Introduction

The term cryoglobulinemia vasculitis (CryoVas) represents a small-medium vessel vasculitis affecting predominantly skin, joints, peripheral nervous system, and kidneys [1•]. In the context of clinical symptoms suggestive of CryoVas, the most important finding is the detection of cryoglobulins in serum. Cryoglobulins are immunoglobulins that precipitate in vitro at temperatures below 4 °C, and dissolved after rewarming at 37 °C [2].

Brouet et al. [3] have proposed a classification based on the clonality and type of immunoglobulins. Type I cryoglobulins consist of single monoclonal immunoglobulins, either IgM or IgG. Type II cryoglobulins consist of polyclonal IgG with monoclonal IgM with rheumatoid factor activity. Type III cryoglobulins are a mixture of polyclonal IgG and IgM with rheumatoid factor activity. Type II and III are often referred to as mixed cryoglobulinemia. Since the discovery of hepatitis C virus (HCV) infection in the late 1980s, it has become clear that HCV represents the most common cause (80 %) of CryoVas [4, 5], being predominantly associated with type II mixed cryoglobulinemia. However, CryoVas has also been associated with other infections, as well as autoimmune diseases and hematologic malignancies. In addition, when no etiologic factor can be identified, CryoVas is defined as idiopathic or essential [6••].

CryoVas may cause clinical manifestations due to two major mechanisms. Hyperviscosity and vascular occlusion is more frequent in type I cryoglobulinemia, usually associated with high levels of serum cryoglobulins [7]. On the other hand, mixed cryoglobulinemia (type II) is associated with formation and deposition of immune-complexes, primarily affecting small and medium vessels [8].

Most data available regarding disease expression, outcomes, follow-up, and treatment options in CryoVas series have focused on HCV-associated cryoglobulinemia. In this review, we aim at describing the clinical presentation, prognostic factors, and treatment options available in patients with non-infectious CryoVas.

Non-Infectious Causes

A variety of clinical disorders have been described in association with CryoVas (Table 1).

Table 1 Non-infectious causes associated with CryoVas
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Autoimmune Diseases

Patients with systemic autoimmune diseases can present with complications of mixed cryoglobulinemia. In this setting, primary Sjögren’s syndrome is the most common rheumatic disease associated with cryoglobulinemia, especially in those patients exhibiting extraglandular manifestations. Detection of cryoglobulins in Sjögren’s patients has also been identified as predictive factor for B-cell lymphoma [9, 10]. Cryoglobulins have been reported, although in lower percentages, in other autoimmune diseases, such as rheumatoid arthritis and systemic lupus erythematosus (SLE). In a large cross-sectional study including 122 SLE patients, cryoglobulins were found in nearly 25 % of patients. Hepatitis C virus (HCV) infection was only detected in 21 % of patients with cryoglobulinemia. Of interest, patients with a cryocrit greater than 1 % showed a higher frequency of HCV infection than those with a cryocrit less than or equal to 1 %. Only cutaneous vasculitis was more common in SLE patients with than in those without cryoglobulins [11].

Neoplasias

B-cell lymphoproliferative disorders are the major cause of cryoglobulinemia associated with malignancy. Type I cryoglobulinemia accounts for nearly 10–15 % of patients [12], and mostly linked with multiple myeloma, Waldenström’s macroglobulinemia, chronic lymphocytic leukemia, and B-cell non-Hodgkin lymphoma [13]. Rarely, cryoglobulins have also been identified in patients with solid neoplasias.

Essential or Idiopathic

Once different causes have been ruled out, CryoVas is considered as idiopathic or essential (nearly 25 % of patients in HCV-negative series) [5]. It should be noted that cryoglobulinemia, as such, is a laboratory finding sometimes not necessarily associated with any clinical manifestation. Several factors have been associated with the development of CryoVas symptomatology, including age, underlying disease, type (especially type II subclass), and high levels of cryoglobulins [4].

Clinical Manifestations

Most studies available in the literature on CryoVas came from series including HCV-associated CryoVas patients. Data on clinical features have also been described extensively for the different types of cryoglobulinemia. We will focus specifically on clinical manifestations from the latest published series on non-infectious mixed CryoVas and type I CryoVas. Table 2 highlights differential features between infectious and non-infectious CryoVas.

Table 2 Differential features between infectious and non-infectious CryoVas
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Non-Infectious Mixed CryoVas

Mixed type II–III cryoglobulins are associated with clinical manifestations typical for small–medium vessel vasculitis. Mixed CryoVas is the result of immune-complex deposits, predominantly in the capillaries, venules, or arterioles. Disease expression is variable, ranging from mild symptoms to life-threatening complications. Skin is the most frequently involved organ, presenting as palpable purpura, ulcers, Raynaud’s phenomenon and acrocyanosis. Renal involvement is usually described as type I membranoproliferative glomerulonephritis. Neurologic manifestations include peripheral neuropathy, mostly sensory-motor mononeuritis multiplex.

A French group has recently published the largest series of non-infectious CryoVas patients. The French multicenter CryoVas survey was designed to describe the clinical presentation, prognostic factors, and treatment efficacy in patients with non-HCV CryoVas. Data including 242 patients showed some differential features between HCV-positive and -negative CryoVas patients. Compared with type III mixed CryoVas, patients with non-infectious type II CryoVas had higher cryoglobulins levels, lower complement levels, and more frequent palpable purpura, peripheral neuropathy, and renal involvement [14••]. As compared with essential mixed CryoVas, connective tissue disease-associated CryoVas patients were predominantly younger women, who had more peripheral neurologic involvement, and less renal involvement.

Type-I CryoVas

In type I cryoglobulinemia, most clinical manifestations are secondary to hyperviscosity syndrome, with cryoglobulin precipitation and vascular occlusion as major pathogenic mechanisms involved. Vascular occlusion is more common in type I CryoVas, although systemic vasculitis may also occur. Clinical symptoms include acrocyanosis, Raynaud’s phenomenon, gangrene, and livedoreticularis. Neurologic (headache, confusion), ocular (blurry vision, visual loss), and rhino-otological (hearing loss, epistaxis) manifestations have also been described [15].

Data on type I CryoVas are scarce in the literature as most published series have focused on mixed CryoVas patients. A survey from the French study group on CryoVas has been recently reported [16••]. Data from 64 cases of type I CryoVas were included: 28 patients with monoclonal gammapathy of unknown significance (MGUS) and 36 with hematologic malignancy. Demographics features (e.g., age at the time of diagnosis and predominance of females) were in keeping with those usually observed in HCV- and non-HCV-related mixed CryoVas. The study revealed that the major clinical manifestations were severe cutaneous involvement (necrosis and ulcers) in almost half the patients, associated with high levels of serum cryoglobulins. It should be noted that frequency of glomerulonephritis (20 %) was lower than reported in previous series. In contrast to what was expected, no clinical manifestation of hyperviscosity syndrome was found in the entire cohort. Finally, type I CryoVas was mostly associated with B-cell lymphoproliferative diseases, confirming the need to systematically screened these patients for an underlying B-cell malignancy.

Prognosis

Disease expression in CryoVas is variable, ranging from mild clinical manifestations to fulminant life-threatening complications (especially glomerulonephritis and systemic vasculitis). Prognosis is mostly influenced by cryoglobulinemic damage to vital organs and by underlying diseases and comorbidities.

Non-Infectious Mixed CryoVas

Evidence on the prognosis of non-infectious mixed CryoVas in the era of HCV screening is limited. Recently, the French multicenter and retrospective CryoVas survey have identified prognostic factors and survival rates in the largest cohort (n = 242) of patients with non-infectious mixed CryoVas so far published in the literature [17•]. After a median follow-up of 35 months, 17 % of patients died, with severe infections (50 %) and vasculitis flare (19 %) as major causes of death. Survival rates were 91 % (1 year) to 65 % (10 years). A prognostic score, the CryoVas score (CVS), for the prediction of survival at 5 years was devised from this study. At diagnosis of vasculitis, pulmonary and gastrointestinal manifestations, renal failure (glomerular filtration rate less than 60 ml/min), and age (older than 65 years) were independently associated with poor outcomes and death.

In contrast, causes of death in HCV-related mixed CryoVas have been described mainly associated with end-stage liver disease and serious infections, but not vasculitic manifestations [18].

Type I CryoVas

Data on the prognosis of type I CryoVas are also lacking. Despite the lack of the evidence, type I CryoVas is considered a life-threatening disease, due to the severity of cutaneous and renal involvement and the prognosis of the underlying hematological disorder. The study from the French CryoVas survey analyzed patients with type I CryoVas. The 1-, 3-, 5-, and 10-year survival rates were 97, 94, 94, and 87 %, respectively. It should be noted that type I CryoVas related to hematological malignancy tended to be associated with a poorer prognosis as compared with MGUS. In this setting, all patients who died had hematologic malignancy, including Waldenstrom’s macroglobulinemia in 3 patients and multiple myeloma in 1 patient.

Therapeutic Management

In general, therapeutic approach in CryoVas patients should be tailored according to the severity of clinical manifestations, etiopathogenic mechanism(s) involved (vasculitis vs. hyperviscosity syndrome) and the associated underlying disorders.

With the discovery of HCV infection as the main cause of CryoVas, most of the research has focused on the safety and efficacy of antivirals and interferon-alpha regimens. Evidence on the clinical spectrum and therapeutic options in non-infectious CryoVas patients is limited. Treatment options have been derived mainly from strategies used in HCV-CryoVas.

Non-Infectious Mixed CryoVas

Treatment options in patients with mild–moderate disease may include resting, avoidance of cold temperatures, nonsteroidal-antiinflammatory drugs (NSAIDs), and colchicine. In cases of severe or life-threatening manifestations, therapy is based on a combination of corticosteroids, immunosupressants, plasmapheresis, and rituximab (RTX). The approach is empiric, as no clinical trial has previously studied these agents in CryoVas.

First line therapy may include:

  • Corticosteroids (moderate-severe manifestations): methylprednisolone (0.5–1 g/day) for 3 days, followed by prednisone 1 mg/kg daily. When disease control is achieved, steroids should be tapered down.

  • Cyclophosphamide (severe cases): oral (2 mg/kg daily) or intermittent IV (750 mg/m2 monthly)

For remission maintenance, regimens include azatioprine (2 mg/kg daily) or mycophenolate mofetil (1 g twice daily).

The most promising biological approach of CryoVas used thus far is B-cell depletion with RTX. The rationale for this approach is that peripheral B-cell depletion should lead to a reduction in the B-cell clones that produce cryoglobulins.

To date, only two studies have addressed the role of RTX in non-infectious CryoVas. The first come from a prospective clinical data, including patients from the French Autoimmunity and Rituximab (AIR) registry [19]. The objective was to evaluate safety and efficacy of RTX in off-trial, real-life patients with non-viral CryoVas (Dosis: 375 mg/m2 × 4). RTX indication was due to refractory disease (75 %) and as first line therapy (25 %). The registry included 23 patients: primary SS (9), essential mixed CryoVas (8), and patients with an underlying hematological disorder (8). It should be noted that RTX has shown clinical and immunological efficacy in all patients, however with a high rate (50 %) of clinical relapses (mean 13.5 months). Tolerance was marked by the occurrence of side-effects (50 %), including severe infections in 6 patients, which occurred in a particular subset of patients: age older than 70 years, with renal failure and high-dose corticosteroids. The authors concluded that RTX showed a dramatic efficacy and a steroid-sparing effect, although safety concerns remained a strong consideration.

The second study come from the largest French CryoVas survey including patients (n = 242) with non-viral CryoVas, in order to evaluate safety and efficacy of different therapeutic regimens. The analysis showed that RTX plus corticosteroids had the greater therapeutic efficacy compared with corticosteroids alone, as well as with cyclophosphamide plus corticosteroids. However, the approach including RTX was associated with high rates of severe infections (HR 1.7, p = 0.41), especially with high doses of corticosteroids [14••]. However, no significant differences in death rates were found in this study.

In conclusion, the available evidence suggests that RTX is the most effective therapy in non-viral CryoVas; however, its safety profile should be considered.

Type I CryoVas

Management of type I CryoVas patients should be individualized based on severity of clinical manifestations and the underlying hematological disorder. Regimens including bortezomib, lenalidomide, thalidomide, and RTX have been investigated in Type I CryoVas. In patients with multiple myeloma, some investigators have suggested initiation of plasmapheresis or plasma exchange along with therapy for underlying hematological disorder [20]. However, as type I CryoVas related to MGUS is more severe, therapy should include different approaches, ranging from corticosteroids and cyclophosphamide, to new biologic agents such as bortezomib, lenalidomide, and RTX.

The efficacy of RTX in Type I CryoVas is still under debate [21, 22]. In the largest series of Type I CryoVas, data from 22 patients on RTX therapy have shown an efficacy rate of 80 % in first- or second-line treatment, supporting its use in naive or relapsing/refractory patients. However, vasculitic flares were shown in 13 %, within 48 h following RTX infusion. RTX should be administered with caution in elderly patients with renal failure receiving high-dose corticosteroids due to the increased risk of severe infections. Data regarding the safety and efficacy of alternative regimens, including thalidomide, lenalidomide, and bortezomib, have also been reported. The efficacy rate of thalidomide and lenalidomide was shown to be nearly 80 % [23, 24], while a bortezomib-based regimen was shown to be effective in 86 %. All of them were well tolerated. Overall, these findings suggest that patients with severe/refractory type I CryoVas, RTX- thalidomide, lenalidomide, and bortezomib regimens could be interesting and appropriate alternative options when combined with corticosteroids.

Conclusions

Although more than 80 % of CryoVas are associated with HCV infection, clinicians should be aware of non-infectious causes of CryoVas. Non-infectious mixed CyoVas seems to have a similar disease expression and outcomes as compared to HCV-related CryoVas. In addition, patients with type I CryoVas showed a higher frequency of severe cutaneous lesions and high levels of serum cryoglobulins. Careful individual work-up to assess the severity of involvement is important when planning therapeutic approaches. Regarding new biologic agents, RTX showed to be dramatically effective but remains associated with severe infections in a subset of patients. The treatment of type I CryoVas is primarily that of the underlying hematological malignancy using the optimal combined chemotherapy. In this setting, the use of RTX, thalidomide-, lenalidomide-, and bortezomib-based regimens has shown to be effective, although their use deserves further investigation.