Chapter 27 Systemic Lupus Erythematosus and Vasculitis

INTRODUCTION

Vasculitis is defined as the inflammation and necrosis of vessel walls as a primary process or as a complication of some other underlying pathologic condition, such as collagen-vascular, rheumatic, infectious, or malignant diseases.¹^–³ Vasculitis is now integrated into a family of “vasculitis syndromes,” which can be classified into two groups: primary vasculitis syndromes and secondary (associated with an underlying disease) vasculitis syndromes (Table 27.1). Accumulating evidence now supports the involvement of autoimmune processes in primary vasculitis syndromes [such as Wegener’s granulomatosis (WG), Churg-Strauss syndrome (CSS), and microscopic polyarteritis] in which anti-neutrophilic cytoplasmic antibodies can be detected.

TABLE 27.1 CLASSIFICATION OF VASCULITIS

Primary Vasculitis

Aorta and main branches:

• Takayasu aortitis (aortitis syndrome)

• Giant cell arteritis (temporal arteritis)

• Kawasaki disease

Medium and small muscular arteries:

• Classical polyarteritis nodosa

• Wegener’s granulomatosis

• Churg-Strauss syndrome (allergic granulomatosis agitis)

• Microscopic polyarteritis

Capillaries, arterioles, venules:

• Essential mixed cryoglobulinemia

• Henoch-Schönlein purpura

• Hypersensitivity vasculitis

Others

• Cutaneous vasculitis syndromes

• Isolated central nervous system vasculitis

• Thronboangiitis obliterans (Burger disease)

Secondary Vasculitis

• Vasculitis associated with collagen-vascular or rheumatic diseases (RA, SLE, PM/DM, SSc, overlap syndrome, MCTD, Sjogren syndrome, Cogan syndrome, anti-phospholipid syndrome, Behcet disease, relapsing polychodritis, spondyloarthropathies, sarcoidosis)

• Vasculitis associated with malignant diseases

• Vasculitis associated with infectious disease

• Vasculitis related to substance abuse

• Radiation vasculitis

• Transplant vasculitis

Primary vasculitis and vasculitis associated with collagen-vascular diseases have been shown to involve immunopathologic mechanisms.¹ Immune complex formation and subsequent complement activation are the main steps in the pathogenesis of systemic lupus erythematosus (SLE). In addition, increasing evidence supports the notion that mechanisms other than those involving immune complexes may be involved in the pathogenesis of vasculitis associated with SLE.¹ In this chapter, we summarize the clinico-pathologic features and discuss the pathogenesis of vasculitis in the prototype autoimmune disease SLE.

CALIBER OF AFFECTED VESSELS AND CLINICAL CONDITIONS

Vasculitis syndromes can be divided into several subgroups based on the size of the affected vessels (Table 27.1 and Fig. 27.1).^5,⁶ Given the size of the affected vessels, one can speculate on the clinical manifestations¹ (Fig. 27.1). Vasculitis in the capillaries, arterioles, or venules in the dermis may result in erythema, palpable purpura, or livedo reticularis. The pathologic features of these conditions are largely leukocytoclastic vasculitis, including hypersensitivity vasculitis (HV), mixed cryoglobulinemia, and Schönlein-Henoch syndrome. The prognosis for these conditions is fairly good.

Fig. 27.1 Caliber of affected vessels in the vasculitic syndromes. Left: caliber of affected vessels in the given clinical manifestations. Right: an individual disease among the vasculitis syndromes.

In contrast, vasculitis in small and medium-size muscular arteries sometimes leads to the infarction of vital organs (the most life-threatening condition in vasculitis syndromes). Necrotizing vasculitis is a typical pathologic picture in this subgroup, particularly in classical polyarteritis nodosa (PAN).¹ Vasculitis affecting large vessels, such as the aorta or main branches, and occurring in conditions such as Takayasu aortitis and temporal arteritis (TA) produces unique clinical manifestations (e.g., pulselessness, hypertension, jaw claudication, and headaches). Necrotizing vasculitis is the most important entity in clinical settings in terms of prognosis because it is intractable and often fatal.¹

INCIDENCE OF VASCULITIS IN SLE

Vasculitis in SLE is a common complication.¹ Cutaneous vasculitic lesions (representing small-vessel involvement) are most common, whereas necrotizing visceral medium- and large-vessel involvement (mimicking primary vasculitic syndromes) may also occur (Fig. 27.1).¹ On the other hand, granulomatous large-vessel disease does rarely occur in connective tissue diseases (anecdotal evidence of an SLE case with granulomatous vasculitis complications has been reported).¹

In a cohort of 540 SLE patients, vasculitis was reportedly observed in 194 cases (36%), and the calculated number of new cases was 0.053 persons/year. Vasculitis was cutaneous in 82.5% of these patients (29.6% overall) and visceral in 12.4% (5% overall). In our experiences with 188 SLE patients, 32.7% of the patients experienced vasculitis. The vasculitis was cutaneous in 78% of these patients (25.5% overall) and visceral in 22% (7.2% overall), suggesting a clinical picture similar to that seen in the previous study (Table 27.2). Among the first episodes of visceral vasculitis in a Mexican study, 66% were mononeuritis multiplex, 17% were digital necrosis, 10% were large-artery vasculitis of the limbs, and 6% were organ infarctions. In contrast, organ infarction was observed in 59%, digital infarcts in 14%, large-artery vasculitis of the limbs in 14%, retinal arteritis in 9%, and mononeuritis in 5% of patients in our institution—indicating different patterns for distinct ethnic groups and environments.

TABLE 27.2 CLINICAL MANIFESTATIONS OF VASCULITIS IN SLE PATIENTS

Clinical Manifestations	Dreskins Study (%, n=540)	Saitama Experience (%, n=188)
Total Vasculitis	36	33
Cutaneous	83	78
Visceral	17	12
Visceral Vasculitis
Mononeuritis multiplex	66	5
Digital necrosis	17	14
Large artery vasculitis	10	14
Organ infarcts	6	59
Retinal arteritis	n.d.	9

The Mexican study also reported that patients with vasculitis had a longer disease duration and follow-up period, a younger age of SLE onset, and a higher incidence in men than SLE patients without vasculitis. Manifestations associated with vasculitis include myocarditis, psychosis, the Raynaud’s phenomenon, serositis, leukopenia, lymphopenia, pleuritis, and anti-phospholipid syndrome. It should be noted that the most frequent manifestation of SLE, glomerulonephritis, was not associated with vasculitis in this series.¹

DIFFERENTIAL DIAGNOSIS OF VASCULITIS AND VASO-OCCLUSIVE DISEASE

Vasculitis occurs in more than half of all patients with SLE, whereas the incidence of anti-phospholipid syndrome (a vaso-occlusive disease) in patients with SLE is about 15%. Although both conditions can be life threatening, aggressive anti-inflammatory therapy is indicated for SLE vasculitis and anti-coagulant therapy is indicated for anti-phospholipid syndrome (requiring a correct diagnosis). However, a differential diagnosis between these two entities is often difficult, especially when a tissue biopsy cannot be easily obtained.¹

The situation is much more complicated if both conditions are simultaneously found in a given biopsy sample, which is often the case. This situation also complicates the analysis of the pathologic mechanism in vasculitis patients. Diagnostic surrogate markers for vasculitis, including soluble adhesion molecules or soluble forms of the thrombin receptor thrombomodulin in the patient’s sera, can assist in a differential diagnoses.¹

PATHOGENESIS OF VASCULITIS IN SYSTEMIC LUPUS ERYTHEMATOSUS

Immune Complexes

The etiology of vascular inflammation is not completely understood. However, the basic pathogenic mechanisms can be explored. The role of immune complexes (ICs) in the inflammatory manifestations of SLE is well documented, particularly in lupus nephritis. In this respect, Churg suggested that evidence of the involvement of ICs in human vasculitis was circumstantial and indirect for the following reasons:¹ serum ICs are rarely detected and the complement level is high in patients with vasculitis, ICs cannot be detected in the vessel wall but are sometimes positive in the healthy skin of patients, and patients with vasculitis rarely have glomerulonephritis complications (the hallmark of immune complex disease), as shown in the Drenkard study.

Autoantibodies

One promising factor in the pathogenesis of vasculitis may be an autoantibody-mediated process. Although the anti-basement membrane antibody is obviously indispensable to the pathogenesis of Goodpasture syndrome, an autoantibody that directly induces vasculitis in SLE patients has not been reported.¹ In fact, anti-neutrophil cytoplasmic antibodies (ANCAs) that have a key role in primary vasculitis syndromes such as Wegener’s granulomatosis, Churg-Strauss, and microscopic polyangitis¹ are infrequent in SLE.¹ However, anti-endothelial cell antibody (AECA) and anti-phospholipid antibody are frequently detected in patients with SLE,¹ and accumulating evidence suggests that these antibodies may be involved in vascular injuries.

Such antibodies may bind to their targets and cross-link neutrophils or lymphocytes, triggering subsequent inflammatory processes.¹ Numerous pitfalls in the use of the cyto-ELISA assay to detect AECA have been reported because reproducible results are difficult to obtain. Moreover, the target antigens recognized by AECA have not been identified. Given these limitations, the binding of these antibodies may induce the up-regulation of adhesion molecules, the production of cytokines and chemokines, or apoptosis in the endothelial cells.¹

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