Immune complex vasculitides present inflammations of vessel walls associated with and mainly elicited by perivascular deposition of immunoglobulins, mostly in the form of immune complexes (ICs).

There are different forms of immune complex vasculitides (Table 1) (1): systemic and skin-limited variants (1) of IgA vasculitis (IgAV) (Figure 1), cryoglobulinemic vasculitis (CV), rheumatoid vasculitis (RV), lupus vasculitis (LE vasculitis), hypocomplementemic vasculitis (Figure 2), and serum sickness, as well as the provisionally defined forms of cutaneous IgM/IgG immune complex vasculitides and a recurrent macular vasculitis induced by hypergammaglobulinemia (Waldenström) (Figure 3) or by exertion or heat, or a, vasculitis in gammopathy other than cryoglobulinemic vasculitis (2, 3).

According to Coombs and Gell, the so-called type III hypersensitivity reaction has been considered among immunologists as a model for immune complex vasculitis. The prototype would have been that of serum sickness that occurs when a certain antigen in the circulation encounters approximately equimolar concentrations of fitting antibodies (4, 5) so that large lattices of circulating immune complexes form, which subsequently become deposited at the walls of small blood vessels, where they activate the complement system and polymorphonuclear neutrophils (PMNs).

This disease has has long been considered to present the prime example for immune complex vasculitis and corresponding animal models, including the Arthus reaction, and has largely dominated the pathophysiological concept of immune complex disease in general and immune complex vasculitis in particular.

However, the pathophysiology of IgA vasculitis has been revealed to differ at least in its initial stages from serum sickness, because it is primarily the altered galactosidation of the IgA1 molecule which mediates its deposition at certain vasculatures and not the size of the IC (6, 7).

Circulating complexes have also been demonstrated to present a major pathophysiological factor for vasculitis in cryoglobulinemia and in rheumatoid arthritis (RA) (1).

Common denominators for immune complex vascultides are perivascular deposition of altered immunoglobulins or immune complexes, and their subsequent full activation of PMNs close to the vessel wall via FcyR or FcαR. Histologically, the resulting picture of small vessel vasculitis is generally that of leukocytoclastic vasculitis of post-capillary venules, which sometimes extends into small veins and may also involve small arterioles. Clinically, the inflammatory infiltrates and ensuing extravasation of blood manifests as hemorrhagic maculae, papules, and plaques, sometimes in a retiform pattern [branched or retiform purpura, a term coined by Warren Piette (8)]. The most characteristic clinical picture as it has engraved in the clinician's eye is that presented by IgA vasculitis, i.e., palpable and macular, round or oval, and sometimes branched or retiform purpura with a predilection for dependent parts, namely the legs (Figure 1). In the other forms of immune complex vasculitis, the lesions are not as numerous and not as accentuated on the lower legs as in IgA vasculitis.

As reflected by the nomenclature of Chapel Hill Consensus Conference (CHCC) 2012 for cutaneous vasculitides, several of the different forms of systemic immune complex vasculitides have a counterpart that seems to occur exclusively on the skin but has the same cutaneous manifestations clinically and histologically as the systemic form. They are referred to as a skin-limited or cutaneous form of the respective systemic vasculitis (e.g., cutaneous IgA vasculitis) (1).

While most cutaneous vasculitides are immune complex-mediated vasculitides of mainly small vessels, there are several other vasculitides of small vessels (ANCA-associated vasculitides), medium (cutaneous periarteritis nodosa), and even large vessels (9) that affect the skin.

Serum sickness disease is a paradigm of a systemic immune complex disease (type III hypersensitivity reaction). In its complete form, it apparently results when large amounts of heterologous (non-human) proteins as antigens encounter approximately equimolar concentrations of fitting antibodies leading to formation of large lattices of immune complexes. It induces not only IgG but also IgE, so serum sickness causes symptoms due to a varying involvement of the activated complement cascade and IgE, depending on the antigen. Histamine-mediated vascular permeability of vessels and joints facilitates perivascular deposition of ICs. Nowadays, serum sickness disease occurs not only after the administration of antithymocyte globulin (rabbit serum) but also after the administration of other foreign sera (antidotes), rituximab, streptokinase, or other drugs. However, one may speculate that there are attenuated or abortive forms with perhaps only skin-limited perivascular deposition of immune complexes, one of whose clinical manifestations could be cutaneous IgG/IgM vasculitis (refer to the following).

The typical symptoms are persistent fever, arthralgia or arthritis mostly of the large joints, lymphadenopathy, asthma, and a polymorphic picture with urticae, maculopapular exanthema, itchy papules, or palpable purpura. In contrast, IgA or IgG/IgM vasculitis would typically present on the skin with only macular or palpable round, oval, or retiform purpura with a predilection for the legs. Symptoms occur 7–14 days after primary administration (and 2–4 days after repeated administration) of a foreign protein. Accordingly, high levels of circulating immune complexes are detectable after 10–12 days and low levels of C4 and C3 on the 10th day, while C3a anaphylatoxin is elevated, accompanied by leukocytosis and sometimes eosinophilia, hematuria, and proteinuria.

Immunoglobulins A vasculitis is an inflammation of small vessels related to tissue deposits of immunoglobulins A (IgA), or, more precisely, galactose-deficient or hypogalactosidated IgA1 (Gd IgA1), most likely bound in immune complexes. It may present as a variant restricted only to the skin (skin-limited IgAV) or as systemic vasculitis [IgAV–Henoch-Schönlein Purpura (HSP)], which manifests as arthritis, gastrointestinal vasculitis, renal vasculitis, and rarely pulmonary or cerebrovascular vasculitis. The reason why there is a skin-limited or a systemic form is not due to presence or absence of perivascular deposition of Gd-IgA1 because we detected Gd-IgA1 around cutaneous vessels in both systemic as well as skin-limited IgAV (10).

Similar to skin-limited IgAV, IgA nephropathy (IgAN), the most frequent form of nephritis in adults, may also present an organ-limited variant in the spectrum of IgA-related vasculitides, restricted to the kidneys. Histopathologically, IgA-nephritis in the course of systemic IgAV is indistinguishable from IgAN [for review (6, 7, 11, 12)]. There are, however, some differences, as the episode of kidney injury in IgAN is mainly chronic and presents with less crescentic lesions and more sclerotic lesions than in IgAV-nephritis; in addition, IgAV-nephritis shows more glomerular capillaritis with subendothelial IgA deposition and significant elevation of serum inflammatory cytokines (13).

The short-term prognosis of systemic IgAV depends on the severity of potential acute involvement of the gastrointestinal tract, while the long-term prognosis is dependent on the extent of the kidney damage. End-stage renal failure may occur more than 10 years after the onset of IgAV (14, 15).

If no IgA, but IgG or IgM, is detected around vessels, this indicates another subtype of immune complex vasculitis, e.g., cryoglobulinemic vasculitis, hypocomplementaemic vasculitis (Figure 2), or systemic disease associated with IC-mediated vasculitis such as rheumatoid arthritis or vasculitis in SLE (Table 1).

Primary or genuine IgG-/IgM-vasculitis (i.e., IgG-/IgM-vasculitis without an underlying systemic disease which is associated with dysregulation of B cells or antibodies), analogous to IgA1-vasculitis, is much rarer than originally assumed. It was mostly meant in the literature and in clinical practice when the terms hypersensitivity vasculitis or leukocytoclastic vasculitis were used. Yet, while many dermatologists are convinced that it exists and that it presents an entity of its own, there are only a few published studies so far which would confirm it (52). Its underlying cause would be the deposition of immune complexes containing IgG or IgM, but no IgA. It may, thus, present a form of a—likely skin-limited—serum sickness reaction. The reason for perivascular deposition of immune complexes in these cases would then be their sheer size (presumably not altered galactosidation). Their larger size might propel them to the edge of vessels where blood flow is much slower (according to the model of laminar, parabolic flow) or also partially turbulent (according to newer models on blood flow). The altered flow or markedly reduced velocity of blood and particles along the vessel wall and the size of the IC may facilitate their entrapment between EC and pericytes (53). Marginating PMNs, which are in the process of adhering to endothelial cells and of transmigration, will also bind to the IgG/IgM complexes via their FcyR. Once PMNs are adherent, they become more easily and more vigorously activated after their FcyR are crosslinked by IgG/IgM complexes (36, 37, 48). The ensuing release of cytotoxic products would subsequently occur close to the vessel wall, perhaps during the diapedesis of PMNs, thus damaging the vessel, a scenario long described and ultrastructurally shown in the Arthus reaction in animals (54).

We learned from IgA vasculitis that this scenario may contain some oversimplifications. Clinically, it would feature palpable and retiform purpura as in IgAV.

Recurrent macular vasculitis in hypergammaglobulinemia is a chronic episodic vasculitis of small blood vessels with vascular deposits of immunoglobulins, often associated with (a) a hypergammglobulinemia (usually polyclonal, but sometimes also monoclonal) and an elevated sedimentation rate and/or (b) induction by vasodilatory or stasis-associated events, such as long-standing and consumption of alcohol (cocktail party), or playing golf, extended hikes in association with warm weather, or other kinds of exertion (thus the different names for it). A characteristic feature is the chronic relapsing sudden occurrence of many (>50) small short-lived hemorrhagic macules on lower legs which hardly leave any traces except occasionally slight macular hyperpigmentation. In contrast to other immune complex-related vasculitides, these lesions are regularly associated with a burning sensation. Since biopsies often, but not regularly, reveal perivascular deposits of IgG or also IgA, the clinical picture may putatively be due to a very transient vascular deposition of immune complexes. In several, but not all patients, IgG or IgA rheumatoid factor (RF) is detected in serum, which is highly soluble and could therefore resolve rapidly after vascular deposition (55). Therefore, vascular damage may be subtle and quickly reversible, thus leading to leakage of red blood cells but not to full, irreversible destruction of vessel walls.

Cryoglobulinemic vasculitis is a leukocytoclastic immune complex vasculitis seen in type II, less often in type III, hypersensitivity mixed cryoglobulinemia. In rare cases, it has been described with type I monoclonal cryoglobulinemia, which, however, are not immune complexes per se (56, 57); it needs to be carefully clarified if it exists independently from gelling of type I cryoglobulins (similarly in vasculitis associated with monoclonal gammopathy) (58).

Cryoglobulins are immunoglobulins that precipitate in vitro at temperatures below 37°C (in vivo depending on pH, ion concentration, high content of hydrophobic amino acids, low content of tyrosine residues, or galactose and sialic acid). Types II and III are immune complexes because in type II cryoglobulinemia, monoclonal IgM forms a complex with IgG. In many cases, this IgG is directed against the non-enveloped core protein of the hepatitis C virus and can then precipitate via a conformational change in the complex at cold temperatures.

In type I cryoglobulinemia, the monoclonal cryoglobulins gel directly in cold and in the presence of one of the above factors, causing hyperviscosity and subsequently vascular occlusion and ischemic necrosis.

Both features may occur simultaneously because the i) slowing of blood flow, cooling, and gelation, as well as ii) the deposition of immune complexes, influence and reinforce each other. Thus, in rare cases, mixed cryoglobulinemia also leads to hyperviscosity (< 3%), and slowing down of blood flow with ensuing deposition of immune complexes and cryoglobulinemia type I result in vasculitis (57).

This vasculitis mainly affects small vessels and can also include medium-sized and even large-sized vessels (aorta and branches). Vasculitis usually involves the skin in the systemic form, but there is a skin-limited form without the involvement of visceral organs.

Thus, the involvement of skin in cryoglobulinemia is due to two major mechanisms of tissue damage: (i) leukocytoclastic immune complex vasculitis (with the formation of cryoglobulins being primarily unrelated to cold) and/or (ii) occlusion of cutaneous vessels by gelling or precipitation of mostly monoclonal type I cryoglobulins in cold-exposed skin areas (all small blood vessels of the upper or deep dermis, as well as the capillaries of the fat lobule, may be involved) (vasculopathy) (59).

Clinically, leukocytoclastic immune complex-mediated vasculitis manifests as palpable or retiform purpura lesions that may coalesce. Occlusion of vessels by cryoglobulins manifests clinically as retiform purpura with dominant central necrosis (larger than the surrounding inflammatory erythema) in cold-exposed, acral areas (hands, feet, lips, ears, and nose), sometimes accompanied by livedo due to only partial obstruction of blood flow.

Rheumatoid vasculitis (RV) is a severe complication of rheumatoid arthritis (RA), characterized by cutaneous and systemic vasculitis affecting small or medium-sized vessels and occurring usually in patients who had high titers of RF over a long period of time. Other factors associated with the development of RV were male gender, joint erosions, subcutaneous nodules, presence of nail fold lesions, and any other extra-articular feature 1 year before the time of diagnosis of RV and intensive treatment with antirheumatic drugs (60).

Rheumatoid factor is an immune complex. Circulating RF contain IgG and IgA (61). Decreased C3 complement levels indicate marked activation of the complement system. Although there is not much recent research on RV, all facts known so far indicate that it is an immune complex vasculitis owed to similar mechanisms as in cryoglobulinemic vasculitis or the Arthus reaction.

Since cutaneous vasculitis in rheumatoid vasculitis ranges from leukocytoclastic vasculitis of post-capillary venules to arteritis located at the dermo-subcutaneous junction or in the panniculus (62), it clinically reveals a spectrum from palpable purpura as in IgAV or IgG/IgM vasculitis to livedo reticularis (racemosa) and ulcerating nodules similar to cutaneous arteritis, or even digital infarcts and gangrene (62).

Cutaneous vasculitis in Lupus erythematodes often occurs as small vessel vasculitis with perivascular IgG deposits, or as so-called hypocomplementemic (urticarial) vasculitis with or without C1q antibodies. It likely is the result of several pathomechanisms, but encompassing immune complexes.

Vasculitis in Sjögren's syndrome is often either recurrent macular vasculitis in hypergammaglobulinemia (as mentioned earlier) or cryoglobulinemic vasculitis or vasculopathy. In the former high titers of small circulating immune complexes containing IgG or IgA, RF has been detected in some but not all cases as part of the gammaglobulin fraction (55). Cryoglobulinemic vasculitis in Sjögren's syndrome bears a risk for lymphoma (57, 63), whereas recurrent macular vasculitis in hypergammaglobulinemia does not share this risk (63).

Although several steps in the pathophysiology of the different immune complex vasculitides have been elucidated, several remain to be explored; some of them emerging from the fog in the form of already deducted hypotheses that wait to be verified or falsified, while others remain in the dark. Shrouded in the mist are the steps to target efficacious therapies, but in this field, light may be ahead at least for some small steps because budesonide or antibodies to complement components showed effects in first clinical trials.

CS contributed to the conception of the work and drafting of the work. LG contributed to the design of the work, drafting of the work, revising it critically for important intellectual content, and provide approval for publication of the content. EP and CM contributed to the conception of the work, drafting of the work, and revising it critically for important intellectual content. All authors contributed to the article and approved the submitted version.