Introduction

The care of the SjogrenÕs syndrome (SS) patient is often shared by many specialists due to the multi-system involvement of this disease. Each of these specialists reads different journals and rarely attends common educational meetings. Thus, each specialty has a slightly different view of the ÒelephantÓ in the room. The primary goal of this book is to bring together a series of experts in different disciplines to provide a common dialogue regarding diagnosis and therapy for SS. Each chapter is written in a manner that preserves the sophistication of their respective Þeld but that employs terminology that will be clear to other specialtists.

Although the rheumatologist frequently becomes the central ÒquarterbackÓ in the treatment of the SS patient, he/she must be familiar with the diagnostic procedures and therapeutic approaches of the other specialties to avoid medication interactions and coordination of care. An additional goal for this volume is to include contributors from around the world including

R.I. Fox ( )

Rheumatology Clinic, Scripps Memorial Hospital and Research Foundation, La Jolla, CA, USA

e-mail: robertfoxmd@mac.com

Europe, the Middle East, South America, Australia, and Asia as well as the USA. Different medications (including herbal) and different diagnostic methods are used in various parts of the world, based on medical resources and technology available. These chapters provide examples about how to manage our patients in a cost-efÞcient manner and new approaches to therapy. Also, it is important for Òwestern physiciansÓ to recognize Òcenters of excellenceÓ among the emerging nations of the world because our patients increasingly travel to these regions for business and pleasure. Our patients may require medical care either for a complication of their SS or for an infection that is endogenous to that region while travelling. It is worth noting that in many parts of the world (as well as certain regions of the USA) the ÒprimaryÓ care of rheumatology patients is under the direction of non-surgical orthopedic surgeons in part to the shortage of available rheumatologists. This volume also is directed to Ònon-rheumatologistÓ who is providing care to the SS patient.

We are fortunate to have contributions in clinical specialties from

¥Ophthalmology

¥Oral medicine

¥Otolaryngology (ENT)

¥Hematology/Oncology

¥Neurology and psychology

¥Dermatology

¥Orthopedic surgery

¥Gastroenterology

¥Nephrology

This multitude of specialists also creates a sit-

uation where there may be disagreements about diagnosis, duplication of efforts, and conßicting therapies. In order to coordinate therapy between so many specialists and to avoid conßicting information/medications to the patient, we extensively use the Internet and transfer of Þles to participating physicians. The patient also needs to be part of the educational and therapeutic process.

Patients are increasingly computer literate and we encourage them to educate themselves regarding their disease and its therapy using resources including the Internet. However, we caution them to use the Internet wisely and use a search engine such as Google scholar (rather than simply Google) to Þnd validated information rather than the often frightening and misleading information found in various chat groups that are found during general web.

1.1Historical Background

The clinical features (both glandular and extraglandular) of the disease, as we currently recognize SS in its ßorid form, were largely outlined in 1956 by Bloch et al. [1]. This clinical report from Massachusetts General Hospital outlined the clinical features associated with a characteristic minor salivary gland pathology that had been recently reported by Morgan et al. in 1953 [2] of the same institution. This pathology report by Morgan et al. acknowledged that they had ÒrediscoveredÓ the minor salivary gland pathology that ÒMikuliczÓ initially reported in 1892 [3] and had been later reported by Sjogren in 1933 [4]. A simple Google scholar search since 1956 lists over 76,000 different articles. Yet the etiology remains largely unknown and the therapy unsatisfactory.

In SS patients with severe dryness, positive autoantibodies, and positive lip biopsies, the issue is the extent of extraglandular involvement and the approaches to therapy. However, many rheumatology consults are requested for evaluation of SS in the patient in whom a positive ANA is detected during the workup of myalgias, arthralgias, neuropathy, nephritis, or chronic fatigue. In these patients, there has been considerable debate about the classiÞcation criteria for patients and the role of the immune system in causing the clinical symptoms. The diagnosis may then have a signiÞcant impact on the types of therapy used. This clinical problem is particularly difÞcult in patients with sicca symptoms and ÒÞbromyalgiaÓ symptoms. The diagnostic criteria for SS (Table 1.1) are discussed in Chapter 5 by Vitali et al. and approaches to therapy of Þbromyalgia in Chapter 21 by Bowman. The ÒdisconnectÓ between Òseverity of clinical symptoms as judged by patientÓ and the objective measurements such as tear ßow, saliva ßow, or neurologic symptoms observed by the clinician is very high. This has led some experts such as Prof. Graham Hughes in London to joke that SS is actually a neurologic disease with peripheral manifestations [5].

Until 2003, there were multiple sets of diagnostic criteria for primary SS including those by American, European (Scandinavian, Italian, and Greek), and Japanese groups [6Ð9]. The inclusion criteria were so signiÞcantly different among these groups that the diagnoses of ÒSSÓ rendered by European physicians were almost 10-fold when utilizing the EEC criteria than in two different US criteria [10]. This discrepancy was largely due to inclusion in the original European criteria of patients with Þbromyalgia, hepatitis C-related sicca or dryness in association with AlzheimerÕs, or demyelinating disorders. Of importance to current readers, the discrepancy in diagnostic criteria led to confusion in the research and clinical trial literature. Thus, readers may be confused by very discrepant results and need to very carefully check the criteria used for inclusion in published studies.

Primary SS using the current consensus criteria is a systemic autoimmune disorder with a

prevalence of about 0.5% in the general population, with a female preponderance of 9:1, which is roughly similar to SLE [11]. This would make

SS one of the three most frequent autoimmune disorders [10], although it has received far less research and therapeutic attention than SLE or PSS.

There are two major age peaks of primary SS, with

¥the first peak incidence after menarche during the twenties to thirties;

¥the second peak incidence after menopause in the mid-50-year age range;

¥SS also presenting in children, as part of the spectrum of juvenile arthritis.

The criteria in current use is the EuropeanAmerican Consensus Group Modification of the European Community Criteria for SS [12] and is described in Chapter 5 by Vitali et al. The key feature of the new criteria is the requirement for objective evidence of the immune system in causing the sicca symptoms, as demonstrated by the requirement for either a characteristic minor salivary gland biopsy or autoantibody against SS-A. Due to logistics of obtaining biopsies in clinical practice, the patients usually fulÞll their diagnostic criteria based on their antibody status. Therefore, the methodologic pitfalls that inßuence diagnosis are brießy discussed below.

Diagnosis of secondary SS (2◦ SS) has not yet been addressed by the American European Consensus Group. However, in practice we usually require the patient to fulÞll the criteria for 1◦ SS and to additionally fulÞll American College of Rheumatology (ACR) criteria for an established connective tissue disease such as RA, SLE, dermatomyositis or myositis, PSS, or biliary cirrhosis. For ease of comparison, the diagnostic criteria for SLE and PSS are provided in Chapter 3.

Exclusions to the diagnosis of 1◦ SS include previous radiotherapy to the head and neck, lymphoma, sarcoidosis, graft-versus- host disease, infection with hepatitis C virus, human T-lymphotropic virus type I, or HIV. Measurements of tear and saliva ßow must be made in the absence of drugs that have anticholinergic side effects.

Although 1◦ SS patients are at increased risk for lymphoma, patients with pre-existing lymphoma are typically excluded from studies to ensure entry of a relatively homogeneous group into studies of therapy and prognosis.

In contrast to the patients with ßorid SS, there are a large number of patients referred to rheumatology with

¥a low titer ANA and vague symptoms of myalgia, trigger points, and fatigue or vague cognitive deÞcits, who are termed Þbromyalgia;

¥a positive ANA but who lack the sicca features of SS, particularly patients in whom the ANA is detected as part of the workup for other problems such as neuropathy, pneumonitis, or nephritis.

1.2Pitfalls in Diagnosis and Methodology

There are two common areas of confusion in clinical diagnosis of SS: (a) the speciÞcity/sensitivity of the ANA and (b) the evaluation of the minor salivary gland biopsy. These tests are generally considered our Ògold standardsÓ for diagnosis of SS and most physicians do not recognize the variability in the results of these tests. Thus, rheumatologists must interpret these results based on the method of laboratory analysis (i.e., IFA or ELISA) and the experience of the pathologist in evaluating minor salivary gland biopsies.

Both primary care physicians and other specialists frequently use the ANA as a ÒscreeningÓ test in patients with rheumatic disease symptoms. The diagnosis of SS is frequently made in a patient with vague symptoms and a positive ANA. However, Tan et al. [13] reported that the frequency in Ònormal individualsÓ of a positive ANA titer using Hep-2 cells at titer 1:40 was 31.7% of individual, at 1:80 was 13%, at 1:160 was 5%, and at 1:320 was 3.3%.

Using a Bayesian analysis, Lightfoot et al. found similar results in ANA testing and calculated that the risk of an individual with an ANA 1:320 developing SLE or SS during a 10year follow-up period was less than 5% [14]. Thus, it is a common mistake for patients or their