Comment: Myalgias are found in nearly 30% of patients with primary SS, although the causes are diverse, including both non-inßammatory (mainly Þbromyalgia) and inßammatory (mainly myositis) processes. The key study was performed by Lindvall et al. [76] and they found that analytical data and histological Þndings do not correlate with clinical myositis. Thus, one third of patients with clinical myositis have normal histology while nearly half of the patients with histologically conÞrmed myositis have no clinical features.

3.4Myths and Pearls About Pathogenesis

3.4.1 Myth

Dryness in SS results from the total destruction of the gland.

Comments: In a lip biopsy from an SS patient with severe dryness, attention is usually focused on the dense lymphoid inÞltrates (shown in Fig. 3.1, frame A). However, it should be noted that residual acinar units are still visible [77].

Indeed, morphometric analysis has shown that only about 50% of the gland acinar or ductal tissue is replaced or destroyed [26, 78]. This may seem somewhat surprising, since a kidney or liver continues to function until its functional units are over 90% destroyed.

The interesting question is Òwhy has the residual gland stopped functioning?” Kontinnen et al. [79] have demonstrated that the glandular tissue (outside the lymphoid inÞltrate) still has its neural innervation based on immunohistology. Studies in man and murine models have indicated the presence of receptors for acetylcholine and other critical neurotransmitters [80Ð82]. It has been shown in animal models that the release of and response to neurotransmitters are strongly inßuenced by inßammatory cytokines including TNF and IL-1 [83Ð85].

Further, the release of metalloproteinases in the inßammatory environment may interfere with the secretory glandÕs ability to maintain spatial orientation necessary for glandular function [86].

Recently, there has been increased interest in the potential role of antibodies directed against the muscarinic M3 receptor [87, 88].

3.4.2 Pearl

The environment plays a key role in exacerbating the patient’s symptoms.

Comments: Although the patient has a decreased rate of aqueous tear formation and increased rate of evaporative loss due to the inßammatory process, each of these processes may be exacerbated by environmental factors.

Factors such as low humidity can be partially helped by humidiÞers and the effect of dry winds by Òwrap aroundÓ sunglasses or Òside shieldsÓ on glasses. However, additional factors such as the markedly decreased “blink rate” associated with the use of computer monitors are not usually appreciated.

Wolf et al. [89] have pointed out that the modern work place environment is often an ofÞce with low humidity where individuals spend a great deal of the day staring at computer screens. Using cameras mounted on the computers, they could demonstrate a 90% decrease in the normal blink rate as the workers concentrated on their computer monitors. Thus, concentration on the ÒscreenÓ can override the normal corneal surface conditions that lead to blinking and spreading of the available tears [90, 91].

3.4.3 Pearl

Antibody SS-A may play an integral role in the induction of SS and the type I IFN gene signature in salivary gland biopsies.

Comments: Recent studies by Bave and others have demonstrated that anti-SS-A antibody complex to the ribonucleoprotein complex (SS- A bound to hYRNA) can bind to Fcj receptors on plasmacytic dendritic cells. The internalized immune complex can then gain access to Toll receptors located in cytoplasmic vacuoles and stimulate production of type I IFN. This model ties together the genetics (HLA-DR3 that