Many concerns over the use of anti-TNF-alpha in AAV treatment have recently arisen. An association between therapeutic inhibition of TNF and solid malignancies was observed during the Wegener’s Granulomatosis Etanercept Trial, which included 180 patients with GPA (Wegener’s). Post-trial follow-up data45
were available for 153 patients (85% of the original cohort), with a median follow-up time of 43 months. Fifty percent of these patients had received ETA. There were no differences in demographic characteristics between the etanercept and placebo groups. Thirteen new solid malignancies were detected, eight in the etanercept group and five in the placebo group. Compared to the general population, the risk of solid malignancies in the ETA group was increased, but was not different from the risk in the placebo group compared to the general population (SIR 2.89 [95% confidence interval 0.94–6.73]). All solid malignancies occurred in patients who had been exposed to CYC. The overall duration of disease and a history of malignancy before trial enrollment were associated with the development of malignancy during post-trial follow-up. It can be concluded, therefore, that the incidence of solid malignancies continued to increase during the long-term follow-up of Wegener’s Granulomatosis Etanercept Trial cohort. However, this could not be attributed solely to ETA exposure during the trial. Anti-TNF-alpha therapy with ETA appears to further increase the risk of malignancy observed in patients with GPA treated with cytotoxic agents, and should be avoided in these patients.
A role for anti-TNF-alpha has also been proposed for mixed cryoglobulinemia (MC), which can be included among the autoimmune reactions in the course of HCV infection. As known, HCV is often associated with self-reactive immunity, which may complicate the course of the infectious disease.46
An interesting study47
was aimed at monitoring, prospectively for 14 weeks, six patients with actively replicating chronic hepatitis C for whom an anti-TNF-alpha treatment had been initiated for an associated rheumatoid arthritis. MC appeared in two of the six patients, and it persisted in two others. No patient developed any new signs of autoimmunity. HCV viraemia remained unchanged. However, these data indicate that TNF antagonists may favor emergence of MC in such patients. For all the reasons described above, the use of anti-TNF-alpha biologics is not advisable in patients with small-vessel vasculitides.
Unlike ant-TNF-alpha, the biologic RTX apparently shows the best efficacy in small-vessel vasculitis; RTX is an anti-CD20 chimeric monoclonal antibody. One of the first reports48
was about the successful, compassionate use of RTX in a patient with chronic, relapsing C-ANCA-associated WG. The patient initially responded to treatment with glucocorticoids and CYC. However, bone marrow toxicity during CYC treatment of a relapse precluded its further use. Azathioprine and mycophenolate mofetil treatment had failed to maintain remission of the WG, and MTX was contraindicated. The patient was given four 375 mg/m2
RTX infusions and high-dose glucocorticoids. Complete remission was associated with the disappearance of B-lymphocytes and C-ANCA. Glucocorticoid treatment was then discontinued. Eight months after the second course of RTX (18 months after the first course), the patient’s WG had remained in complete remission. The authors concluded that elimination of B-cells by RTX therapy might prove an effective and safe new treatment modality for AAV.
In a subsequent case report,49
a 26-year-old man with two relapses of WG was treated with a single standard course of RTX while continuing steroids and mycophenolate. After 4 months, RTX led to the resolution of pulmonary lesions and caused rapid normalization of elevated anti-PR3. There were no side effects from RTX reported.
In another study,50
two women with myeloperoxidase-ANCA-positive MPA and seven patients (five men and two women) with proteinase 3-ANCA-positive WG who were resistant to conventional therapy or who had repeatedly relapsed after cessation of CYC were treated with intravenous infusions of RTX once a week, two times (in three cases) or four times (in six cases). Eight of nine patients responded completely, and one case partially responded. Minor relapse in the nose occurred in two cases. No adverse events or major infections were noted.
In another case, a 42-year-old Caucasian woman who had been diagnosed with WG 15 years ago with end-stage renal failure was described.51
She suffered from continuous relapses involving pulmonary hemorrhage, and treatment became increasingly difficult. Symptoms resolved soon after a single administration of low-dose RTX.
Note that in 2011, the year that subtypes of AAV were officially renamed according to key pathological characteristics, important progress was made not only in differentiating these subtypes, but also in understanding – and treating – their eponymous manifestations.52
In a retrospective study,53
the RTX tolerance of patients who had received at least two RTX maintenance infusions was analyzed. Identified were 28 patients (four with MPA and 24 with GPA; median age 55.5 years [range 18–78]; 17 [60%] males) who received a median of four (range 2–10) RTX maintenance infusions, with median follow-up of 38 months (range 21–97) since diagnosis or last flare. None experienced an RTX infusion-related adverse event. Fifteen patients (among the 21 with available data) had hypogammaglobulinemia (predominantly IgM) prior to their last RTX maintenance infusion. Three had infectious events (one cutaneous abscess, one otitis, and one fatal case of H1N1 flu). Two suffered pulmonary relapses shortly before a planned RTX maintenance infusion (both had increased antineutrophil cytoplasmic antibody levels), and one had CD19+ lymphocyte reconstitution. The conclusion of this study was that RTX maintenance therapy was well tolerated but did not completely prevent relapses or persistent “grumbling” disease.
However, a recent cohort study,54
involving more than 200 patients and trials focused on RTX use for patients with refractory GPA and MPA, showed that RTX was not inferior to CYC for the induction of remission in severe GPA and MPA. In particular, the RAVE trial further showed that RTX was superior to CYC for patients with severe disease relapses. In addition, reports are emerging on the use of RTX for remission maintenance in chronically relapsing patients. All these studies underline the fact that RTX is the first proven alternative to CYC for remission induction in severe GPA and MPA. RTX is the preferred agent for patients presenting with severe disease flares, and its use has become the de facto standard of care for patients with chronically relapsing refractory GPA.
In a further study,55
43 patients with refractory GPA received at least two courses of RTX. All had remission of the disease during the depletion of B-cells, and the median time to the return of B-cells was 8.5 months. Relapses occurred in all patients after the reconstitution of B-cells, and these relapses were accompanied or preceded by an increase in ANCA levels. Infusion related adverse events occurred in 16 patients. During the period of B-cell depletion, 30 infections requiring antimicrobial therapy were recorded. From this study, RTX appears to be effective and safe for the induction and maintenance of remission in patients with relapsing GPA. Repeated B-lymphocyte depletion seems to be associated with low risk of infections.
RTX appears to be effective also in CSS. CSS is usually considered a Th2-mediated disease, but Th1 and Th17 responses might also play a role. Corticosteroids, often in combination with cytotoxic agents, comprise standard therapy. However, a number of patients appear to be resistant to treatment, and there is a need for more effective regimens. B-cell depletion may be an effective treatment option for CSS.
A single-center, open-label pilot study56
using RTX (375 mg/m2
/week × 4) for the induction of remission in CSS patients with renal involvement was carried out. Patients were eligible if they were untreated, had failed glucocorticoid therapy, or had failed glucocorticoid dose reductions because of disease relapses. Only three patients were enrolled. All achieved the primary end point of renal remission within the first 3 months and remained in renal remission during the year following RTX treatment. One patient experienced a nonrenal relapse (eye and joint involvement) at 6 months, coinciding with the reconstitution of CD19+ cells and eosinophilia. He was retreated with RTX, achieving remission within 6 weeks. No major adverse effects were recorded.
Excellent results have also been obtained by the use of RTX in MC. Immune-induced B-lymphocyte expansion represents the underlying pathological alteration frequently triggered by HCV infection.
Fifteen consecutive patients with type II MC (HCV-related in 12 of 15) were treated with RTX, 375 mg/m2
intravenously weekly for 4 weeks. Only medium- to low-dose steroids were allowed. All patients had active disease that was poorly controlled or difficult to manage with previous treatments, including corticosteroids in all cases. RTX proved effective on skin vasculitis manifestations (ulcers, purpura, and urticaria), subjective symptoms of peripheral neuropathy, low-grade B-cell lymphoma, arthralgias, and fever. Nephritis of recent onset went into remission in one case. Laboratory-increased C4 was associated with the clinical efficacy. Treatment was well tolerated, with no infectious complications.57
In a multicenter study,59
the effects of RTX in a large series of patients with active MC was evaluated. A significant clinical improvement was observed in a relevant percentage of cases, regardless the presence or absence of associated HCV infection. Importantly, cryoglobulinemic nephropathy, observed in 38 patients, significantly improved in 95% of cases. A complete remission of abdominal vasculitis was also observed in one patient. The safety of RTX was confirmed by the small number of side effects recorded during the 6-month follow-up. According to these results, RTX may be regarded as a useful and safe pathogenetic treatment of cryoglobulinemic vasculitis.59
From analysis of these and other published studies, RTX appears a very powerful tool for the treatment of small-vessel vasculitides. Further controlled studies are needed to reinforce the current favorable data.
Other biologics are currently available for the treatment of either inflammatory rheumatic diseases or other autoimmune diseases. These include golimumab (an anti-TNF-alpha agent) and abatacept (a fusion protein including the extracellular domain of CTLA-4 that inhibits the costimulation of T cells). Another is ustekinumab, an anti-IL-12 and IL-23 monoclonal antibody that is licensed for the treatment of plaque psoriasis but which is also investigated for other indications such as psoriatic arthritis, Crohn’s disease, and relapsing/remitting multiple sclerosis. Yet another is alefacept, which blocks costimulatory molecule LFA-3/CD2 interaction, inhibiting both CD4+ and CD8+ T-cell activation.
Regarding golimumab, very few and apparently conflicting data have been reported. In one study, the use of golimumab was suggested to be efficacious in uveitis and associated ocular vasculitis.61
However, Parekh et al62
reported the onset of WG in a patient treated with golimumab for rheumatoid arthritis.
Abatacept has recently been proven effective in cases of rheumatoid vasculitis.63
The rationale of abatacept use in vasculitides is based on both increased expression of CTLA-4 by B- and T-cells64
and polymorphisms in the CTLA-4 gene observed in WG.65
However, additional studies are needed to assess the actual clinical usefulness of abatacept in vasculitis-syndrome therapy.
No data are currently available on the use of ustekinumab and alefacept in the treatment of vasculitides. An issue that must also be addressed is that in the near future, many new therapeutic agents for treating inflammatory rheumatic diseases, and possibly vasculitides, will be available, including the so-called small molecules. In this regard, particular attention should be focused on the possibility of targeting proinflammatory Th17 cells, which play a pivotal role in the pathogenesis of most autoimmune diseases.66