Immune Complex Small-Vessel Vasculitis: IgA Vasculitis (Henoch–Schönlein) and Hypersensitivity Vasculitis

Definition and Classification

IgAV is the most common systemic vasculitis of childhood. ^, It is characterized by nonthrombocytopenic purpura, arthritis and arthralgia, abdominal pain, gastrointestinal hemorrhage, and glomerulonephritis. A diagnostic triad of purpuric rash, arthritis, and abnormalities of the urinary sediment was proposed by Schönlein in 1837, and Henoch described the association of purpuric rash, abdominal pain with bloody diarrhea, and proteinuria in 1874. The term anaphylactoid purpura was applied by Gairdner in 1948. The American College of Rheumatology (ACR) criteria for the classification of Henoch–Schönlein purpura (HSP) in 1990 were based on adult data and have been superseded by new criteria for pediatric vasculitides in 2010. They were proposed by the vasculitis working group of the Pediatric Rheumatology European Society (PReS) and endorsed by the European League Against Rheumatism (EULAR). These criteria require palpable purpura with lower limb predominance plus at least one among the following four features: (1) diffuse abdominal pain, (2) biopsy showing typical leukocytoclastic vasculitis or proliferative glomerulonephritis with predominant IgA deposition, (3) arthritis or arthralgia, and (4) renal involvement (any hematuria and/or proteinuria). In the case of purpura with atypical distribution (i.e., not predominantly affecting lower limbs), a demonstration of IgA deposit in a biopsy is required. The PReS/EULAR criteria have been prospectively validated through international, Web-based prospective data that included 827 patients with IgAV and 349 with other vasculitides. The sensitivity and specificity of the new classification criteria were 100% and 87%, respectively. Table 33.1 summarizes these criteria and the sensitivity and specificity of individual clinical features for the classification of IgAV.

In 2012, a new definition of HSP was proposed as part of an overall updating of nomenclature of systemic vasculitides undertaken at the International Chapel Hill Consensus Conference. It must be emphasized that definitions of disease are not the same as formal, validated classification criteria, however. Using this nomenclature, HSP is now referred to as IgA vasculitis (Henoch–Schönlein) ; the term IgAV will thus be used for the remainder of this chapter .

Although a common vasculitis in children, well-designed controlled studies addressing diagnosis, management, and outcome are lacking. In 2013 the Single Hub and Access point for pediatric Rheumatology in Europe (SHARE) initiative brought together a panel of 16 international experts from pediatric rheumatology and pediatric nephrology to develop internationally agreed consensus recommendations for the diagnosis and treatment of children with IgAV. An extensive systematic literature review was performed, and evidence-based recommendations were made. A total of seven recommendations for the diagnosis and 19 recommendations for the treatment of pediatric IgAV were accepted.

Epidemiology

IgAV is predominantly a disease of childhood with an incidence of 3 to 26.7 cases per 100,000 children. ^{, ,} A similar syndrome is reported in adults, but with an overall perception that the disease is more severe when it occurs in adulthood. The reported incidence has been remarkably consistent over the past 25 years. However, the use of different classification criteria, as well as variation in case-finding strategies, may have led to an underestimation of the true incidence. Most surveys are exclusively based on hospital discharge data and fail to identify cases not referred to a hospital. ^{, ,} IgAV occurs most frequently between the ages of 3 and 12 years, and it is rare in children younger than 2 years old. In a study from the United Kingdom, although the combined incidence was 20.4 per 100,000, the incidence was 70.3 per 100,000 in the 4- to 6-year-old age group. IgAV is more common in boys than girls, with a male-to-female ratio of 0.9 to 1.8. ^{, , , ,} Mean age at onset observed ranges from 6.1 to 6.5 years at diagnosis. ^{, , , ,} IgAV appears to be a ubiquitous disease with no clear geographical, racial, or ethnic variations in disease risk. In one UK study, a three- to fourfold lower incidence in black populations compared with white or Asian populations was observed; however, the sample size was small. Farley et al. observed a cluster of 16 cases of IgAV in a 7-month period with a higher incidence among Hispanic children and children in lower socioeconomic groups compared with children in higher socioeconomic or different racial groups. Striking seasonal variations have been observed, with most cases occurring in winter, often (30% to 50%) preceded by an upper respiratory tract infection. ^, IgAV preceded by an upper respiratory tract infection was described in 30% to 65% of cases. Other studies have also noted seasonal variations, with almost twice as many cases occurring in autumn and winter than in the summer months. ^{, , , , , ,} A prospective study in French children, using the new Pediatric Rheumatology International Trials Organization (PRINTO)/EULAR/PReS criteria, found an annual incidence of 18.6 per 100,000 children (54% boys) with a mean age at onset of 6.5 years. The incidence was significantly lower in summer, and 72% of cases were preceded by infectious symptoms, mainly of the upper respiratory tract.

Etiology and Pathogenesis

Although a variety of infectious and chemical triggers are recognized, the underlying cause of IgAV remains unknown. The striking autumn-winter incidence peak would suggest a climate-related environmental trigger, particularly for infection. IgAV has been linked to a wide array of pathogens including bacteria (e.g., β-hemolytic streptococcus, ^{, ,} Mycoplasma pneumoniae, ^, Bartonella henselae, and Helicobacter pylori ), viral infections (e.g., varicella, hepatitis A and B), ^, and protozoa, ^, but no consistent causative agent has been identified. Studies in China have shown very high rates of H. pylori infection in children with IgAV, especially in those with gastrointestinal symptoms. Furthermore, eradication therapy was associated with ameliorated clinical manifestations and a decrease of recurrence of IgAV.

IgAV may develop after exposure to pharmaceutical agents, such as antibiotics or antirheumatic therapy, including methotrexate and anti–tumor necrosis factor (TNF) agents. Single cases of IgAV have been reported in children after several months of treatment with etanercept, adalimumab, ^, and infliximab. All cases showed full resolution of disease after discontinuing the medication and in several cases restarting the same anti-TNF agent led to a recurrence of IgAV.

Concerns have been raised about a possible link of IgAV with vaccinations. Since 2000, 11 cases of IgAV developing postimmunization have been reported in the English-language literature. However, a systematic literature review did not identify a causative association between vaccinations and vasculitides, including IgAV. ^,

A possible pathogenic role of IgE in IgAV has been suggested for some cases of IgAV nephritis. In adults, IgAV has been linked to an increased incidence of concurrent or preceding solid cancers, especially in patients with renal disease.

The characteristic vascular deposition of IgA strongly suggests, however, that IgAV is a predominantly IgA-mediated dysregulated immune response to antigen and may operate through the alternative complement pathway. ^, Although the pathogenic mechanisms of nephritis are still not delineated, studies suggest that galactose-deficient IgA1 (Gd-IgA1) is recognized by antiglycan antibodies, leading to the formation of circulating immune complexes and their mesangial deposition, which results in renal injury in IgAV. An increase in the levels of Gd-IgA1 in patients with IgAV nephritis has been observed, but this appears insufficient in itself to cause IgAV nephritis. ^, Thus it is likely that a “second hit” is required for high levels of Gd-IgA1 to form immune complexes that result in nephritis. It is suggested that this second hit is the formation of antiglycan IgG or IgA antibodies (perhaps triggered by infection) that then form large circulating immune complexes with the Gd-IgA1. Currently, the genes controlling IgA1 glycosylation are unknown, but it is likely that a genetic predisposition, mucosal infection, and concomitant interleukin-6 production all play a role.

It has been hypothesized that IgA nephropathy, IgAV nephritis, and nonrenal IgAV affecting the skin, joints, and other organs are all entities of the same disease. However, the role of Gd-IgA1 complexes, present in IgA nephritis, is disputed in nonrenal IgAV. ^, Heineke et al. suggest that IgAV can be viewed as a dual disease. In addition to the deposition of Gd-IgA1 complexes leading to renal damage, IgA1 possibly recognizes endothelial cell antigens, leading to deposition of IgA1 in small-vessel walls and resulting in inflammation and subepidermal hemorrhages through neutrophil migration and activation via the IgA-Fc receptor.

Disorders of coagulation and its activation are also associated with the development of an IgAV-like vasculitis. It is recognized that disease activity may be linked to a rapid decline of factor XIII, particularly in patients with severe abdominal involvement. Factor XIII also declines prior to recurrence of IgAV, and it is not known whether this is merely a secondary epiphenomenon or a true causative association.

Makay et al. suggest that an elevated circulating neutrophil-to-lymphocyte ratio (NLR) might be a predictor of gastrointestinal hemorrhage in children with IgAV. This finding was not replicated in a separate study that excluded those already bleeding, which is of particular relevance as acute hemorrhage is associated with neutrophilia. Thus, the clinical utility of the NLR in IgAV is questionable.

Genetic Background

No mutations have been shown to directly cause IgAV. The disease almost always occurs sporadically. A review of the literature by Ostini et al. found a total of 100 affected cases in 47 families. Age at presentation, male-to-female ratio, and findings were similar in familial (both simultaneous and nonsimultaneous occurring) and sporadic cases of IgAV. The authors conclude that genetic predisposition, therefore, likely plays a minor role in the development of IgAV. When comparing genetic variants between healthy and IgAV patients, the biggest difference was found in human leukocyte antigen (HLA) genes. Variants HLA-DRB1∗01 and HLA-DRB1∗11 were associated with IgAV susceptibility, whereas HLA-DRB1∗07 was negatively associated with IgAV. HLA-B∗4102 was found to be a susceptibility marker for IgAV development irrespective of HLA-DRB1 status.

Other genes involved in cytokine and chemokine production, the renin-angiotensin system, complement activation, and endothelium activity regulation have also been implicated in IgAV susceptibility. ^,

In studies from Israel and Turkey, mutations in the familial Mediterranean fever ( MEFV ) gene were frequent in patients with IgAV, and patients with these mutations may have more severe clinical findings with a higher inflammatory response.

Several polymorphisms relating to disease susceptibility, severity, and risk of renal involvement have been described. Studies of this nature have been hampered by relatively small patient numbers and thus lack the power to be definitive or necessarily applicable to all racial groups. It is, however, increasingly apparent that the genetic contribution is complex and polygenic in nature.

Clinical Manifestations

Clinical characteristics of IgAV are presented in Table 33.2 . ^, The onset is often acute, with the principal manifestations appearing sequentially over several days to weeks. Nonspecific constitutional signs, such as a low-grade fever or malaise, are often present. Skin manifestation is the presenting symptom in approximately three-quarters of cases, in one study preceding other symptoms by a mean of 4 days, whereas joint or gastrointestinal involvement preceded skin symptoms in 15% and 11%, respectively.

Cutaneous Involvement

The presence of palpable purpura is characteristic. This rash, usually symmetrical, is most prominent on dependent or pressure-bearing surfaces, especially the lower extremities and buttocks, but it may occur in other areas. The cutaneous lesions range from small petechiae to large ecchymoses to rare hemorrhagic bullae ; they tend to occur in crops and progress in color from red to purple to brown ( Figs. 33.2 and 33.3 ). Ulceration may occasionally develop in large ecchymotic areas. The rash is often preceded by maculopapular or urticarial lesions. Subcutaneous edema over the dorsa of the hands and feet and around the eyes, forehead, scalp, and scrotum may occur early in the disease, particularly in the very young child. One study reported a mean duration for skin lesions of 10 days.