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Rheumatology Advance Access originally published online on January 17, 2006
Rheumatology 2006 45(7):842-846; doi:10.1093/rheumatology/kel004
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© The Author 2006. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Rituximab treatment for glomerulonephritis in HCV-associated mixed cryoglobulinaemia: efficacy and safety in the absence of steroids

L. Quartuccio, G. Soardo1, G. Romano, F. Zaja2, C. A. Scott3, G. De Marchi, M. Fabris, G. Ferraccioli4 and S. De Vita

Rheumatology Clinic, DPMSC, 1 Internal Medical Clinic, DPMSC, 2 Hematology Clinic, DPMSC, 3 Institute of Pathology, DRMM, University of Udine, and 4 Rheumatology Clinic, Catholic University of Sacred Heart, Rome, Italy.

Correspondence to: S. De Vita, Rheumatology Clinic, University of Udine, Piazzale Santa Maria della Misericordia 1, 33100 Udine, Italy. E-mail: salvatore.devita{at}med.uniud.it


   Abstract
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 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Objective. Rituximab, an anti-CD20 monoclonal antibody, has been used in lupus nephritis and membranous idiopathic nephropathy and has proved effective in non-renal manifestations of type II mixed cryoglobulinaemia (MC) syndrome. We investigated the possible efficacy and safety of rituximab in the treatment of cryoglobulinaemic nephritis.

Methods. Five patients with active, biopsy-proven, glomerulonephritis in hepatitis C virus (HCV)-related type II MC syndrome were treated with four weekly infusions of rituximab (375 mg/m2) in monotherapy, without steroids whenever possible. Rituximab was the first-line therapy in three cases.

Results. A rapid and sustained renal response was observed in all patients, in one of them without retreatment up to the last follow-up (month 21+). Renal biopsy was repeated after 6 months in one patient and histopathological improvement was documented. Three patients relapsed, at months +5, +7 and +12 of follow-up, respectively. Two of them were then retreated with rituximab and again presented a rapid improvement in renal function. Maintenance therapy with rituximab was performed in two patients: nephritis remission was maintained in both. Fc-{gamma} receptor 3a (Fc{gamma}RIIIa) genotype characterization was consistent with the clinical response observed. Rituximab also proved effective against other active MC manifestations, when present. No major side-effects occurred and steroids were not required in the follow-up.

Conclusions. Rituximab may provide effective and safe therapy in type II MC-related glomerulonephritis, possibly as first-line therapy, avoiding steroids and hazardous immunosuppressive treatment.

KEY WORDS: Cryoglobulinaemia, Nephritis, Rituximab, Steroid


   Introduction
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 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Type II mixed cryoglobulinaemia (MC) syndrome is a systemic vasculitis mainly linked to immune complex deposition in several organs and to hepatitis C virus (HCV) infection [1, 2]. Therapeutic strategies can target either the viral trigger HCV, if present, or pathogenic events downstream from the triggering infection, e.g. the proliferating B cells directly [3].

Cryoglobulinaemic glomerulonephritis leads to decreased survival in MC syndrome [4]. Severity of renal disease, treatment failure, side-effects or contraindications may limit the use of the antiviral approach as a first-line therapy [5]. On the other hand, current immunosuppressive approaches may prove ineffective or poorly tolerated as well. High-dose or prolonged corticosteroid treatment greatly increases morbidity. Thus, a more effective and safer approach is often required for MC nephritis.

Rituximab selectively targets the B-cell compartment, including rheumatoid factor (RF)-positive B cells [6–8]. It has been successfully used in non-renal manifestations of MC syndrome [7, 8], in systemic lupus erythematosus (SLE) nephritis [9] and in membranous idiopathic nephropathy [10]. Here we describe the efficacy and safety of rituximab in five consecutive unselected patients with MC syndrome and active glomerulonephritis. With respect to previous preliminary reports (12 cases in total) [7, 8, 11–14], novel data are provided concerning the efficacy of rituximab without concomitant corticosteroid treatment, the use of rituximab as first-line therapy, the possible long-term response to rituximab and maintenance therapy with this drug, the efficacy of retreatment, and the association between the Fc-{gamma} receptor 3a (Fc{gamma}RIIIa) (CD16) polymorphism and drug efficacy [15]. Morphological and immunological evidence of rituximab-mediated effects on the damaged renal tissue is also provided for the first time.


   Methods
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 Abstract
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 Methods
Results
 Discussion
 References
 
Five consecutive unselected patients with type II MC glomerulonephritis were treated with four weekly infusions of rituximab at the dose of 375 mg/m2. The initial response of patient 3 has been reported previously [7]. Data on the patients are reported in detail in Table 1.


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  		TABLE 1. Characteristics of the patients at baseline

 
Renal biopsy was performed in four of five patients 2 weeks before rituximab treatment. Patient 1 could not undergo a planned renal biopsy because of severe thrombocytopenia not sufficiently corrected with platelet infusion. In patient 3, renal biopsy was repeated 6 months (month +6) after the beginning of rituximab therapy (Fig. 1). All patients had active nephritis. Patients 3, 4 and 5 had been followed previously at other centres, with no treatment given, and rituximab was used as first-line therapy (Table 1). Concomitant manifestations related to MC syndrome were recorded (Table 1).


Figure 1
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  		FIG. 1. (a) Pretreatment biopsy from patient 3 showing diffuse and global thickening of capillary walls with mesangial interposition. Glomerular cellularity was increased due to the mesangial component and a monocytic intracapillary infiltrate; Acid Fuchsin orange stain (AFOG)-positive deposits and a few capillary thrombi were evident. (AFOG, 40x). (b) Repeat biopsy with glomerulus in the same patient at month +6 showing increased mesangial cellularity and matrix; capillary walls are thickened or collapsed (AFOG, 40x). (c) IgM fluorescence on the pretreatment biopsy showing mesangial and capillary wall deposits and capillary thrombi (40x). (d) IgM fluorescence in month +6 biopsy showing reduced deposits and no thrombi (40x).

 
Fc{gamma}RIIIa genotypes were determined in all the patients using the polymerase chain reaction according to published methods (Table 1) [15].

The study was approved by the local institutional review board. All patients provided written informed consent prior to their participation, after adequate explanation of the aims, methods, anticipated benefits and potential hazards of the study.


   Results
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 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
Response to treatment
A rapid decrease in proteinuria was observed in all cases after the first rituximab cycle, from a mean (±S.D.) of 1747.0±1267.3 mg/24 h at baseline to a mean of 500.2±729.5 at month +2. Renal function improved in 3/3 cases with decreased glomerular filtration rate at baseline: serum creatinine values and glomerular filtration rate (corrected for age and sex according to the algorithm of D.W. Cockcroft and M.H. Gault [16]) normalized in two patients at month +2 and in the third at month +6 (Table 2).


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  		TABLE 2. Laboratory features of the patients during the follow-up

 
Duration of response
In patient 1, remission of nephritis was sustained, persisting up to the last follow-up without any rituximab retreatment or maintenance therapy. Relapse was observed in three patients (patient 3, 4 and 5) at months +7, +12 and +5, respectively. At this time, an increase in proteinuria in 3/3 (proteinuria of 500, 557 and 2200 mg/24h in patients 3, 4 and 5, respectively) was noted; urinary sediment became active in 1/3 (patient 4) and there was microhaematuria in 2/3 (patients 3 and 5). A transient increase in the creatinine level due to decompensated cirrhosis appeared in patient 2 at month +6; this responded to rehydration. Patient 2 then underwent maintenance therapy with rituximab from month +6, when nephritis was still in remission.

Treatment of relapse
A second full cycle of rituximab (375 mg/m2 every week, four times) was administered to patients 3 and 5 at the time of renal relapse. Renal function improved in both patients 1 month after retreatment. Nephritis was still in remission at month +24 after retreatment (last follow-up) in patient 3 (Table 2); patient 5 underwent maintenance treatment with rituximab.

Maintenance treatment
Patient 2, suffering from decompensated liver cirrhosis, underwent two additional cycles of rituximab (375 mg/m2, four times) as maintenance therapy and no renal relapse occurred, the first cycle at month +6 and the second cycle at month +12. A transient increase in serum creatinine levels was noted at months +6 and +9 (Table 2), but this was due to hypovolaemic state and rapidly returned to previous levels with rehydration. This patient was then followed at another centre and underwent liver transplantation at month +13.

Maintenance therapy with rituximab was also administered to patient 5, starting 4 months after retreatment, due to renal relapse. One rituximab infusion (375 mg/m2) was given three times at intervals of 2 months. Nephritis is currently in remission 1 month after the last maintenance infusion.

Steroid-sparing effects
No patient had been treated with corticosteroids before rituximab, and corticosteroids were avoided as concomitant therapy with rituximab if possible. Only patient 3 needed low doses of steroids (6-methylprednisolone at 4–6 mg/day) 18 months after the first rituximab cycle for persistent arthralgias. Steroids were not required in all the remaining cases up to the last follow-up.

Side-effects
No acute or delayed severe side-effects or infectious complications were observed. Premedication included paracetamol 1 g and clorphenamine maleate 10 mg. A transient moderate neutropenia (676/mm3) occurred in patient 4 at month +2, and bradycardia and hypotension in patient 3 at the first infusion; these were easily managed by reducing the infusion rate. There was no evidence of liver toxicity after treatment (Table 2). HCV serum viral load was not evaluated during follow-up, based on previously reported favourable experience in 32 patients [7, 8]. No patient presented a serum sickness-like disorder.

Effects on other MC manifestations
Beneficial effects of rituximab therapy were noted on other MC features, including the persisting disappearance of purpura in 4/4 cases (patients 1, 2, 4 and 5), of fever in patient 1, and of sensory neuropathy symptoms and arthralgias in patient 3. Sensory neuropathy relapsed at month +7 after the first rituximab cycle, and responded to the second rituximab cycle, while arthralgias relapsed at month +18 after the first rituximab cycle, requiring low-dose steroids. Sensory neuropathy symptoms decreased markedly also in patient 1 (data not shown).

Laboratory features and Fc{gamma}RIIIa polymorphism
B-cell depletion in the peripheral blood was achieved in all the patients from the first evaluation at the end of month +1 (data not shown). At the last follow-up, B-cell depletion in peripheral blood B cells was still present in patients 2 (month +12) and 5 (month +15); in patients 1, 3 and 4, the percentage of peripheral blood CD19+ B cells was 18.6, 6 and 7%, respectively (Table 2). An initial recovery of peripheral blood B cells was observed in two out of three patients at the time of renal relapse (patients 4 and 5); in patient 3 renal relapse occurred despite prolonged B-cell depletion in the peripheral blood (but B cells were non-depleted in the bone marrow at the same time; Table 2).

A significant reduction in RF serum levels (P<0.05 at month +12) was noted after treatment (Table 2). However, RF remained positive in all the patients during follow-up. Only in one out of three relapsed patients (patient 5) did the level of RF increase at the time of relapse (data not shown). Significant reductions in the serum level of IgM (P<0.05 at months +6 and +12) were also noted after treatment (Table 2). By contrast, no significant decrease in serum IgG and IgA was noted (data not shown). Serum levels of cryoglobulins decreased after treatment, but in the subsequent follow-up we observed fluctuating serum cryoglobulin levels not related to rituximab retreatment or maintenance therapy (Table 2). Only patient 1 showed the disappearance of cryoglobulins (Table 2). No significant increase in serum C4 level was noted.

Only patient 1 was homozygous for the high-affinity allele (VV) of Fc{gamma}RIIIa. Notably, this was the only patient showing a very long response. Patients 2, 3, 4 and 5 were heterozygous (VF) for the Fc{gamma}RIIIa genotype –158V/F (Table 1).

Renal pathological findings
Renal biopsy could be repeated after rituximab therapy only in patient 3, at month +6. The repeated renal biopsy at month +6 showed a morphological and immunohistochemical improvement in active lesions (Fig. 1). A mild renal relapse was documented 1 month after the repeated biopsy in our case, followed by long-term remission with one additional cycle of rituximab.


   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
Glomerulonephritis is associated with reduced patient survival in MC syndrome [4], but the optimal therapeutic approach for this organ manifestation is still ill-defined.

In this study, rituximab proved safe and effective in MC nephritis, with no need for steroids. Renal function improved within 2 months in all five cases treated; furthermore, long-term improvement was noted and no relevant short-term or delayed side-effects occurred. Interestingly, similar efficacy in time to response, duration of improvement and lack of side-effects has been recently reported in SLE nephritis treated with rituximab [17].

This is the first study in which rituximab was used and proved effective as a first-line therapy in MC nephritis without steroids. This approach, if confirmed by further studies, may represent a major advance in patients in whom steroids should be avoided or minimized, e.g. elderly patients with chronic underlying viral infection in MC.

Novel preliminary data from this study are also provided concerning the long-term management of MC nephritis with rituximab maintenance infusions or retreatment at relapse. Overall, the present results suggest that there is a need for repeated rituximab administrations for adequate control of nephritis, since only one patient achieved persistent remission after a single cycle. Although a maintenance regimen may theoretically be safer and more effective in the long term (as already suggested for lymphomas [18] and SLE [19]), retreatment at the time of renal flare was also effective in our experience.

RF remained positive after rituximab in all cases, suggesting that rituximab may control rather than cure the MC syndrome. However, in the only patient (patient 1) in whom very prolonged remission was achieved there was complete disappearance of cryoglobulins with persistent RF reduction, consistent with an important effect of rituximab on RF and cryoglobulin production [7, 8, 11]. B cells may also play a pathogenic role as antigen-presenting cells rather than as autoantibody-secreting cells, as recently suggested in SLE [20] and also in idiopathic membranous glomerulonephritis [21]. In SLE patients, the response to rituximab correlates with B-cell depletion rather than with a decrease or disappearance of autoantibodies [19]. Tissue rather than systemic effects of rituximab may be also relevant, and tissue effects on the damaged glomeruli were noted in patient 3. Thus, rituximab may be effective in targeting the ongoing immune complex-related glomerular injury in MC nephritis despite the persistence of laboratory abnormalities.

Polymorphism of Fc{gamma}RIIIa might influence the degree of B-cell depletion by antibody-dependent cellular cytotoxicity [15] and may be related to treatment efficacy. Of note, the only patient in whom nephritis is still in remission after a single cycle of rituximab in our series (patient 1) is homozygous for the high-affinity allele (VV). In addition, no patient showed the Fc{gamma}RIIIa genotype with the lowest affinity for IgG-Fc (FF). Additional work is worthwhile to clarify whether Fc{gamma}RIIIa genotyping has a role in predicting the response to rituximab in MC nephritis.

In conclusion, rituximab may prove effective and safe in patients with active, non-acute renal involvement in MC syndrome, even as first-line therapy and without steroids. A multicentre controlled study is now being performed to find out whether rituximab may be superior to current best-available treatments.
Figure 2


   Acknowledgments
 
Laboratory investigations were supported by a grant from Società Italiana di Reumatologia (S.I.R.) and Ministero Italiano della Salute.

The authors have declared no conflicts of interest.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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Submitted 8 September 2005; revised version accepted 6 October 2005.
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