Discussion
Cryoglobulinemic vasculitis (CV) or mixed cryoglobulinemic syndrome (MCS) is classified among the group of vasculitides affecting small vessels [
45]. The most frequent etiology is the HCV infection, followed by SjS and hematologic malignancies [
46,
47].
However, in the last 5 years, the introduction of the new DAAs is rapidly decreasing the HCV-related CV in favor of other etiologies [
48].
Nevertheless, B-cell abnormal activation downstream of the trigger drives the pathogenesis of CV and is the main biological target [
49].
RTX, a chimeric monoclonal antibody that targets CD20 positive B cells, has been employed successfully in many systemic autoimmune diseases [
50,
51], including ANCA-associated vasculitides [
52], in which it is now the worldwide accepted alternative to cyclophosphamide in the induction phase of the treatment. Notably, the first cases of CV treated with RTX [
53] date back to 1999 and anticipate a few years the administration of RTX to the first case of granulomatosis with polyangiitis [
54].
The placement of RTX in the different clinical scenarios of CV was discussed in the 2011 Consensus Conference of GISC in the wider context of the treatment recommendations for CV [
8]. The role of RTX was proposed for patients with severe CV according to published works [
21,
26,
55‐
61] and the single RCT available in abstract form [
62].
As a matter of fact, in 2011, it was clearly stated that further investigations, especially RCT, were strongly needed in order to provide further data on several open issues on RTX management in CV: more solid clinical criteria for the application, combination with antiviral therapy, steroid sparing effect, effects on liver function and immune response, duration of response, and re-treatment and maintenance strategies were necessary.
For this reason, the most recent consensus conference has focused on the efficacy and safety of RTX in CV on the basis of a preliminary meta-analysis on the usefulness of RTX in CV. Most of these issues have been addressed in several relevant works published in the last years [
5,
15,
16,
19,
22,
23,
27,
30,
33,
39] and three RCTs were conducted [
10,
11,
13], finally bringing important evidence-based support to the actual consensus conference. However, most of the trials were not primarily focused on the treatment in study (RTX), and, therefore, this observation represents a limitation of our consensus and it affected the LoE.
Firstly, even if the number of RCTs comparing RTX with the standard of care is still low [
10,
13], several observational studies also support the notion that RTX is effective and safe in patients with major clinical manifestations of CV, not immediately life-threatening [
5,
13‐
16,
18,
19,
22].
The management of both severe CV manifestations, such as glomerulonephritis [
5,
13,
19,
21‐
24], skin ulcers [
5,
10,
19,
22,
24,
28] and sensory-motor progressive peripheral neuropathy [
5,
10,
19,
22,
24,
26‐
28], and minor manifestations such as purpura, arthralgia, and fatigue [
5,
17,
21,
22,
24,
28] were evaluated, resulting in favor of RTX effectiveness together with an acceptable safety profile. Hence, the use of RTX has gained more strength based on the above-mentioned works, showing a higher level of evidence (LoE) of actual statements concerning RTX, compared to the previous recommendations (from LoE 3C for the single statement only available in 2011 to actual several and more detailed statements, respectively: LoE 1B concerning the overall statement, LoE 1B concerning in particular the efficacy on skin ulcers; LoE 2C concerning the efficacy on glomerulonephritis and peripheral neuropathy, LoE 2B concerning the minor manifestations). However, the heterogeneity of the works, the low number of RCTs, and the low number of patients included did not allow the most recent published meta-analyses on CV manifestations, especially for renal involvement [
12], or CV neuropathy [
63] to support the efficacy of RTX in CV observed in observational studies so far [
4]. The absence of a standardized response criteria in CV, and in particular in the renal involvement, could greatly affect the final conclusions and it represents an important unmet need for the research agenda in CV.
Importantly, it is widely agreed that low-dose regimen is equally effective than high-dose regimen of RTX in CV [
14,
15,
18,
30,
39], even if life-threatening manifestations (such as intestinal vasculitis or alveolar hemorrhage) could require the high-dose regimen, even in combination with cyclophosphamide or plasma exchange [
4].
Moreover, the role of RTX as steroid sparing agent in patients with severe clinical manifestations was confirmed [
10,
13,
24]: therefore, RTX can be considered a valid approach to greatly cut down the long-term administration of low-to-medium dose of glucocorticoids. This topic was widely faced also in the previous consensus conference of 2011, in which glucocorticoid-related side effects were highlighted, considering the older age of many patients, the high incidence of co-morbidities, the concomitant chronic HCV or HBV infection, and the risk of other infections. In fact, the statement in the actual consensus conference gained a higher LoE (from LoE 3C to LoE 2B).
As concerns subsequent cycles of RTX, RTX re-treatment after the first cycle appeared successful and safe in patients with major relapse [
10,
18,
19,
30,
33]. Moreover, maintenance with RTX can be required in severe or life-threatening CV [
4]. Monitoring the serum level of immunoglobulins is advisable in this scenario for the risk of hypogammaglobulinemia and infections.
As far as safety outcomes are concerned, RTX does not increase the risk of clinical reactivation of hepatitis in HCV-related CV [
10,
13,
14,
18,
21,
22,
24,
33]; however, regarding viral load, even if RTX was not associated with increasing viral load in most papers [
13,
14,
17,
18,
22,
26,
57], a transient not clinically relevant increase in HCV viral load can occur [
21,
28]. By contrast, the management of HBV-related CV requires more caution by the clinicians given the occurrence of serious HBV reactivation under B-cell depleting therapy [
64]. Overall, RTX does not increase the risk of serious adverse events [
5,
10,
17,
18,
22,
24,
26], including infusion reactions [
11,
13,
22]. Importantly, previous treatments with corticosteroids and/or cyclophosphamide can increase the risk of superimposed infections under RTX [
10]. Nevertheless, data from the French AutoImmunity and Rituximab (AIR) registry showed the occurrence of severe infections in the elderly, with essential type II mixed cryoglobulinemia and renal failure with a glomerular filtration rate lower than 60 ml/min, and receiving high-dose corticosteroids [
65].
Yet, the French group suggested caution in a subgroup of CV, in which RTX could determine severe infusion reaction [
34], or even RTX-associated immune complex vasculitis [
66]. Since RTX-associated cryoglobulinemia vasculitis flare has been linked to high mortality rate and resistance to corticosteroids and/or plasma exchange, clinicians should consider the following risk factors for this dangerous condition: renal vasculitis, B cell lymphoma, higher level of cryoglobulin, and lower level of C4. The correct application of the protocol of premedication before RTX infusions including intravenous methylprednisolone (100 mg), intravenous chlorpheniramine maleate (10 mg), and paracetamol (1 g), and eventually the use of plasma exchange before RTX [
34,
66], or the lower doses of RTX, if appropriate, might mitigate this complication.
RTX can be used in combination with antivirals in HCV-related CV [
11,
18]. Additionally, it is effective in patients with persistent and severe CV despite viral clearance [
10,
13‐
15,
17,
18,
21,
22,
24,
28]. This observation is of particular relevance, even in the era of DAAs, the most effective drugs against HCV, because cryoglobulin production can persist after HCV eradication in about 50% of patients [
67], and also CV can persist or relapse even after HCV disappearance [
68].
Unfortunately, no sufficient data were available to declare that RTX could be effective in non-infectious CV as in HCV-related ones. Skin manifestations were reported to be more susceptible to RTX than neuropathy or glomerulonephritis in noninfectious CV [
69]. However, safety issue is a matter of concern in this setting, especially for the risk of superimposed infections [
70].
Pharmacoeconomics is a pressing topic nowadays, then biosimilars of RTX are worldwide applied in all approved indications [
71] and even in the off-label use [
72].
RTX biosimilar CT-P10 has been approved in Europe. One recently published observational study analyzed 51 MCS patients treated with CT-P10 in the interventional arm, compared with a retrospective group of 75 MCS patients treated with RTX originator. No significant difference between the two groups emerged in terms of severe adverse events and clinical efficacy [
73]. Supported by this positive result, CT-P10 may replace the RTX originator, considering its cost/efficacy ratio.
Very recently, combining different B-cell targeting therapies is becoming a new treatment strategy with preliminary success in some autoimmune diseases, including SjS. Also, this treatment approach may be effective even in refractory cases of CV [
74‐
76].
In conclusion, for over two decades, RTX has been successfully employed in many people suffering from hematological malignancies and many different autoimmune diseases, and it has been finally stated in the WHO Model List of Essential Medicines which should be available in all healthcare systems. CV is a rare systemic vasculitis, in which an increasing amount of knowledge has been provided since the discovery of the HCV as the main etiology in the 1990. The scientific effort of the last years allowed us to generate new statements with stronger LoE regarding the efficacy and safety of RTX in CV, now placing RTX together with DAAs, for HCV-related CV, as fundamental therapy for the management of people suffering from CV. As monotherapy or in combination with other treatments, by applying low-dose regimen or high-dose regimen, RTX has been proved effective in the whole spectrum of CV manifestations from the mildest to the most severe ones, thus now representing the backbone immunosuppressive treatment of CV. Importantly, the optimal use of RTX in CV should be tailored on each case by the expert clinician, since the number of studies with the highest level of evidence is still low. Yet, the level of evidence on the efficacy and safety of RTX in noninfectious CV is still low and requires further larger studies. Finally, improvement of RTX efficacy in CV by adding other B-cell targeting therapies seems to be promising in refractory cases of CV, in particular in SjS-related CV.