Relationship Between Cryoglobulinemia-associated Nephritis and HCV Infection

Dario Roccatello; Osvaldo Giachino; Elisa Menegatti; Simone Baldovino

Disclosures

Expert Rev Clin Immunol. 2008;4(4):515-524. 

In This Article

Novel Therapeutic Strategies

A more critical aim in the development of novel therapeutic strategies is the validation of alternative treatment options to steroids administered alone or in combination with immunosuppressive drugs in the acute manifestations of cryoglobulinemia. Such alternative therapies could further prolong patient survival (which has already improved in the last decade[3]) by reducing cardiovascular risks.

Rituximab has raised the hope for a new therapeutic approach for patients with systemic signs of severe vasculitis and active nephropathy.[35,36,37,38,39,40] Rituximab is a humanized mouse monoclonal antibody directed at CD20, a B-cell-specific membrane protein with four transmembrane-spanning domains, which are members of a family that includes Fc-γR chains.

Besides publications reporting one or two cases alone, in PubMed we were able to collect reports on six cohorts involving a total of 59 patients, including 22 nephritis cases, seven of whom had post-kidney transplantation cryoglobulinemia-associated nephritis ( Table 3 ). The lymphoma protocol, consisting of four weekly infusions of 375 mg/m2, was generally used in these studies. Two additional doses at 1-month intervals were administered in Roccatello's open study.[37] No additional therapy was given in two of the studies, which included half of all the nephritis patients.[37,38]

Remission of nephritis occurred in 20 out of 22 patients. Side effects were limited in nontransplanted patients. Unexpectedly, viral load did not substantially increase. Relapses were frequent after a mean of 6 months. Relapses (usually occurring after 6-15 months) seemed to be delayed (12-36 months) in Roccatello's study using the '4-plus-2' protocol, including two more infusions in the first and the second month. The rationale of this protocol is trying to also affect, with a deeper drug-induced depletion, tissue B lymphocytes. The cost of infusions is approximately US$2500 each.

Our present experience consists of 19 patients with at least 12 months of follow-up, with HCV infection in 18 cases and severe systemic manifestations, including renal involvement (12 cases, ten with biopsy-proven diffuse membranoproliferative GN), bone marrow clonal restriction, large necrotizing skin ulcers and polyneuropathy (13 cases, extremely severe in five). All 19 patients were considered eligible for rituximab therapy because of resistance or intolerance to conventional therapy or bone marrow infiltration. The four most recent cases received rituximab as first-line therapy. Each patient received our '4-plus-2' protocol.

Both rheumatoid factor and IgM significantly decreased in the first 9 months, whereas C4 values symmetrically increased; liver enzymes remained stable. With regards to nephritic patients, a prompt and significant decrease in proteinuria was already observed in the first month. Bone marrow abnormalities reversed to normal in all four cases in whom biopsy was repeated. Constitutional symptoms, skin ulcers, purpura, arthralgia, weakness and fever disappeared or improved. Lastly, 13 patients in this cohort had severe polyneuropathy. Previous treatments included corticosteroids in 11 patients: immunosuppressants, plasma exchange and interferon in four, three and four patients, respectively. Paresthesias were present in 11 patients, while six complained of burning feet. Muscle asthenia was present in 12 patients. After treatment, only six patients still had paresthesias, two had burning feet and two had asthenia. One patient was unable to walk when he came to our observation. He recovered after the third infusion. Both sensory-nerve conduction velocity and amplitude sensory-nerve action potential improved.

No acute or delayed side effects were observed and, most interestingly, with only two exceptions, HCV viral load remained stable or actually even decreased.

The selective depletion of IgM-producing B cells represents a basis for rituximab treatment in MC. Indeed, in addition to the classic pathogenetic pathway of glomerular deposition of megacomplexes composed of HCV antigens, IgG anti-HCV and IgMκ rheumatoid factor,[1] it has been suggested that the IgMκ produced by a permanent clone of B cells might share a strong affinity for the glomerular matrix and, thus, deposit in the glomerulus together with the IgG anti-HCV that was previously bound in circulation or subsequently fixed through an in situ binding mechanism.[7] MC-associated nephritis represents a unique condition of an immune-mediated disorder in which rituximab might also target the nephrotoxic immunoglobulin-producing cells.

In conclusion, rituximab appears to be a safe and effective therapeutic option in symptomatic patients with HCV-associated MC, with GN and/or severe vasculitis affecting the skin and the PNS. These are potentially disabling manifestations and their typical clinical course is characterized by frequent flare-ups requiring iterative interventions. These patients are at a high risk of both cumulative toxicity from current treatments and also of increasing the damage caused by active disease.

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