Anti-pyruvate dehydrogenase complex (anti-PDC) antibodies, which are the hallmark of PBC, have been detected in other autoimmune rheumatic diseases by immunoßuorescence. In a multicenter study, Zurgil et al. [32] examined sera from 1,400 patients with autoimmune rheumatic diseases and showed that anti-PDC antibodies detected by ELISA were present in 22% of SS patients, 17% of SLE patients, 10% of rheumatoid arthritis patients, and 10% of scleroderma patients. The prevalence of anti-PDH was higher among patients with coexistent SS and either SLE or RA compared to patients with only SLE or RA [32].

17.3Autoimmune Hepatitis (AIH)

AIH is a chronic autoimmune liver disease of unknown etiology that can progress to cirrhosis. It is characterized histologically by an interface hepatitis, biochemically by elevated transaminase levels, and serologically by the presence of autoantibodies and increased levels of immunoglobulin G. Seropositivity for smooth muscle and/or antinuclear antibodies deÞnes type 1 AIH, while positivity for liver kidney microsomal type 1 antibodies deÞnes type 2 AIH, more common in pediatric ages [33, 34]. Anti-inßammatory/immunosuppressive treatment usually induce remission, since amelioration of symptoms is observed along with improvement in biochemical markers (aminotransferases, bilirubin, gamma globulin levels) and histological Þndings [35].

AIH and SS are rarely observed together. Until 2009, 56 cases of coexistence of AIH with SS had been described (all of them were of type 1 AIH) [20]. Of note, there are overlapping cases of AIH-PBC as up to 8% of AIH patients have autoantibodies against PDC. These individuals have histological features compatible with both AIH and PBC and a cholestatic biochemical pattern [36]. Indeed, many of the cases described with coexistence of SS with AIH manifested characteristics that were not typical for AIH but were consistent with the diagnosis of an overlapping syndrome of AIH-PBC.

17.4 Hepatitis C Virus (HCV) Infection and Sicca Syndrome

Viral infection has been considered for a long time as a putative trigger for SS. A possible association between HCV (found in the saliva) and SS was reported for the Þrst time by Haddad in 1992 [37], who found that histological changes characteristic of SS were signiÞcantly more common in anti-HCV positive patients (57%) compared to controls (5%). From these patients, less than half complained of dry mouth and none reported dry eyes. Only later, Pawlotsky et al. examined 61 labial minor salivary gland biopsies of anti-HCV positive patients

and reported that 49% had lymphocytic capillaritis. However, these patients did not have any sicca features or positive anti-Ro/SSA antibodies [38]. Scott et al., comparing salivary gland biopsies from 22 HCV patients and 10 SS patients, showed that there was similar degree of tissue damage but a lesser extent of inßammation in samples from HCV patients compared with those from SS patients [39]. Koike et al. reported that transgenic mice expressing HCV envelope genes developed exocrinopathy of lacrimal and salivary glands, which resembled SS [40].

HCV infection can produce a clinical picture that is very similar to SS. Comparing SS patients with and without HCV infection, SS patients with chronic HCV infections manifest a higher frequency of cryoglobulinemia and rheumatoid factor positivity compared to SS patients who do not have HCV, but the prevalence of anti-Ro/SSA and anti-La/SSB is lower. Extraglandular manifestations such as pulmonary, renal, or joint involvement are less common among HCV-infected SS patients [41Ð44]. In 2006, Ramos-Casals et al. compared SS patients who had autoimmune liver involvement with SS patients who had viral liver involvement. They reported that liver tests were elevated in the same pattern in the two groups, but the patients with autoimmune liver involvement had higher mean values of sedimentation rate, circulating gamma-globulins, and higher prevalence of serum ANA, AMA, anti-SMA, and anti-Ro/SSA and anti-La/SSB, while patients with chronic viral hepatitits had a higher frequency of cryoglobulinemia and hypocomplementemia [45].

Considering all these Þndings, HCV infection appears to be able to cause a clinical picture that is very similar, but not identical, to SS. In addition, there are histological and serological differences between these two clinical entities. Thus, a term that may be appropriate to describe this situation is Òsicca syndrome associated with HCV infection.Ó

17.5 Algorithm for the Diagnosis of Liver Involvement in SS

Taking into account all the above, we propose the following algorithm for patients with SS who have altered liver function tests (Fig. 17.1). First, hepatic steatosis, drug-induced liver injury, and metabolic and lymphoproliferative disorders that can affect the liver need to be excluded. Second, HCV infection must be excluded. Third, the serological and immunological proÞles of the patient must be characterized. SS cases with a cholestatic pattern may have PBC (most of them are AMA positive). SS patients who have a hepatocellular biochemical pattern and are ANA or anti-SMA positive may have autoimmune hepatitis. Liver biopsy is reserved for cases in which the diagnosis cannot be made on the basis of serological or immunological proÞles, or when histological data are required for staging purposes.

Altered liver profile

Non-SS related

Metabolic/lymphoproliferative

Steatosis SS-related

Alcohol abuse

Hepatotoxic drugs

Fig. 17.1 Diagnostic algorithm for a SS patient with liver involvement. LFT liver function tests, AIH autoimmune hepatitis, PBC primary biliary cirrhosis, AIC autoimmune cholangitis

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Chapter 18

Pancreatic Disease in Sjögren’s Syndrome

and IgG4-Related Disease

Arezou Khosroshahi, John H. Stone, and Vikram Deshpande

Contents

A. Khosroshahi (*) • J.H. Stone

Division of Rheumatology, Allergy and Immunology, Massachusetts General Hospital, Boston, MA, USA

V. Deshpande

Department of Pathology, Massachusetts General Hospital, Boston, MA, USA