*4.10. Pancreatic and Hepatobiliary Manifestations*

The pancreas being an exocrine gland, it is not surprising to find cases of acute pancreatitis, chronic pancreatitis or pancreatic insufficiency in 0–7% of pSS patients. Moreover, 25% to 33% prevalence of chronic pancreatitis-like morphologic changes suggest that there are many asymptomatic cases [226]. Hepatomegaly is found in 10–20% of patients. Liver tests are disrupted in 10–50% of patients, usually mildly and with no particular clinical significance. pSS can be associated with Primary Biliary Cirrhosis (PBC)—another autoimmune epithelitis—or with autoimmune hepatitis (AH). Pseudolymphoma has been described to occur in liver like it may occur in salivary or lacrimal glands [226,227].

## *4.11. Uronephrologic Manifestations*

Schematically, renal involvement linked to pSS can be divided into 3 groups: (1) tubulointerstitial nephritis linked to autoimmune epithelitis characterized by peritubular lymphocyte infiltration, (2) glomerulonephritis associated with immune complexes and (3) disorders linked to the presence of specific autoantibodies. According to different cohorts, about 5% of pSS patients have a renal involvement. However, this figure seems clearly underestimated if occult tubular involvement is systematically assessed [211,228].

Tubular involvement can be associated with dysfunction of any part of the renal tubule and can be responsible for polyuropolydypsic syndrome, low molecular weight proteinuria, aminoaciduria, euglycemic glycosuria, acidosis with normal anion gap, hypokalaemia that may be complicated by paralysis or disturbed heart rhythm, hypophosphoremia linked to increased phosphate excretion that may be complicated by osteomalacia, nephrocalcinosis or the formation of recurrent kidney stones [228,229]. More anecdotally, acquired Gitelman or Bartter syndrome has been described, possibly linked to the presence of specific autoantibodies targeting transporters (ie NaCl co-transporter in Gitelman syndrome) [228,230]. Glomerular disease occurs later in the history of the disease and most often corresponds to a mesangioproliferative glomerulonephritis (MPGN) caused by the deposition of immune complexes, usually cryoglobulinemia, which should be looked for [211,228].

Interstitial cystitis is a chronic inflammatory disease of the bladder that can be found in pSS patients. This rare manifestation is characterized by complaints such as pollakiuria, lower abdominal pain, urinary urgency, painful micturition, haematuria and dysuria [231]. Interstitial cystitis can be complicated by bilateral hydronephrosis and obstructive renal failure [231].

#### *4.12. Haematological Manifestations*

Anaemia is present in 20% of pSS cases, usually normochromic normocytic, of various mechanisms: anaemia of chronic disease or haemolytic, more rarely secondary to aplastic or pernicious anaemia or myelodysplastic syndrome [232,233]. Leukopenia is found in 15% of patients and most often corresponds to lymphocytopenia. Agranulocytosis is rare. Thrombocytopenia is found in 15% of patients, of peripheral origin, whether or not involved in Evans syndrome [232,233]. Rare cases of Thrombotic Thrombocytopenic Purpura (TTP) [234–236] and Hemophagocytic lymphohistiocytosis (HLH) [237] have been described.

Reactive multiple lymphadenopathy is possible, statistically associated with the presence of synovitis [212]. The intense stimulation of B cells explains the occurrence of hypergammaglobulinemia, hyperviscosity syndrome, monoclonal gammapathy, cryoglobulinemia and amyloidosis [232,238]. The formation of immune complexes leads to complement fraction consumption.

CD4-Lymphocytopenia is mainly found in anti-Ro-SSA positive patients and is associated with an increased risk of non-Hodgkin's lymphoma (NHL) [232]. NHL has a prevalence of 4.3% in pSS patients [205]. Schematically, pSS-associated NHL can be divided into two main categories: the first has an indolent course and is dominated by the extranodal marginal zone (MZ) B cell lymphomas of MALT-type, and the second corresponds to the high-grade lymphomas such as de novo or secondary diffuse large B cell lymphoma (DLBCL). In pSS patients, MALT lymphomas are indolent diseases characterized by a good performance status, small tumour burden and infrequent B symptoms. They are preferably located in one or more extranodal sites such as SG, stomach, nasopharynx, lung, liver, kidney, orbit and skin [205]. It is interesting to note that almost all of these sites are organs involved in autoimmune epithelitis. Locoregional nodal involvement can be observed while bone marrow infiltration is rare. DLBCL are aggressive and have a poor prognosis. A certain proportion of them probably come from a transformation from a low-grade lymphoma. NHL mainly occurs in pSS patients with cryoglobulinemia, palpable purpura and C4 fraction consumption [205].
