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Treatment for hepatitis C virus‐associated mixed cryoglobulinaemia

Overview of attention for article published in Cochrane database of systematic reviews, May 2018
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Treatment for hepatitis C virus‐associated mixed cryoglobulinaemia
Published in
Cochrane database of systematic reviews, May 2018
DOI 10.1002/14651858.cd011403.pub2
Pubmed ID

Nuria Montero, Alexandre Favà, Eva Rodriguez, Clara Barrios, Josep M Cruzado, Julio Pascual, Maria Jose Soler


Hepatitis C virus (HCV)-associated mixed cryoglobulinaemia 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. The immune complexes formed precipitate mainly in the skin, joints, kidneys or peripheral nerve fibres. Current therapeutic approaches are aimed at elimination of HCV infection, removal of cryoglobulins and also of the B-cell clonal expansions. The optimal treatment for it has not been established. This review aims to look at the benefits and harms of the currently available treatment options to treat the HCV-associated mixed cryoglobulinaemia with active manifestations of vasculitis (cutaneous or glomerulonephritis). We searched the Cochrane Kidney and Transplant Specialised Register to 30 November 2017 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov. All randomised controlled trials (RCTs) and quasi-RCTs looking at interventions directed at treatment of HCV-associated cryoglobulinaemic vasculitis (immunosuppressive medications and plasma exchange therapy) have been included. Two authors independently assessed the retrieved titles and abstracts. Authors of included studies were contacted to obtain missing information. Statistical analyses were performed using random effects models and results expressed as risk ratio (RR) or mean difference (MD) with 95% confidence interval (CI). The planned primary outcomes were kidney disease, skin vasculitis, musculoskeletal symptoms, peripheral joint arthralgia, peripheral neuropathies, liver involvement, interstitial lung involvement, widespread vasculitis and death. Other planned outcomes were: therapy duration, laboratory findings, adverse effects, antiviral therapy failure, B-cell lymphoma, endocrine disorders and costs of treatment. Ten studies were included in the review (394 participants). None of them evaluated direct-acting antivirals. Seven studies were single-centre studies and three were multicentre. The duration of the studies varied from six to 36 months. The risk of bias was generally unclear or low. Three different interventions were examined: use of rituximab (3 studies, 118 participants); interferon (IFN) (IFN compared to other strategies (5 studies, 223 participants); six IFN months versus one year (1 study, 36 participants), and immunoadsorption apheresis versus only immunosuppressive therapy (1 study, 17 participants).The use of rituximab may slightly improve skin vasculitis (2 studies, 78 participants: RR 0.57, 95% CI 0.28 to 1.16; moderate certainty evidence) and made little of no difference to kidney disease (moderate certainty evidence). In terms of laboratory data, the effect of rituximab was uncertain for cryocrit (MD -2.01%, 95% CI -10.29% to 6.27%, low certainty evidence) and HCV replication. Rituximab may slightly increase infusion reactions compared to immunosuppressive medication (3 studies, 118 participants: RR 4.33, 95%CI 0.76 to 24.75, moderate certainty evidence) however discontinuations of the treatment due to adverse reactions were similar (3 studies, 118 participants: RR 0.97, 95% CI 0.22 to 4.36, moderate certainty evidence).Effects of lFN on clinical symptoms were evaluated only in narrative results. When laboratory parameters were assessed, IFN made little or no difference in levels of alanine transaminase (ALT) at six months (2 studies, 39 participants: MD -5.89 UI/L, 95%CI -55.77 to 43.99); rheumatoid factor activity at six months (1 study, 13 participants: MD 97.00 UI/mL, 95%CI -187.37 to 381.37), or C4 levels at 18 months (2 studies, 49 participants: MD -0.04 mg/dL, 95%CI -2.74 to 2.67). On the other hand, at 18 months IFN may probably decrease ALT (2 studies, 39 participants: MD -28.28 UI/L, 95%CI -48.03 to -8.54) and Ig M (-595.75 mg/dL, 95%CI -877.2 to -314.3), but all with low certainty evidence. One study reported infusion reactions may be higher in IFN group compared to immunosuppressive therapy (RR 27.82, 95%CI 1.72 to 449.18), and IFN may lead to higher discontinuations of the treatment due to adverse reactions (4 studies, 148 participants: RR 2.32, 95%CI 0.91 to 5.90) with low certainty evidence. Interferon therapy probably improved skin vasculitis (3 studies, 95 participants: RR 0.60, 95% CI 0.36 to 1.00) and proteinuria (2 studies, 49 participants: MD -1.98 g/24 h, 95% CI -2.89 to -1.07), without changing serum creatinine at 18 months (2 studies, 49 participants: MD -30.32 μmol/L, 95%CI -80.59 to 19.95).Six months versus one year treatment with IFN resulted in differences terms of the maintenance of the response, 89% of patients in the six months group presented a relapse and only 11% maintained a long-term response at one year, while in the one year group only 78% relapsed and long-term response was observed in 22%. The one-year therapy was linked to a higher number of side-effects (severe enough to cause the discontinuation of treatment in two cases) than the six-month schedule.One study reported immunoadsorption apheresis had uncertain effects on skin vasculitis (RR 0.44, 95% CI 0.05 to 4.02), peripheral neuropathies (RR 2.70, 95%CI 0.13 to 58.24), and peripheral joint arthralgia (RR 2.70, 95%CI 0.13 to 58.24), cryocrit (MD 0.01%, 95%CI -1.86 to 1.88) at six months, and no infusion reactions were reported. However when clinical scores were evaluated, they reported changes were more favourable in immunoadsorption apheresis with higher remission of severe clinical complications (80% versus 33%, P = 0.05) compared to immunosuppressive treatment alone.In terms of death, it was not possible to present a pooled intervention effect estimate because most of the studies reported no deaths, or did not report death as an outcome. To treat HCV-associated mixed cryoglobulinaemia, it may be beneficial to eliminate HCV infection by using antiviral treatment and to stop the immune response by using rituximab. For skin vasculitis and for some laboratory findings, it may be appropriate to combine antiviral treatment with deletion of B-cell clonal expansions by using of rituximab. The applicability of evidence reviewed here is limited by the absence of any studies with direct-acting antivirals, which are urgently needed to guide therapy.

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Mendeley readers

Mendeley readers

The data shown below were compiled from readership statistics for 239 Mendeley readers of this research output. Click here to see the associated Mendeley record.

Geographical breakdown

Country Count As %
Unknown 239 100%

Demographic breakdown

Readers by professional status Count As %
Student > Master 32 13%
Student > Bachelor 30 13%
Student > Postgraduate 19 8%
Researcher 17 7%
Student > Ph. D. Student 17 7%
Other 36 15%
Unknown 88 37%
Readers by discipline Count As %
Medicine and Dentistry 66 28%
Nursing and Health Professions 17 7%
Biochemistry, Genetics and Molecular Biology 9 4%
Psychology 7 3%
Pharmacology, Toxicology and Pharmaceutical Science 7 3%
Other 28 12%
Unknown 105 44%
Attention Score in Context

Attention Score in Context

This research output has an Altmetric Attention Score of 14. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 30 July 2019.
All research outputs
of 25,461,852 outputs
Outputs from Cochrane database of systematic reviews
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Outputs of similar age
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Outputs of similar age from Cochrane database of systematic reviews
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Altmetric has tracked 25,461,852 research outputs across all sources so far. Compared to these this one has done well and is in the 89th percentile: it's in the top 25% of all research outputs ever tracked by Altmetric.
So far Altmetric has tracked 12,090 research outputs from this source. They typically receive a lot more attention than average, with a mean Attention Score of 38.2. This one has gotten more attention than average, scoring higher than 58% of its peers.
Older research outputs will score higher simply because they've had more time to accumulate mentions. To account for age we can compare this Altmetric Attention Score to the 341,735 tracked outputs that were published within six weeks on either side of this one in any source. This one has done well, scoring higher than 84% of its contemporaries.
We're also able to compare this research output to 151 others from the same source and published within six weeks on either side of this one. This one is in the 35th percentile – i.e., 35% of its contemporaries scored the same or lower than it.