EP33 Sjögren’s and lymphoproliferative disorders

Abstract Case report - Introduction Sjögren’s syndrome (SS) is a chronic autoimmune inflammatory condition characterised by lymphocytic infiltration of predominantly exocrine glands as well as other organs involving more commonly in skin, lungs, and neurological system. It is associated with increased risk of both benign and malignant lymphoproliferative disorders. Case report - Case description A 29-year-old woman with 5-year history of Primary SS (ANA, Ro/La positive) was reviewed in a routine follow up. She has mild dry eyes, intermittent vasculitic rash around the ankles, occasional pleuritic chest pain but no cough or dyspnoea initially. She used artificial tears but took no regular mediations. Oxygen saturation at rest was 99% and BP 127/70. Heart sounds were normal, and chest was clear. Blood results showed alanine transaminase (ALT) had risen from 50 (normal 5-45) to 145 over 6 months. Viral screen (hepatitis, HIV, CMV, EBV) and liver ANA panel were negative. C4 was low 0.09 (n 0.15-0.55), C3 normal and DsDNA antibodies 1 (n 0-15.1). Ig G was high, fluctuating between 27 - 33 (n 7.67-15.9). ESR had been mildly elevated at 26 (n 0-19). CRP had always been within normal limits. Ultrasound abdomen showed enlarged spleen (15 cm). CT chest abdomen and pelvis showed multifocal groundless opacification affecting mid to upper zones, bilateral cyst formation, solid nodularity, and mild septal thickening with no pleural effusion. There were multiple prominent bilateral axillary and mediastinal lymph nodes measuring upto15 mm. The spleen measured 15.4 cm. Six months later, she developed mild dyspnoea on exertion. Examination revealed fine basal crackles. Oxygen saturation remained 99% at rest. TLco was mildly reduced and Kco in lower limit of normal. Echocardiogram was normal. Ultrasound guided core biopsy of axillary lymph node showed benign reactive features with follicular hyperplasia and plasmacytosis. The diagnosis of lymphocytic interstitial pneumonitis was made. She was started on a reducing dose of Prednisolone 30 mg and Mycophenolate stepwise increment to 1 gm BD. Chest pain resolved shortly after starting glucocorticoid therapy and exercise tolerance improved. Liver enzyme normalised. Case report - Discussion The diagnosis of lymphocytic interstitial pneumonia (LIP) in this patient was incidental from the retrospective investigation of the persistently abnormal unexplained liver function test. Splenomegaly is a recognised manifestation of active systemic SS. The main differential diagnoses are lymphoma and other types of interstitial lung diseases (ILD). Her presentation was insidious and there were no constitutional symptoms. Her ANA, Ro, La and Rheumatoid factor were strongly positive. She has hypergammaglobulinemia which is commonly associated with LIP. Histological findings were typical reactive changes with characteristic polymorphic plasmacytosis. In the absence of malignant lymphoid cells and radiological features of ground glass changes and bilateral cysts formation suggested that the most likely diagnosis was LIP secondary to primary SS. The management strategies vary for different types of ILD based on their etiological conditions. There are no specific guidelines for the treatment of LIP. For initial acute stage, glucocorticoid therapy is usually prescribed for symptomatic improvement. For later stages and cysts, immunosuppressants are used and depending on the severity, azathioprine, cyclosporin, rituximab and cyclophosphamide have been used. Median survival for LIP is 11.2 years. Increased risk of secondary infection because of immunosuppressive therapy is common and there are recommendations for atypical chest infection prophylaxis. Case report - Key learning points Interstitial lung disease is commonly associated with SS and predicts a higher mortality rate. Glucocorticoid is the main stay of treatment for ILD acute stage with active inflammatory changes. For refractory cases and chronic cystic stages on radiological findings, further immunosuppression therapy may be required. Standardised treatment guidelines are not available. Secondary chest infections may be seen in those with cystic disease and on immunosuppression. Close monitoring and MDT approach is required in the management of LIP. LIP may transform into lymphoma or co-present with lymphoma associated with SS.

Case report -Discussion: This lady believes to have contracted Hepatitis C in the early 80s during a surgical procedure for removal retained products of conception following an incomplete miscarriage in South Africa. She was found to be positive for hepatitis C in the early 90s when she tried to donate blood in the UK. She had genotype 1 hep C. on diagnosis her fibro scan was normal and live biopsy showed mild fibrosis. After regular surveillance during the following years, she was treated with AbbVie 3D regime and ribavirin in 2016 and she was declared to be clear in 2017 (Hepatitis Cwas undetectable). This lady received a diagnosis of Sjö gren's syndrome in the early 2000s which was based on the fact that she had Sicca symptoms, Positive ANA of 9.2, positive anti-La and anti-Ro, Rheumatoid factor of 13 and lymphocytic clusters in lip biopsy. There are many studies linking Hepatitis C and Sjö gren's syndrome. Sicca symptoms are common in hepatitis C, as chronic sialadenitis is a well-known extrahepatic manifestation. A recent meta-analysis showed a strong association between Hepatitis C infection and Sjö gren's syndrome (OR3.31). This lady was diagnosed with hypothyroidism in the early 90s. Thyroid autoantibodies were not checked then. Thyroid autoimmunity is quite common in Hepatitis C positive patients. Higher prevalence of anti-TPO (21%) and anti-thyroglobulin antibodies (17%) has been demonstrated in Hepatitis C positive population even before they develop hypothyroidism. She was diagnosed with Type 1 Diabetes mellitus in 1997 at the age of 55 after she presented with Diabetic ketoacidosis. She was strongly positive for Anti-GAD antibody (>2000). Again, pancreatic autoimmunity is highly prevalent in non-diabetic Hepatitis C population (1.4% vs 0.4%). There are several case reports of patients who developed type 1 DM after acute hepatitis C infection. Case report -Key learning points: As chronic infections are known to trigger autoimmune diseases, it is advisable to screen for them in patients with multiple or atypical autoimmune diseases. Treating the infection itself will leadto completeremissionof these autoimmuneconditions.

North West Anglia NHS Foundation Trust, Peterborough, United Kingdom
Case report -Introduction: We present a case of a young woman with long-standing history of difficulty swallowing and progressively worsening abdominal pain who was later found to have weakly positive ANA and microcystic changes in submandibular glands bilaterally. Barium swallow demonstrated gastroparesis and the diagnosis of primary Sjö gren's syndrome (pSS) was made. There is conflicting evidence in the literature onthe prevalence of gastroparesis in pSS population. The case is remarkablebecauseabdominalsymptoms and problemswith swallowing rather than sicca syndrome prompted investigations and later confirmed the diagnosis. Case report -Case description: A nineteen-year old woman had longstanding issues with dry throat, problems with swallowing and sensation of phlegm in the throat, which she felt had started after she swallowed a bone. Provisional diagnoses of globus pharyngeus and chronic throat clearing were made by ENT team. She had trials of sodium bicarbonate, Gaviscon and PPI. She then had a neck USS to exclude goitre and was found to have microcystic changes in submandibular salivary glands bilaterally. This prompted referral to Rheumatology clinic. She reported post-prandial abdominal pain with bloating and early satiety. She had transient pruritic rashes. Therewas no history of joint pains or swelling. She had dry eyes. There was no other history suggestive of connective tissue disorder. Her past medical history included tonsillectomy and iron deficiency anaemia secondary to heavy menses. Her family history was unremarkable. Examination did not demonstrate synovitis or rashes. Her cardiovascular and abdominal examination was normal. Her blood tests showed negative anticardiolipin antibody, negative ds-DNA, negative MPO and PR3, negative ANA by HEp2 and negative rheumatoid factor. She had a weakly positive smooth muscle antibody and a positive ANA by CIA which was negative by HEp2 and therefore thought to be of doubtful clinical significance. She had normal complement, creatine kinase and CRP, and a low ferritin with low haemoglobin, in keeping with known iron-deficiency anaemia.
In view of iron deficiency and low vitamin D levels coeliac screen was performed which was negative. Her chest x-ray was normal. Barium swallow demonstrated significant gastroparesis thus solidifying the diagnosis of Sjö gren's disease. She had a trial of metoclopramide to improve gastric motility, which was not effective. Following a consultation with Gastroenterologist shehad atrial of erythromycin which greatly improved her abdominalsymptoms and swallowing. Sheremains well.
Case report -Discussion: pSS is a chronic systemic autoimmune disease which primarily affects the exocrine glands, most commonly the salivary and lacrimal glands. The prevalence of pSS is estimated to be about 7 per 100,000 person-years. It is characterised by a high female-tomale ratio of 9:1 and the mean age of onset is around the 4th to 5th decade of life. Signs of an autonomic nervous system dysfunction involving the gastrointestinal and the urinary systems can be observed in the majority of pSS patients. However,thishighoccurrenceis rarelyassociatedwith clinically significant symptoms, according to one study. Nevertheless, another study of 38 patients with pSS, demonstrated a higher prevalence of selfreported symptoms of autonomic parasympathetic dysfunction, such as urinary disorder, and gastroparesis (females only) in comparison to controls. Our patient's presentation was unusual due to the early age of onset as well as the fact that it was the swallowing problems that triggered autoimmune investigations. She did not report classic sicca symptoms initially, therefore the index of suspicion of underlying primary Sjö gren's syndrome was low. The most prominent clinical symptom was abdominal pain and bloating as well as a feeling of fullness after meals. Her immunology screen was not typical of Sjö gren's syndrome with negative anti-Ro and anti-La antibodies, negativerheumatoid factor, and normal CRP. The patient does not meet ACR criteria for diagnosis of Sjö gren's syndrome, as there is no tissue diagnosis and lacrimation and salivary tests have not been performed yet. However, the presentation with gastroparesis, sicca symptoms, microcystic changes in salivary glands and raised ESR are highly suggestive of primary Sjö gren's syndrome. Case report -Key learningpoints: Rarity of pSS and consequently small numbers of patients recruited in the studies of abdominal disorders in pSS make data interpretation difficult. Symptoms arise from impaired function of exocrine glands located across the entiregastrointestinalsystem.Theautonomic nervous system (ANS) may also be involved in the disease manifested by various autonomic dysfunction (AD) symptoms. In pSS, the degree of exocrine gland destruction and function often correlate poorly. Since exocrine secretion is modulated by the ANS, impaired secretion could partly be due to interferencewith nervous signals to the exocrine glands. There is also an immunological hypothesis of symptoms progression in pSS. Such an association between autoimmunity and GI dysfunction has been suggested previously, as there have been reports of coexisting inflammatory bowel disease and severe dysmotility. There is evidence that patients with pSS have antibodies against muscarinic receptors located in vascular smooth muscle cells, particularly in gastrointestinal and genitourinary systems as well as exocrinegland cells. Gastroparesis is perhaps better known in association with diabetes, with a prevalence between 30% and 50%. However, in one study involving 28 patients with pSS 43% of patients showed signs of impaired gastric emptying, while 29% fulfilled the criteria for gastroparesis. Another study demonstrated that a pathological delay in gastric emptying was present in 70%of patients with pSS. By presenting this case report we are hoping to generate a discussion and learn from experience of other centres in management of these patients. Given the early age and childbearing potential of the patient treatment options are limited. There are reports of successful use of intravenous immunoglobulin in patients with pSS which was shown to neutralize antimuscarinic M3 receptor antibodies and may improve symptoms of autonomic dysregulation.

Great Western Hospital, Swindon, United Kingdom
Case report -Introduction: Sjö gren's syndrome (SS) is a chronic autoimmune inflammatory condition characterised by lymphocytic infiltration of predominantly exocrine glands as well as other organs involving more commonly in skin, lungs, and neurological system. It is associated with increased risk of both benign and malignant lymphoproliferative disorders. Case report -Case description: A 29-year-old woman with 5-year history of Primary SS (ANA, Ro/La positive) was reviewed in a routine follow up. She has mild dry eyes, intermittent vasculitic rash around the ankles, occasional pleuritic chest pain but no cough or dyspnoea initially. She used artificial tears but took no regular mediations. Oxygen saturation at rest was 99% and BP 127/70. Heart sounds were normal, and chestwas clear. Blood results showed alanine transaminase (ALT) had risen from 50 (normal 5-45) to 145 over 6 months. Viral screen (hepatitis, HIV, CMV, EBV) and liver ANA panel were negative. C4 was low 0.09 (n 0.15-0.55), C3 normal and DsDNA antibodies 1 (n 0-15.1). Ig G was high, fluctuating between 27 -33 (n 7.67-15.9). ESR had been mildly elevated at 26 (n 0-19). CRP had always been withinnormal limits. Ultrasound abdomen showed enlarged spleen (15 cm). CT chest abdomen and pelvis showed multifocal groundless opacification affecting mid to upper zones, bilateral cyst formation, solid nodularity, and mild septal thickening with no pleural effusion. There were multiple prominent bilateral axillary and mediastinal lymph nodes measuring upto15 mm.The spleenmeasured 15.4 cm. Six months later, she developed mild dyspnoea on exertion. Examination revealed fine basal crackles. Oxygen saturation remained 99% at rest. TLco was mildly reduced and Kco in lower limit of normal. Echocardiogram was normal. Ultrasound guided core biopsy of axillary lymph node showed benign reactive features with follicular hyperplasia and plasmacytosis. The diagnosis of lymphocytic interstitial pneumonitis was made. She was started on a reducing dose of Prednisolone 30 mg and Mycophenolate stepwise increment to 1 gm BD. Chest pain resolved shortly after starting glucocorticoid therapy and exercisetolerance improved. Liver enzyme normalised. Case report -Discussion: The diagnosis of lymphocytic interstitial pneumonia (LIP) in this patient was incidental from the retrospective investigation of the persistently abnormal unexplained liver function test. Splenomegaly is a recognised manifestation of active systemic SS. The main differential diagnoses are lymphoma and other types of interstitial lung diseases (ILD). Her presentation was insidious and there were no constitutional symptoms. Her ANA, Ro, La and Rheumatoid factor were strongly positive. She hashypergammaglobulinemia whichis commonly associated with LIP. Histological findings were typical reactive changes with characteristic polymorphic plasmacytosis. In the absence of malignant lymphoid cells and radiological features of ground glass changes and bilateral cysts formation suggested that the most likely diagnosis was LIP secondary to primary SS. The management strategies vary for different types of ILD based on their etiological conditions. There are no specific guidelines for the treatment of LIP. For initial acute stage, glucocorticoid therapy is usually prescribed for symptomatic improvement. For later stages and cysts, immunosuppressants are used and depending on the severity, azathioprine, cyclosporin, rituximab and cyclophosphamide havebeen used. Median survival for LIPis 11.2 years. Increased risk of secondary infection becauseofimmunosuppressive therapyiscommonandtherearerecommendations for atypical chestinfection prophylaxis. Case report -Key learning points: Interstitial lung disease is commonly associated with SS and predicts ahigher mortality rate. GlucocorticoidisthemainstayoftreatmentforILDacutestage withactive inflammatory changes. For refractory cases and chronic cystic stages on radiological findings, furtherimmunosuppression therapymay be required. Standardised treatment guidelines are not available. Secondary chest infections may be seen in those with cystic disease and onimmunosuppression. Close monitoring and MDT approach is required in the management of LIP. LIP may transform into lymphoma or co-present with lymphoma associated withSS.

King's College Hospital, London, United Kingdom
Case report -Introduction: Sjö gren's Syndrome (SS) is a chronic autoimmune inflammatory condition characterized by lymphocytic infiltration of the lacrimaland salivaryglands resulting in dry eyesand mouth. Onethirdof patients present with systemic extra glandular manifestations, including neurological symptoms. Sjö gren's syndrome as a paraneoplastic mimic to ovarian cancer has been rarely reported in the literature. We present the caseofa49-year-oldfemalepatientwhowasreferredtorheumatologywith features suggestive of Sjö gren's syndrome which were likely to have been triggeredbyanunderlyingprimaryovarianmalignancy. Case report -Case description: A 50-year-old female was referred from neurology with a three-week history of right sided facial numbness affecting her lower lip and chin, fatigue, and concomitant oral sicca syndrome. She also experienced facial allodynia to the right side of her lower lip. There was noassociated fever, night sweatsorweight loss. Her past medical history was unremarkable except for mild eczema. Physical examination revealed marked reduction to soft and sharp touch with normal two-point discrimination. Dryness of the mucosa was noted on examination of the oropharynx. The remainder of her neurological examination was unremarkable. Her cardiovascular, respiratory, and abdominal examination revealed no abnormality. There was no enlargement of the salivary glands, cervical adenopathies, joint pathology or rashes. Her erythrocyte sedimentation rate and C-reactive protein were elevated at 53mm/hr (0-22mm/hr) and 27mg/L (0-5mg/L) respectively. Immunology revealed a positive Ro-52 antibody on the extended ENA panel but negative ANA. Her full blood count, renal and liver function, immunoglobulins and protein electrophoresis, haematinics and HBA1c were within normal limits. Schirmer's testing was also negative. Magnetic resonance imaging of the brain showed bilateral cisternal trigeminal nerve pathological enhancement withextensionsintothedeepdivisionswithherface,raisingthepossibilityofa vasculitic process. Despite her age, sex, xerostomia, and presence of Ro-52 antibodies which may be suggestive of primary Sjö gren's syndrome, she did not meet the 2016 classification criteria. Considering these findings, raised inflammatory markers and equivocal antibodies, she underwent an FDG PET scanwhichshowedthe presence of aprimaryovarianmalignancy withmetastatic spread to her mediastinal lymph nodes and peritoneal tumour deposition.Thepatienthassubsequentlybeenreferredtothegynae-oncologyteam forfurthergrading,stagingandconsiderationofchemotherapy. Case report -Discussion: There is a well-established association between Sjö gren's syndrome and haematological malignancy, notably non-Hodgkin's lymphoma. It is also known that paraneoplastic autoimmune rheumatic syndromes such as the idiopathic inflammatory myopathies can precede the clinical manifestations of solid organ tumours. Sjö gren's syndrome as a paraneoplastic mimic to ovarian cancer has been rarely reported. One cohort study of 111 patients investigating the incidence of non-lymphoid cancers in SS documented only a sole case of ovarian malignancy. Sensory trigeminal neuropathy in association with Sjö gren's 's syndrome has been reported and is characterised by numbness and hyperaesthesia to the face. The prevalence of this presentation varies, but one large case series reported that 17% (15/92) had a pure sensory trigeminal neuropathy, six had symmetrical involvement. While the distribution and character of this patient's neuropathy could be explained by a Sjö gren's related sensory syndrome, there is overlap in the underlying pathogenesis in the development of Sjogren's associated polyneuropathy and paraneoplastic neurologic syndromes (PNS). In SS an autoimmune vasculitic process and autoantibodies are thought to be contributors to the pathogenesis of nerve damage. There is a suggestion that trigeminal neuropathy occurs secondary to vasculitis or ganglionitis. Similarly, autoimmune processes are implicated in pathogenesis of PNS where the driving hypothesis is that tumours express antigens present on nervous system tissues. Several paraneoplastic antigens have been described, including Ro-52 antibodies. Of interest, one study reported the co-existence of Ro-52 and Jo-1 antibodies in patients with anti-synthetase syndrome appeared to confer a higher risk of malignancy and a further small study of 38 Ro-52 positive patients reported that 8 (18%) had past or present malignancy. We felt that the acute onset of this patient's sicca symptoms and trigeminal nerve enhancement on MRI scan warranted further investigation for a more sinister underlying pathology.

Case report -Key learningpoints
Ovarian cancer can present as a mimic of Sjö gren's syndrome Up to one third of patients with primary Sjö gren's syndrome can present with extra-glandular manifestations, including cranial nerve neuropathies. Sensory trigeminal neuropathies have been reported in the literature and can occur bilaterally The rapid onset of symptoms and the absence of other classification criteria should prompt further investigations to characterise the disease further Ro-52 antibodies have been associated with Sjogren's syndrome and systemic lupus erythematosus, but also in some small studies with an increased risk of malignancy. Further studies are warranted into the significance of isolated Ro-52 positivity. Is it important for rheumatologists to remain vigilant for co-existing malignancies, particularly breast and ovarian cancer? Finally, this was a completely unexpected diagnosis for our patient who had seen two different specialities prior to a rheumatological assessment and has now been referred to the gynae-oncology specialist nurse for further support. Empathy, effective communication, and multi-disciplinary team working remain pivotal to our speciality.

Michael Chen-Xu and Mark Sykes
West Suffolk NHS Foundation Trust, Bury St Edmunds, United Kingdom