppressive drugs, concurrent use of extracorporeal therapies, the route of administration (e.g. whether oral or intravenous), the doses of drug given (if single or multiple doses) and the duration of the treatment (e.g. 1, 2, 6, 12 months). Adverse effects will be tabulated and assessed with descriptive techniques, as they are likely to be different for the various agents used. Where possible, the risk difference with 95% CI will be calculated for each adverse effect, either compared to no treatment or to another agent.
Sensitivity analysis
We will perform sensitivity analyses to explore the influence of the following factors on effect size.
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Repeating the analysis excluding unpublished studies
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Repeating the analysis taking account of risk of bias, as specified above
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Repeating the analysis excluding any very long or large studies to establish how much they dominate the results
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Repeating the analysis excluding studies using the following filters: diagnostic criteria, language of publication, source of funding (industry versus other), and country.
