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role in the pathogenesis of vasculitis in SjS, but the inciting event(s) leading to immune complex deposition within blood vessel walls at a point years into the disease process remain unknown. B cell activation and the production of cryoglobulins also contribute in many cases of vasculitis, but the relationships of these and other immunologic events to the development of clinical vasculitis are not clear [6]. Type II cryoglobulins, generally monoclonal IgM-kappa immunoglobulins that possess rheumatoid factor activity, appear to participate directly in disease pathophysiology in many cases of SjS-associated vasculitis. However, these cryoglobulins are neither necessary nor sufficient to cause vasculitis in SjS.
12.6Clinical Findings
Vasculitis is usually not a subtle event in SjS and can generally be suspected and recognized easily. The clues to the presence of vasculitis are found most often in the skin, but multiple organs and tissues can be involved. In addition to cutaneous involvement, vasculitis has been described in SjS in the peripheral nerves, muscles, kidneys, gallbladder, small and large bowel, liver, spleen, pancreas, salivary glands, central nervous system, and the organs of the reproductive tract. The discussion in this chapter focuses upon vasculitis in the skin and the peripheral nervous system, two organs in which vasculitis commonly occurs in SjS, and on the central nervous system, an organ system in which true vasculitis is rare.
12.7Skin
Ramos-Casals et al. described the clinical, laboratory, and histological features of SjS patients with skin vasculitis, demonstrating that small-vessel involvement was the rule in 95% of cases and that only 5% of patients had medium-vessel involvement [3]. Small-vessel cutaneous vasculitis can be manifested by a host of skin findings, including purpura (both palpable and non-palpable) (Fig. 12.1), urticaria, pustules, vesicles, and flat, confluent patches [7]. In contrast, medium-vessel disease is associated with livedo reticularis (racemosa), nodules (Fig. 12.6), and ulcers (Fig. 12.2). Cutaneous vasculitis is occasionally the complaint that brings the patient’s SjS to medical attention [8].
Approximately three quarters of SjS patients with vasculitis manifest palpable purpura. Purpura, which can be associated with stinging or pain, appears most commonly on the lower limbs. In extensive cases, the upper extremities, lower trunk, and even the face can be involved. Purpuric lesions tend to be exacerbated by dependency and activity and may leave residual hyperpigmentation (Fig. 12.7). Palpable purpura is closely associated with the presence of circulating cryoglobulins, but cryoglobulins are not necessary for vasculitis to occur.
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Fig. 12.6 Nodules. Medium-vessel vasculitis in Sjögren’s syndrome can be manifested by cutaneous nodules
Fig. 12.7 Palpable purpura with hyperpigmentation. The vasculitis in Sjögren’s syndrome is frequently recurrent, with repeated bouts of purpura. This figure reveals acute purpuric lesions superimposed upon older, healed lesions that have left a residual hyperpigmentation due to lipofuscin
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Fig. 12.8 Urticaria. Sjögren’s syndrome-related vasculitis leads occasionally to lesions that resemble urticaria, although pruritus is often not associated with these findings.
The lesions last for more than 24 h permitting them to be distinguished from common urticaria (which resolve generally in 6–12 h). Koebner’s phenomenon, the purpuric streaks on the skin, is also evident in this figure
Erythematous macules and papules appear in a significant subset of patients with SjS-associated cutaneous vasculitis and may be termed urticaria with or without the presence of pruritus (Fig. 12.8). These lesions differ from the classic urticaria in that they last for longer than 24 h (classic urticaria generally resolve in 6–12 h). Other clinical findings in the cutaneous vasculitis of SjS include violaceous discoloration of fingers and toes, subcutaneous nodules (Fig. 12.6), and ulcerations caused by medium-vessel disease in the deep dermis or sub-cutis.
12.8Peripheral and Central Nervous System
Peripheral neuropathy is a well-described manifestation of vasculitis in SjS patients. Although vasculitis is an important mechanism of peripheral neuropathy, it is far from the only cause of peripheral neuropathy in this disease. The prevalence of peripheral neuropathy in SjS is estimated to be about 2%, and the various causes can be dissected through electrophysiological studies and biopsies of skin, peripheral nerve, and muscle.
Among the multiple types of peripheral neuropathy, only sensorimotor neuropathies and mononeuritis multiplex are associated with vasculitis of the vasa nervosum. In contrast, pure sensory neuropathies, sensorimotor demyelinating polyneuropathies, and small fiber neuropathies occurring in the context of SjS appear to have other
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disease mechanisms. It is important to remember that most peripheral nerves are mixed nerves, containing both motor and sensory fibers. Thus, when vasculitis involves peripheral nerves, both motor and sensory findings are generally present.
Biopsy specimens from patients with moneuritis multiplex show fibrinoid necrosis in the vasa nervosum and infiltrates by T cells and macrophages. In a study of 40 patients with neuropathy secondary to SjS [9], the authors described 8 patients with lymphocytic vasculitis and 14 with necrotizing vasculitis. Comparing these two subgroups of SjS patients, no significant difference regarding the clinical or the biological picture has been revealed [9]. Patients with peripheral neuropathy occurring in the setting of SjS should be evaluated for the possibility of vasculitis, including perhaps biopsy of both nerve and muscle. The simultaneous biopsy of nerve and muscle is synergistic for the diagnosis of vasculitis and has an estimated sensitivity of 85% [10].
In contrast to peripheral nervous system vasculitis, the incidence of true CNS vasculitis in SjS appears to be very low [11, 12]. The diagnosis is difficult to make because of imperfect sensitivities of brain biopsy. High prevalences of CNS involvement (not necessarily vasculitis) have been reported in SjS in the past, but such reports likely represent substantial overestimates of the true prevalence of CNS disease. They are probably attributable to the fact that patients who did not strictly fulfilled the diagnostic criteria of SjS were included [12]. The enrichment of reported cases of CNS disease is likely due to the inclusion of patients with overlap syndromes of SLE and SjS rather than primary SjS.
12.9Other Organs
Vasculitis that affects other organs in SjS such as the gastrointestinal tract, kidneys, and lungs is unusual but known to occur. In such cases, the vessels involved are usually medium-sized and the vascular inflammation in these vessels typically co-exists small-vessel vasculitis and cutaneous disease [4]. Vasculitis of internal organs can be life-threatening, especially if the physician is not familiar with the subtle clinical and laboratory findings accompanying this situation. Such findings include diarrhea, “intestinal angina” (post-prandial abdominal pain), clinical symptoms of appendicitis, hypertension with hematuria and proteinuria (mesangial proliferative glomerulonephritis) [13], myalgias (muscle involvement), and elevated acute phase reactants. Systemic vasculitis appears late in the natural history of SjS and is accompanied by cryoglobulinemia in about half of the cases.
12.10Vasculitis and Mortality
The development of vasculitis constitutes an adverse prognostic sign in SjS. Ioannidis et al. [14] identified the fact that the combination of palpable purpura and low C4 serum levels correlate with the evolution of lymphoproliferative disorders in