chronic hepatitis c virus ( hcv ) infection is an important cause of chronic liver disease worldwide and a major indication for liver transplantation . despite the exciting and promising discovery of direct - acting antiviral agents , pegylated interferon alpha ( peg - ifn ) and ribavirin
numerous extrahepatic features are associated with chronic hcv infection , of which essential mixed ( type ii ) cryoglobulinaemia is well recognised .
mixed cryoglobulinaemia is a systemic vasculitis affecting small and medium - sized arteries and veins .
it is characterized by the deposition of immune complexes containing rheumatoid factor , igg , hcv rna and complement on endothelial surfaces , eliciting vascular inflammation through poorly understood mechanisms .
these signs and symptoms tend to occur in the setting of detectable circulating hcv rna levels and normally respond to therapy with peg - ifn and ribavirin .
exacerbations of vasculitic symptoms have been reported during interferon therapy , but they have almost always occurred in those with pre - existing vasculitis or cryoglobulinaemia [ 4 , 5 ] .
occurrence of de novo cryoglobulinaemic vasculitis after successful viral suppression late in the course of interferon therapy is unusual , especially with use of the pegylated form .
we report a case of severe de novo cryoglobulinaemic mononeuritis multiplex ( mnm ) that occurred during week 30 of antiviral treatment for chronic hcv infection .
cryoglobulins had been undetectable in the pre - treatment period and at the time of presentation the patient was hcv rna - negative .
a 47-year - old caucasian man was referred by his primary care physician to the hepatitis clinic at our institution following the finding of abnormal liver function tests and elevated serum ferritin .
risk factors for liver disease included a brief period of injection drug use 20 years previously .
his alcohol intake was within the national recommended limits ( 20 units / week ) and there was no prior history of neurological , psychiatric or rheumatological illness . on examination
screening blood tests showed positive serology for hcv , genotype 1a , with a viral load of 1.68  10 iu / ml ( pcr , abbott ) .
an exhaustive screen for other causes of chronic liver disease ( including hfe gene mutation analysis ) was negative and abdominal ultrasonography was unremarkable .
percutaneous liver biopsy revealed incomplete cirrhosis ( ishak fibrosis stage 5 ) , with a necroinflammatory score of 6/18 , there being no histological evidence of iron overload . in view of the advanced hepatic fibrosis , antiviral treatment
this included potential side effects such as  flu - like and neuropsychiatric symptoms , haematological side effects and the small risk of hepatic decompensation .
pre - treatment bloods tests were as follows : haemoglobin 15.3 g / dl ( 13.518 ) , white blood cells 5.5  10/l ( 4.011.0 ) , platelets 203  10/l ( 150450 ) , bilirubin 9 mol / l ( 021 ) , alanine aminotransferase ( alt ) 226 iu / l ( 041 ) , alkaline phosphatase 68 iu / l ( 40129 ) , albumin 44 g / l ( 3448 ) , inr 1.0 ( 0.81.2 ) .
rheumatoid factor was elevated at 88 iu / ml ( 014 ) and c4 complement low at 0.03
whilst anti - nuclear antibody ( ana ) had been positive on initial referral ( 1:160 titre ) , this was negative on repeat testing and cryoglobulins were undetectable . in accordance with current guidelines , antiviral treatment with peg - ifn 2a ( pegasys , roche ) 180 g weekly and weight - based ribavirin ( copegus , roche ) 1,000 mg
early virological response ( evr ; undetectable hcv rna at week 12 of treatment ) was achieved and in the initial stages antiviral treatment was well tolerated , except for mild lethargy .
the patient presented to hospital during week 30 of antiviral therapy with progressive painful bilateral foot drop of 2 weeks duration , associated with left ankle monoarthritis and weakness and sensory loss in the distribution of the left ulnar nerve . a week later the right ulnar nerve had become involved although less severely .
a clinical diagnosis of mnm was made , corroborated by compatible neurophysiology studies suggesting an asymmetrical mixed sensory and motor peripheral neuropathy .
cerebrospinal fluid analysis and magnetic resonance imaging of the spine showed no abnormality . when repeated , cryoglobulin levels were found to be significantly elevated ( 8% ) and analysis demonstrated a mixed ( type ii ) picture .
ana was again positive ( 1:160 titre ) with an elevated rheumatoid factor ( 201 iu / ml vs. 88 iu / ml at initiation of antiviral therapy ) and low c4 ( 0.03
g / l , unchanged from pre - treatment levels ) with normal c3 levels .
peg - ifn and ribavirin were discontinued immediately and oral prednisolone 40 mg daily was commenced . despite immunosuppression
the patient 's clinical state worsened over the following week with the development of cutaneous vasculitic stigmata and progressive bilateral median and common peroneal nerve palsies . in view of the progressive disease and persistence of cryoglobulinaemia
, plasma exchange was performed ( 5 sessions over 1 week ) and cylophosphamide initiated ( 150 mg / day ) .
cyclophosphamide was well tolerated and continued for 2 months before changing to azathioprine 75 mg twice daily .
prednisolone was increased to 80 mg daily and subsequently weaned progressively , aiming to taper completely over 12 months .
a slow but steady partial neurological recovery was observed in the outpatient clinic over the following 4 months , with resolution of median and common peroneal nerve palsies and improvement in the other affected areas .
given that the severe mnm occurred during the course of antiviral therapy , we deemed it appropriate to discontinue peg - ifn and ribavirin .
this was a difficult decision in view of the advanced hepatic fibrosis and encouraging initial response to treatment with achievement of evr .
however , since mnm was the more immediately life - threatening condition with progressive weakness affecting all four limbs , discontinuation of antiviral therapy was justified .
not unsurprisingly , the patient developed virological rebound in hcv rna ( 5.6  10 iu / ml ) approximately 1 month after the withdrawal of antiviral therapy and initiation of immunosuppression .
the time course of alt , hcv rna , rheumatoid factor and cryoglobulin levels in relation to antiviral treatment , the development of mnm and immunosuppression are shown in fig .
1 . unfortunately , 3 months after the onset of neurological disease the patient 's mood worsened with the development of biological features of depression .
antidepressants were commenced but his depression worsened , and regrettably the patient died following a drug overdose 10 months after the onset of mnm .
post - mortem examination indicated that the cause of death was unrelated to liver disease or cryoglobulinaemia .
we have described a patient with hcv - related cirrhosis who developed de novo cryoglobulinaemic mnm late in the course of antiviral therapy with peg - ifn and ribavirin . at the time of neurological presentation he had received 30 weeks of antiviral treatment with negative hcv rna since week 12 of therapy .
there was no prior history of vasculitis and pre - treatment testing for cryglobulins had been negative .
our case is unique as occurrence of de novo cryoglobulinaemic vasculitis after successful viral suppression late in the course of interferon therapy is most unusual .
exacerbations of vasculitic symptoms have in fact been reported during interferon therapy , but almost always occur in those with pre - existing vasculitis or cryoglobulinaemia [ 4 , 5 ] .
mnm is a well - documented complication of chronic hcv infection , normally associated with hcv viraemia , and typically responds to antiviral treatment . in our case
the temporal association ( both in terms of onset and recovery ) between neurological symptoms , cryoglobulinaemia and the use of antiviral treatment raises the intriguing possibility that mnm could have been induced by antiviral therapy .
however , it must be emphasised that at present this presumed association between peg - ifn 2a and mnm remains speculative .
the various immunomodulatory effects of interferon that may have contributed to the development of mnm include upregulation of mhc class i and downregulation of mhc class ii expression , increased cytolytic activity of natural killer cells , increased dendritic cell activation and antigen uptake and presentation from apoptotic cells and finally increased production of autoantibodies [ 7 , 8 ] .
the association between hcv and vasculitis is well established , related usually to the development of cryoglobulinaemia or , less commonly , a non - cryoglobulinaemic polyarteritis nodosa - type disease .
estimates of mixed cryoglobulinaemia prevalence in patients with hcv infection vary widely from 10 to 70% , perhaps a reflection of population selection and lead time biases .
high viral titres and the presence of type ii cryoglobulinaemia , as present in this case , increase the likelihood of clinically apparent vasculitic disease .
when present pre - treatment these diseases usually abate and improve with the initiation of peg - ifn and ribavirin and hence antivirals can be used for treatment of symptomatic cryoglobulinaemia associated with hcv infection .
however interferon therapy has also been associated with the development / exacerbation of various underlying autoimmune diseases including hcv - associated vasculitis , systemic lupus erythematosus and rheumatoid arthritis [ 11 , 12 ] .
there are also reports of the development and/or exacerbation of cryoglobulinaemic disease upon commencement of pegylated interferon therapy [ 4 , 5 ] , though these have almost always occurred in those with pre - existing vasculitis .
the time span between the initiation of interferon therapy and the development or exacerbation of vasculitis is usually short , typically within the first few doses .
de novo mnm during pegylated interferon therapy for hcv is more unusual , with only two prior published cases [ 13 , 15 ] . in the case
the patient achieved a rapid virological response ( undetectable hcv rna by week 4 of treatment ) and first presented with mnm 6 weeks into antiviral therapy .
describe a case of mnm occurring later in the course of peg - ifn treatment , with the onset of neurological symptoms at week 40 in a patient with negative hcv rna since week 24 .
similar to our case report , these two patients were also men and at least one also had advanced hepatic fibrosis . however in both cases it is unclear whether there was pre - existing cryoglobulinaemia before the initiation of antiviral therapy . in contrast , cryoglobulins were undetectable in our patient prior to therapy , though pre - treatment work - up did reveal a positive ana ( titre 1:160 ) , elevated rheumatoid factor and suppressed c4 level .
the significance of these findings in the absence of detectable cryoglobulins or clinical evidence of vasculitis is uncertain .
conceivably they could be representative of low - level cryoglobulinaemia below the threshold for detection , resulting in an increased propensity to develop a nascent autoimmune process .
when performed , nerve biopsy in patients with mixed cryoglobulinaemic mnm typically shows a perivascular lymphocytic infiltrate .
however , as indicated above , it is possible for the direct neuropathic effects of both hcv and peg - ifn to result in an ischaemic rather than vasculitic neuropathy .
our patient did not undergo nerve biopsy and it may be argued that histology is required in order to discriminate between direct ifn-induced and mixed cryoglobulinaemic neuropathies . in the case
we describe there was a significant deterioration in symptoms following withdrawal of peg - ifn and disease only stabilised and subsequently ameliorated once specific therapy for cryoglobulinaemic disease had been initiated . additionally , the clinical picture was that of mnm rather than progressive peripheral neuropathy usually associated with ifn .
we would therefore maintain that the clinical course in this case strongly favours mixed cryoglobulinaemic vasculitis over ifn-induced neuropathy .
in summary we report a patient with hcv - related cirrhosis who developed de novo mnm associated with cryoglobulinaemia during week 30 of antiviral therapy , having achieved evr . while interferon therapy is the treatment of choice for hcv - related mnm ,
exacerbations have been reported during its use . usually this has been reported in those with pre - existing cryoglobulinaemia and in the setting of detectable hcv viraemia .
the de novo development of mnm during hcv therapy with undetectable hcv rna is most unusual .
this raises the possibility that mnm could have developed as an adverse immunomodulatory effect of interferon therapy
. however it must be re - emphasized that at present this association remains speculative .
nonetheless , such patients with advanced hepatic fibrosis present a challenging dilemma as the inevitable virological rebound after discontinuation of antiviral therapy can have grave implications .
clinical trials exploring interferon - free hcv treatment regimens are ongoing and these could ease the management of such patients in the future .
 cryoglobulinaemic mononeuritis multiplex ( mnm ) is an extrahepatic manifestation of chronic hepatitis c virus ( hcv ) infection for which interferon - based antiviral therapy is currently the treatment of choice . 
 rarely mnm can be associated with hcv treatment though generally in the setting of pre - existing cryoglobulinaemia and detectable hcv viraemia . 
 we report an unusual case of de novo mnm occurring late during the course of pegylated interferon and ribavirin therapy for chronic hcv infection , following a prolonged period of viral suppression . 
 the patient had no evidence of cryoglobulinaemia prior to hcv treatment and undetectable hcv rna levels at the time of presentation with mnm . 
 the case raises the possibility that mnm could develop as an adverse immunomodulatory effect of pegylated interferon therapy . 