Persistent mixed cryoglobulinaemia vasculitis despite hepatitis C virus eradication after interferon-free antiviral therapy

Rheumatology key message

• HCV-associated cryoglobulinaemic vasculitis may persist despite achieving a sustained virological response to interferon-free antiviral therapy.

Sir , Mixed cryoglobulinaemia vasculitis (MCV) is a systemic vasculitis of the small and medium-sized vessels caused by HCV in > 80% of cases. It is characterized by the presence of circulating cryoprecipitable immune complexes composed of polyclonal IgGs and mono- or polyclonal IgMs with RF activity. The disease expression is variable, ranging from purpura, arthralgia and asthenia to more serious lesions with neurological and renal involvement [ 1 ]. Unlike other viral-induced vasculitides in which the infectious agent cannot be eradicated, HCV RNA clearance following antiviral treatment with peginterferon (pegIFN)/ribavirin has been associated with the disappearance or at least an improvement of the clinical and laboratory manifestations of HCV-related MCV (HCV-MCV) in most cases [ 2–4 ]. New highly potent and well-tolerated direct-acting antivirals (DAAs) used in IFN-free regimens have proven to be effective in chronic hepatitis C, with sustained virological response (SVR) rates >90%; however, there are limited data on their efficacy in HCV-MCV patients [ 5 , 6 ]. This report describes the results of treatment with different all-oral DAA combinations in seven patients with HCV-MCV. The study was approved by the Institutional Ethics Committee (L. Sacco Hospital) and all the patients provided their informed consent.

Between July 2014 and June 2015 seven consecutive patients with HCV-MCV started anti-HCV treatment with new DAAs within an expanded access programme or after their approval. They were positive for HCV RNA, had cryocrit levels ⩾2%, and showed a wide range of MCV manifestations, including severe arthralgias, extensive purpura, peripheral neuropathy, skin ulcers and nephropathy. Along with the purpura, nephropathy was the most frequent manifestation, with the clinical picture of severe nephrotic syndrome and/or stages 3–4 chronic kidney disease. Liver disease was mild to moderate in all patients except one who showed cirrhosis (METAVIR fibrosis score F4). Six out of seven patients had failed sequential therapy with pegIFN/ribavirin and rituximab (four patients) or treatment with rituximab alone (two patients). Patients were treated with a variety of IFN-free DAA regimens, including ombitasvir/paritaprevir/ritonavir and dasabuvir, sofosbuvir plus ribavirin, sofosbuvir plus daclatasvir and sofosbuvir plus simeprevir, according to HCV genotypes. Treatment was given for 12 weeks in five cases and for 24 weeks in two. All patients achieved an SVR at post-treatment week 12 (confirmed at week 24 for five of them, on a longer follow-up). Serum cryoglobulins were undetectable in four patients at the end of treatment, but were raised again in three during follow-up. At post-treatment week 12, a clinical response was observed in only two patients; specifically, it was complete in patient 6 and partial in patient 4. However, 8 weeks later, patient 6 experienced a relapse of MCV despite HCV RNA being still undetectable ( Table 1 ).

Table 1

Patient characteristics and outcomes to antiviral therapy

Patient	Sex	Age	Clinical features	Metavir score	HCV genotype	Basal cryocrit (%)	DAA regimen	EOT cryocrit (%)	FU cryocrit (%)	Clinical response a
1	F	73	Arthralgias, purpura, peripheral neuropathy	F1	1b	5	3D	N	5	No
2	F	72	Nephropathy, purpura, skin ulcers	F1	1b	3	3D	3	2	No
3	F	58	Nephropathy, purpura	F4	2	5	SOF/RBV	7%	10	No
4	M	59	Nephropathy, purpura, arthralgias, peripheral neuropathy	F2	1a	2	SOF/DCV	N	N	Yes
5	M	46	Nephropathy	F1	4	3	SOF/SIM	N	2	No
6	M	54	Nephropathy, purpura	F1	2	9	SOF/RBV	N	8	No
7	M	71	Purpura, skin ulcers, peripheral neuropathy	F1	2	4	SOF/DCV	4	4	No

^a At last assessment. DDA: direct-acting antiviral; EOT: end of treatment; FU: follow-up; 3D: ombitasvir/paritaprevir/ritonavir and dasabuvir; SOF: sofosbuvir; RBV: ribavirin; DCV: daclatasvir; SIM: simeprevir; N: negative.

To our knowledge, this is the first reported series of patients with HCV-MCV showing a marked dissociation between virological and clinical responses to treatment with different IFN-free antiviral regimens. Previous studies on pegIFN/ribavirin (with or without first-generation DAAs telaprevir or boceprevir) showed that most MCV patients achieving SVR also experienced a complete and persistent clinical–immunological response [ 3 , 4 ], even in the case of severe and/or refractory disease [ 3 ], although persistent MCV was occasionally seen [ 7 , 8 ]; furthermore, they demonstrated lower SVR rates in patients with MCV than in those without [ 4 ]. Very few data are available about the efficacy and tolerability of all-oral DAA regimens in HCV-MCV patients. In a recent series of patients with HCV-MCV, treatment with sofosbuvir plus simeprevir or ribavirin resulted in an 83% SVR rate associated to improved renal function in those with glomerulonephritis and to decreased cryoglobulin levels in most cases, although resolution of MCV occurred in only a minority of patients [ 6 ]. Conversely, permanent recovery from symptoms and disappearance of serum cryoglobulins were reported in a severe HCV-MCV case treated with ombitasvir/paritaprevir/ritonavir, dasabuvir and ribavirin [ 5 ].

Our report differs from previous observations for its extraordinary 100% SVR rate, which confirmed the efficacy of IFN-free DAA regimens even in a historically difficult-to-treat population, such as HCV-MCV patients, and for its unsatisfactory 14% clinical response rate, which sharply contrasted with results from previous studies of IFN-based therapies [ 3 , 4 ]. Several hypotheses can be formulated to explain clinical non-response in most of our patients: greater severity and a more advanced stage of MCV, which may have reduced the impact of viral eradication on the disease expression or require combined therapy with DAAs and rituximab; a delayed clearance of circulating cryoglobulins compared with HCV clearance, which could require longer follow-up to better define clinical and immunological outcomes following SVR; and/or an incomplete suppression of the B cell clonal proliferation driving cryoglobulin production that may be quite independent of the viral trigger, which could suggest that the antiviral effect of new DAAs should still be combined with the antiproliferative and immunomodulatory effects of pegIFN for better outcomes.

In conclusion, SVR to IFN-free antiviral therapy in HCV-MCV patients may lead to no clinical improvement. Thus, in the era of new DAAs the optimal treatment for HCV-MCV remains to be determined.

Funding : No specific funding was received from any bodies in the public, commercial or not-for-profit sectors to carry out the work described in this manuscript.

Disclosure statement : The authors have declared no conflicts of interest.