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Case report - Introduction Primary Sjögren’s patients are a higher risk of developing non-Hodgkin lymphoma (NHL) compared with patients with other autoimmune disorders and to the general population. Parotid and submandibular salivary glands are the most frequent localization of MALT lymphomas in pSS. Here we report a case of marginal zone lymphoma of the breast in a patient with long-standing primary Sjögren’s, and we will discuss the clinical and serological predictors for the development of lymphoma. Case report - Case description A 79-year-old female with a 19-year history of primary Sjögren’s syndrome (anti-Ro, anti-La positive) was reviewed in the rheumatology clinic for progressive worsening of sicca symptoms. Her past medical history included recurrent pulmonary emboli, osteoporosis of the spine, asthma, microscopic colitis, Ischemic heart disease and hypothyroidism. She was a non – smoker and consumed minimal alcohol. Her past surgical history included excision of her left salivary gland, 10 years ago. She was undergoing investigation for a new left breast mass for which a biopsy revealed possible involvement by marginal zone lymphoma. A PCR was performed which was equivocal. Subsequently, she developed a right breast lump and an ultrasound scan showed a well-defined 23 x 10 mm oval hyperechoic lesion in the right upper quadrant and a 29 x 9 mm right axillary lymph node. A staging CT chest abdomen and pelvis and bone marrow sample revealed localized disease. Biopsy of breast lump was performed with PCR analysis. This revealed morphological and immunophenotypical appearances most consistent with a low-grade B –Cell lymphoma and favour a marginal zone lymphoma. The patient was reviewed by an oncologist and was treated with 24 Gy radiotherapy in 12 daily fractions and followed up by the advanced practitioner. Case report - Discussion Primary Sjögren’s Syndrome is an autoimmune disease characterised by lymphocytic infiltration of exocrine glands which can manifest in specific organs or as a systemic illness. Patients are at elevated risk of developing lymphoproliferative diseases including non-Hodgkin's lymphoma with a reported prevalence of 5%. On histological analysis, most patients demonstrate low-grade marginal zone B cell lymphoma with approximately 85% occurring in extranodal locations including the parotid and submandibular glands. Some patients may go on to develop high-grade lymphoma. Concerning overall disease activity, it has been recently demonstrated that a stable moderate/high disease activity, calculated either with the EULAR Sjögren’s syndrome disease activity index (ESSDAI) or with the ClinESSDAI, an ESSDAI variant excluding the biological domain, was independently associated with subsequent lymphoma occurrence. Symptomatic cryoglobulinaemic vasculitis (CV) is observed in about 3–4% of pSS patients and has been linked to the development of lymphoma. Other clinical markers of lymphoma such as palpable purpura, low levels of C4, lymphocytopenia, low levels of IgM, elevated levels of β2-microglobulin Malignant proliferation has been reported in the literature and, to the best of our knowledge, only two case reports of a marginal zone lymphoma of the breast complicating primary Sjögren’s syndrome exist. Case report - Key learning points 1/ This case emphasises the need for careful clinical examination in this exceedingly rare entity. 2/ Although parotid and submandibular gland are commonest extranodal site for NHL, other organs such as thyroid, ovaries and breast might be rarely be affected. 3/ Clinicians should be alert if there are some clinical and serological features such as cryoglobulin and persistently low complement which usually predicts the development of lymphoma.

Case report - Introduction Distal renal tubular acidosis (RTA) type 1 is a rare condition in adults, which is characterised by impaired distal urine acidification. It is caused by failure of alpha intercalated cells and presents with alkaline urine (pH.5.5), metabolic acidosis, hypokalaemia, osteomalacia, nephrocalcinosis and hypercalciuria. Autoimmune diseases, such as Sjögren’s Syndrome (SS) and Rheumatoid Arthritis are among the most common causes. RTA can be the presenting feature of the rheumatic disease. SS is typically characterised by impaired lacrimal and salivary gland function but has a broad spectrum of symptoms and disease severity, which includes renal involvement in up to 40%. Case report - Case description We present the case of a 29-year-old female, referred to rheumatology by endocrinology following a recent emergency admission. The patient, who had woken with severe muscle paralysis of sudden onset, presented at A&E and imminently suffered a Pulseless Electrical Activity arrest. Urgent investigations identified profound hypokalaemia (serum potassium During her admission, under the care of endocrine and renal teams, a diagnosis of Distal RTA was reached. A CT scan showed medullary nephrocalcinosis. Immunology results: ANA 1:2560 (speckled pattern) and strongly positive Ro antibodies; polyclonal IgG of 19g/l, normal complement. Renal function returned to normal and she had negligible albuminuria. The causation of RTA was not certain. She was discharged well and on magnesium, potassium, and bicarbonate supplements. No renal biopsy was performed. Past medical history included a pregnancy resulting in c-section (intrauterine growth retardation), six months previously. The baby was normal but post-partum the patient remained unwell with fatigue, nausea, and vomiting. She was diagnosed with postnatal depression. She had no other significant medical history but since the admission had suffered from a pneumonia and hearing loss due to recurrent otitis media. As SS was considered as a possible cause of RTA, she was referred for a rheumatological opinion. She was fatigued but denied sicca symptomatology (Schirmer’s test was negative, and normal saliva production). She had a patch of alopecia, but no other classical features of SS. Salivary glands ultrasound were unremarkable. Her biochemistry was now normal except a low normal bicarbonate; inflammatory markers were within normal range. Case report - Discussion This patient presents several challenges. She represents a common scenario of the balance between the high clinical suspicion and the failure to meet the ACR/EULAR diagnostic criteria for SS and the resultant management dilemma. She has no sicca symptoms, normal salivary gland US and hence biopsy was not sought. Anti-Ro/SSA and anti-La/SSB antibodies are detected on average 5 years before the appearance of an overt clinical phenotype of SS and thus serve also as predictive markers of the disease. In this patient with a strongly positive speckled ANA with anti RO along with RTA1(and renal microcalcification indicating long duration) without other explanation is almost certainly SS. The absence of renal biopsy in this patient also added to the challenge of clarification of her renal pathology. Renal involvement in SS is divided into: Overt glomerular disease which presents with haematuria, proteinuria or frank nephrotic syndrome; and Covert tubular disease which manifests with the metabolic abnormalities due to: proximal tubular injury; distal RTA or urinary concentrating defects. The prevalence of overt (glomerular) renal disease in SS is 4.3-5%. The prevalence of covert disease is 10-42% (Proximal tubular injury 10-42%; Distal RTA 5-24%; urinary concentrating defect 17-28%). Type1 RTA is confirmed by inappropriately alkaline urine (PH > 5.3) during systemic acidosis. The acidosis may occur spontaneously or be induced by an acid load test (NH4CL). Also, by stimulating intercalated cell acid secretion using a combination of fludrocortisone and furosemide. In tubular disease, as in this patient, treatment to correct the metabolic abnormalities (with e.g. Bicarbonate) is normally required. However, as tubular interstitial nephritis (TIN) is the usual cause for renal tubular defects there is evidence that these patients respond to immunosuppression. Monitoring of long-term effects, such as on bone metabolism, is required and thus patients warrant input from a multidisciplinary team for management. Case report - Key learning points This case is a reminder of the considerable prevalence of renal involvement in Sjögren’s Syndrome. TIN is a typical manifestation of SS, and we should keep in mind the possible evolution to Distal RTA. Our routine clinical work up for SS includes a urine dip and we may focus on proteinuria and haematuria to monitor for glomerular disease and ignore the pH. We perhaps ought to routinely check calcium, magnesium bicarbonate in addition to renal function in patients with SS. A plain abdominal X Ray would detect nephrocalcinosis in chronic RTA. Beware nausea and vomiting may be a warning sign of tubular renal disease. A renal biopsy is critical in the evaluation of renal disease in SS. Our renal team is reluctant to biopsy this patient. Thus, with the lack of tissue diagnosis, the patient not fulfilling ACR/EULAR criteria and the history of significant recent infections has made the introduction of immunosuppression difficult in this young woman.

Case report - Introduction Sicca symptoms and Raynaud’s disease are amongst the common presentation of Sjögren’s syndrome (SS) which has an estimated prevalence of 1%. We are reporting a case that was initially considered as SS, but subsequent lip biopsy confirmed histological evidence of sarcoidosis in the presence of abnormal nailfold capillaroscopy and negative autoimmune profile. Sarcoidosis can be associated with various autoimmune diseases including systemic sclerosis, Hashimoto's thyroiditis, systemic lupus erythematosus, rheumatoid arthritis, Sjögren’s syndrome and spondyloarthropathy. Case report - Case description A 29-year-old Caucasian man was referred to rheumatology clinic, suffering with ongoing sicca symptoms including dry itchy gritty eyes, sore red eyelids, persistent mouth dryness and cracking ulcers. He has history of Raynaud’s disease, dysphagia for solid, dry cough and photosensitive rash on his chest and arms. His other symptoms were polyarthralgia, myalgia, headache, persistent fatigue, poor memory, dry skin over the hands and tingling sensation at the feet. There was no history of joint swelling, uveitis, chest pain or shortness of breath. He has hypothyroidism secondary to radioiodine treatment and is currently on levothyroxine. He works in a factory, drinks alcohol occasionally and is non-smoker. There was no family history of autoimmune conditions. General and systemic examination was unremarkable, and there were no stigmata of connective tissue disease except for tenderness and crepitus at the right knee joint. His saliva flow rate was 0.4ml/5 mins and Schirmer’s test was 20mm/5 mins (both were normal values). Autoimmune profile was negative; ANA: 0.2 units, RF factor: Nailfold capillaroscopy shows grade1 enlarged capillaries, prominent capillary ramifications in the form of bushy capillaries and some microhaemorrhages, a pattern suggestive of mixed connective tissue disease. Lip biopsy showed small non-caseating epithelioid granuloma within the parenchyma. The initial working diagnosis was a possible serology-negative SS, but the later results of lip biopsy confirmed sarcoidosis. He was commenced on Hydroxychloroquine and advised about cognitive-behavioural therapy for generalised ache and fatigue. As he was not responding to pilocarpine, a referral for ophthalmology review was requested. Case report - Discussion Sarcoidosis is a multisystem disease of unknown aetiology, known to exist worldwide with a variable prevalence of around 20 per 100,000 in the UK. It is characterized by the presence of multiple non-caseating granulomas, inflammation which may occur in any tissue in the body manifested as local symptoms with or without systemic features. Involvement of the salivary and lacrimal glands can result in xerostomia and xerophthalmia, respectively. Chronic sarcoid has an often subtle, insidious, progressive, and highly variable clinical course; it can be asymptomatic in a significant percentage of the cases. In addition to the clinical and radiological findings, the diagnosis of sarcoidosis should be based on the histological proof of non-caseating granulomas and ruling out other diseases that shares similar features. SS has many features in common with sarcoidosis; these may include sicca symptoms, arthralgia, myalgia, arthritis, erythematous rash, lymphadenopathy, peripheral neuropathy, fatigue and raised inflammatory markers. Moreover, positive rheumatoid factor, defective T suppressor cell regulation and HLA-DR3 are linked to both diseases. Pulmonary involvement in either of them may have similar clinical and radiographic manifestations, making it difficult for the clinician to distinguish between these diseases. In terms of management, hydroxychloroquine may help the skin and joint manifestations in both diseases whereas more severe diseases may require treatment with glucocorticoids, methotrexate, and azathioprine. Nevertheless, prompt confirmation of the diagnosis is crucial provided the difference in response to medication, complications, outcome, and prognosis. Based on the clinical and lip biopsy findings, the above case was diagnosed with sarcoidosis. The case did not meet the criteria for the diagnosis of SS provided the negative results of Schirmer’s test, saliva flow test and autoimmune profile. Case report - Key learning points Raynaud’s phenomenon (secondary Raynaud’s) with positive capillaroscopy findings was an unusual early presenting feature of sarcoidosis in the above case. There was one case report of similar presentation published in 2011. However, literature did not reveal specific information about abnormal nailfold capillaroscopy results in sarcoidosis. Dry eyes and dry mouth may occur in sarcoidosis mimicking the presentation of primary SS. In addition, true coexistence of sarcoidosis and SS has also been defined based on the histopathologic examination of the exocrine glands. Diagnostic criteria need to be applied for patients with suspected overlap of the two diseases. Clinicians will need to be vigilant and perform appropriate investigations for overlapping rheumatic conditions with sarcoidosis. Lip biopsy remains a crucial investigation for cases referred with sicca features, not only to establish the diagnosis of SS but also to exclude associated lymphoma or sarcoidosis.

Case report - Introduction Primary Sjögren’s syndrome is a systemic autoimmune disease affecting the exocrine glands, commonly resulting in dryness of mouth and eyes. It can also rarely present with neurological symptoms most commonly peripheral neuropathies. The case highlights a rare case of sensory and motor neuropathy with some features suggestive of Sjögren’s syndrome as an underlying diagnosis. Case report - Case description A 54-year-old Caucasian lady was transferred from a local hospital for specialist neurology care. She described widespread paraesthesia over two months progressing to lower limb weakness worsening over a two-day period. Her symptoms further progressed to involve her arms and new blurred vision. On further questioning she reported previous severe mouth ulcers, possible genital ulcers and painful jaw swelling with long standing history of dry mouth. On thorough neurological examination, the positive findings were mild ptosis of the right eye, paraesthesia on palpation of face, upper limbs had a flaccid tone with reduced power and pseudoathetosis of outstretched arms, reduced proprioception, and absent reflexes. Lower limbs were more affected with worse power and absent proprioception. Schirmer’s test showed normal tear production but saliva production was reduced. MRI brain and spine were reported as pathological enhancement in both optic nerves, no obvious brain parenchymal abnormality, no obvious spinal cord abnormality. Lumbar puncture CSF pro 0.38, white cells 12 (poly 50%, mono 50%), red cells 3700, no organisms on gram stain, opening pressure 21.5 cmH2O. Sural nerve biopsy demonstrated profound loss of sensory axons, severe loss of large myelinated fibres in all fascicles with motor nerve involvement. Muscle biopsy demonstrated chronic neurogenic atrophy. Rheumatology screen showed positive anti Ro 52 antibodies (on an extended myositis screen). EMG demonstrated neurophysiological evidence of widespread marked loss of sensory axons in the upper and lower limbs and partial loss of motor axons in several lower limb territories. USS parotid glands showed some possibly mildly abnormal areas, minor salivary gland biopsy was normal. She received methylprednisolone, IV immunoglobulin and two courses of plasma exchange. Given some improvement following this treatment, further immunosuppression was felt to be appropriate. Initially Mycofenolate mofetil was started and Rituximab is now being considered. Case report - Discussion This case demonstrates a mixed neuropathy picture. Following thorough investigations, many differential diagnoses of mixed neuropathy were considered and excluded (e.g. Guillain Barre, Syphilis, MS, HIV, Hepatitis). Neurological symptoms can develop before the onset of sicca symptoms in Sjögren’s syndrome. With a positive Anti Ro52, xerostomia and clinical improvement with methylprednisolone and plasmaphereses it seems likely there is an underlying autoimmune diagnosis in this case and despite a normal biopsy she would meet the 2016 ACR/EULAR classification criteria for Sjögren’s syndrome. Case report - Key learning points Sjögren’s syndrome should be considered as a potential underlying cause in patients with a sensory ganglionopathy. Neurological symptoms can develop before the onset of sicca symptoms in Sjögren’s syndrome.

Case report - Introduction Autoimmune diseases are a group of disorders where the body produces an immune response against its own tissue constituents. The understanding of the immune mechanisms underlying autoimmunity has significantly deepened and broadened recently. The viral infection is a well-known trigger of autoimmunity and chronic hepatitis is known to cause various auto-immune diseases; organ-specific or systemic. Self-reactivity is part of the normal regeneration and healing. Auto-reactive T&B cells are kept dormant by the concerted action of a variety of mechanisms. Hepatitis C can disrupt this by molecular mimicry, by providing adjuvant and even by directly affecting B cell function. Case report - Case description We report a case of a 77 yr old Caucasian lady from South Africa who presented to Addenbrooke's hospital complaining of general decline, multiple constitutional symptoms, and low-grade fever for nearly 6 weeks. She did not have any infective symptoms. She had a past medical history of Type 1 DM, Hypothyroidism, Sjögren’s syndrome Osteoporosis and chronic hepatitis C infection which was treated 4 years ago. Family history was not significant, and she was a non-smoker. She was found to be thin with a BMI of 18, pyrexical with a temperature 37-38'c; otherwise, examination findings were unremarkable. Initial investigations revealed high inflammatory markers with an ESR of 99 and CRP of 120. WCC was within the normal range as were her renal and liver function tests. She was thoroughly investigated for Pyrexia of Unknown Origin. Her septic screen including Echocardiogram was negative. There was no detectable serum Para-protein and tumour markers were negative. Her CT scan of the chest abdomen and pelvis, MRI scan of the spine and PET scan were reported to be normal. The Serum Pro-calcitonin was low. Rheumatology team was enlisted at this point. On further assessment, the patient mentioned of having an ongoing mild generalised headache - described as a 'fullness in the head' and mild generalised scalp tenderness. She also had an aching pain in her legs. There was no history of visual symptoms, jaw, or tongue pain. On examination, she had generalised scalp tenderness which was worse over the left temporal artery. She had a temporal artery biopsy which showed typical features of GCA (disruption of IEL and giant cell) Following which she was commenced on steroids to which she had a remarkable response. After a month she was commenced on Tocilizumab with quick wean off steroids in view of her elevated risk for fractures. 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 C was undetectable). This lady received a diagnosis of Sjögren’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 Sjögren’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 Sjögren’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 lead to complete remission of these autoimmune conditions.

Case report - Introduction Sjögren’s is an autoimmune multisystem disorder characterised by xerostomia, keratoconjunctivitis sicca and extra glandular manifestations. The presence of sicca symptoms helps with diagnosis but up to 20% patients do not have these. The prevalence of lung involvement has been reported up to 9-24% and includes changes such as NSIP and organising pneumonia. We present an interesting patient who had no sicca symptoms but positive immunology to suggest Sjögren’s. Changes in sequential CT chest scans were in keeping with Connective Tissue Disease- Associated Interstitial Lung disease (CTAILD). However, presentation with an acute renal injury resulted in a diagnosis of ANCA positive vasculitis. Case report - Case description A 64-year-old Indian gentleman with medical background of controlled asthma was referred after 9 months of investigations for gluteal weakness. Initial blood tests included normal CK, ESR, CRP, vitamin B12, HbA1c and TFTs. Rheumatoid factor was low positive (20IU/ml), CCP negative. ANA was 1:80 with positive Ro, negative dsDNA. MRI of thighs was normal -no evidence of myositis. Nerve conduction studies showed no active denervation to suggest inflammatory myopathy and muscle biopsy showed myopathic features only. A CT scan revealed 3 small lung nodules recommending repeat scan. When seen in rheumatology clinic, there was additional bilateral shoulder arthralgia with no reports of sicca symptoms or rashes. A repeat autoimmune screen and CT chest was sent. His ANA was 1:1280 with Ro antibodies; CT showed new ground glass changes (with old nodules). Organising Pneumonia was suggested, and respiratory opinion sought. Extended myositis screen was negative. When seen in respiratory clinic he had new haematuria- ANCA screen showed positive anti-PR3 antibody (23U/ml) with normal U+Es, urine PCR and CRP 8mg/L. Based on these results a renal biopsy was performed-which showed no obvious morphological abnormalities. Thus, a suspected diagnosis of CTAILD with Sjögren’s was made. In clinic 2 months later, there was new shortness of breath and haemoptysis. Urine dip showed haematoproteinuria and Chest X-ray showed increase in peri-hilar masses. He was admitted urgently- blood tests showed a decline in renal function- urea 26.8mmol/L, Creatinine 838umol/L, CRP of 435mg/L and Haemoglobin 100g/L. Urgent repeat renal biopsy was done and CT thorax showed deterioration with bilateral consolidation and new lung lesions. Urgent Plasma exchange and dialysis (9 cycles) was given. Initial results from renal biopsy showed presence of crescents and he was started on cyclophosphamide. On this kidney function has improved- urea 18.4mmol/L and Creatinine 302umol/L; he remains on oral cyclophosphamide. Case report - Discussion With ongoing symptoms, an underlying autoimmune cause of his symptoms was felt likely. However inflammatory markers remained normal and so did CK. Despite this MRI and muscle biopsies were performed - which again were normal. The only tests that were positive were immunology (Ro antibodies) and a CT chest (showing initial small lung nodules). These findings pointed toward CTAILD with Sjögren’s being the likely diagnosis. As new lung nodules were seen, repeat CT scans were done- which showed gradual interstitial changes- the main radiological differential diagnosis was Organising pneumonia. Further investigations were delayed due to patient travel and COVID, but ongoing respiratory advice was sought. Even with changes in CT findings the patient remained stable with normal inflammatory markers. However, the clinical picture changed quite rapidly over a month (despite 2+ years of previous symptoms) with presentation of pulmonary-renal vasculitis. Plasma exchange and dialysis were given. A good response with a positive renal biopsy confirmed the most likely diagnosis was Granulomatosis with Polyangiitis (GPA). This case was interesting- the main complaint was of myopathy with no physical signs. Despite this biopsy were performed (muscle and kidney), which were all normal. The red herring in his case was a normal renal biopsy- steering us in the direction of CTD-AILD instead of GPA. Case report - Key learning points In patients with clear symptoms matching their investigations the diagnosis is often obvious. When this is not the case and symptomatology does not match results (i.e. no Sicca symptoms but positive immunology to suggest Sjögren’s) suspicion should remain high. Multidisciplinary working can provide insight, which this case does highlight-with input required from Neurology, Respiratory and Renal medicine. Negative results should be taken in context with patients and their symptoms. Initial renal biopsy in this case was normal- however after a review, further comments were made on the sparsity of glomeruli in the sample. Therefore, tissue obtained for diagnosis should always be questioned and clinical suspicion should remain high. In addition, repeat investigations (6 monthly CT scans) can help note any interval change. Thorough history and examination in follow up of patients can help look out for evolving changes. With the new symptoms of haemoptysis and haematoproteinuria this pointed us to the eventual diagnosis. The road to diagnosis in this case was prolonged with an acute drop in kidney function and pulmonary haemorrhage needing urgent Plasma exchange and dialysis. Thankfully, the patient continues to make a good recovery. A last point to add is although isolated myalgia has been described as a presentation of systemic vasculitis in the literature, those patients have had elevated CK and positive muscle biopsy. Our patient did not have any positive findings with over 2 years of symptoms. Therefore, we feel this case was unique in presentation and has valid learning points as above.

Case report - Introduction We present the case of a 70-year-old female with a background of anti-Ro positive Sjögren’s syndrome with difficult sicca symptoms who presented with worsening Raynaud’s, bilateral lower limb petechiae/purpura, fatigue, and progressive peripheral neuropathy. Blood tests revealed positive cryoglobulins with hypocomplementemia, and nerve conduction studies objectively confirmed the peripheral neuropathy. The patient was diagnosed with cryoglobulinaemic vasculitis and treated with pulsed intravenous cyclophosphamide and oral prednisolone, which resolved her rash and halted the progression of her symptoms. Cryoglobulinaemic vasculitis is a rare complication of Sjögren’s syndrome occurring in only 3–4% of patients with the disease. Case report - Case description A 70-year-old female with known Sjögren’s syndrome presented with a two-month history of an intermittent red, pin-prick rash affecting her lower legs, worsening fatigue and Raynaud’s, and a progression of longstanding symptoms of pins and needles from her ankles up to her knees, shortly after an acute Epstein-Barr virus infection. Her Sjögren’s syndrome was diagnosed after she presented with difficult sicca symptoms, fatigue and Raynaud’s phenomenon, and strongly positive ANA and anti-Ro antibodies (>240 u/mL). Past medical history was notable for microscopic colitis. On examination, she had bilateral pitting oedema with a purpuric rash affecting both legs. She had reduced sensation to both knees, but with normal power and downgoing plantars. Her joints examined normally. There were no ischaemic changes in her peripheries. Blood tests showed a positive cryoglobulin consisting of a monoclonal IgM paraprotein with polyclonal lambda light chains. She had a normal kappa: lambda ratio and Bence-Jones proteins. Inflammatory markers were raised (CRP 34mg/L, ESR 93mm/hour), with hypocomplementemia (C4 0.05g/L, normal C3). Otherwise, her full blood count, electrolytes, renal and liver function tests, chest X-ray, urine dipstick, hepatitis serology, ANCA profile, B12, folate and ferritin were unremarkable. Nerve conduction studies showed a length-dependent, moderately severe sensory motor axonal peripheral neuropathy, which Neurology agreed was due to a vasculitic process. The patient was diagnosed with a cryoglobulinaemic vasculitis with peripheral nerve involvement secondary to her Sjögren’s syndrome. This was initially treated with prednisolone 40mg daily, intravenous pulsed cyclophosphamide, which resolved her rash and halted the progression of her peripheral neuropathy. Pregabalin was prescribed for pain relief. After completing six cycles of cyclophosphamide, the patient was commenced on azathioprine. This was then replaced with mycophenolate due to leukopenia. She was gradually weaned off steroids, and her vasculitis to date remains biochemically and clinically stable. Case report - Discussion The presence of the combination of a petechial/purpuric rash on her lower limbs, worsening fatigue and Raynaud’s, and symptoms consistent with a progressive peripheral neuropathy raised the suspicion of a vasculitic process in this patient, which warranted urgent investigation. She had a type II mixed cryoglobulinemia which is the most common type of cryoglobulinemia found in Sjögren’s syndrome, evidenced by the presence of a monoclonal IgM paraprotein with polyclonal lambda light chains. Cryoglobulinaemic vasculitis is a systemic vasculitis characterised by the deposition of immune complexes into small vessels, commonly affecting the peripheral nerves, skin, and joints. Clinically, this can manifest with arthralgias/arthritis; constitutional symptoms, such as fatigue and fever; neurologically, with peripheral neuropathies, cranial nerve and central nervous system involvement; and with vascular symptoms, such as petechiae/purpura, skin ulcers, hyperviscosity syndrome, and Raynaud’s. Laboratory features consistent with a diagnosis of cryoglobulinaemic vasculitis aside from the sine qua non of positive cryoglobulins include hypocomplementemia (especially complement C4), positive rheumatoid factor, and a positive serum monoclonal component. We suspect that her cryoglobulinaemic vasculitis was most likely due to Sjögren’s syndrome, although it could have been triggered by the preceding Epstein-Barr virus infection, as this can be associated with cryoglobulinemia also. The decision to treat aggressively with pulsed intravenous cyclophosphamide and prednisolone was made given the severity of the patient’s symptoms, especially her progressive peripheral neuropathy. Given the paucity of data in the literature on the management of cryoglobulinaemic vasculitis secondary to rheumatological conditions, cyclophosphamide and prednisolone were chosen as these are proven in the other small vessel vasculitides, such as ANCA-associated vasculitis. This case is of interest as cryoglobulins are found in approximately 7–16% of patients with Sjögren’s syndrome, with cryoglobulinaemic vasculitis seen in only 3–4% of patients with the disease. Case report - Key learning points Cryoglobulins are uncommon in Sjögren’s syndrome, occurring in 7–16% of those with the disease. Symptomatic cryoglobulinaemic vasculitis among those with Sjögren’s syndrome is rare, seen in only 3–4% of cases. The presence of cryoglobulins in Sjögren’s syndrome is of clinical significance, as it is associated with higher global systemic disease activity and extra glandular involvement. Compared to non-cryoglobulinaemic patients with Sjögren’s syndrome, those with cryoglobulinemia are more likely to have lymphadenopathy, constitutional symptoms, peripheral nervous system and pulmonary involvement, and glandular, articular, and cutaneous features of the disease. The type of cryoglobulinemia found in Sjögren’s syndrome is the mixed type, which are either formed from a monoclonal immunoglobulin (usually IgM) and a polyclonal immunoglobulin (type II), or two polyclonal immunoglobulins (type III). Other conditions associated with mixed cryoglobulinemia include rheumatoid arthritis and systemic lupus erythematosus (SLE), although the most common cause of these is chronic hepatitis C (80–90% of cases). Other causes of mixed cryoglobulinemia include other viral infections, including Epstein-Barr virus and hepatitis B, and certain bacterial and parasitic infections. Most of the literature on the management of cryoglobulinaemic vasculitis is in the context of patients with this due to chronic hepatitis C and revolves around treating this with the appropriate antiviral therapy. Consequently, the current treatment options for moderate-to-severe cryoglobulinaemic vasculitis secondary to rheumatological conditions are the same as those for the other small vessel vasculitides, using a combination of cyclophosphamide and glucocorticoids to induce remission, and azathioprine as maintenance therapy. In severe cases, plasma exchange and rituximab can also be considered as agents to induce remission in cryoglobulinaemic vasculitis.

Case report - Introduction Sjögren’s Syndrome (SS) is a chronic autoimmune inflammatory condition characterized by lymphocytic infiltration of the lacrimal and salivary glands resulting in dry eyes and mouth. One third of patients present with systemic extra glandular manifestations, including neurological symptoms. Sjögren’s syndrome as a paraneoplastic mimic to ovarian cancer has been rarely reported in the literature. We present the case of a 49-year-old female patient who was referred to rheumatology with features suggestive of Sjögren’s syndrome which were likely to have been triggered by an underlying primary ovarian malignancy. 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 no associated fever, night sweats or weight 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 with extensions into the deep divisions with her face, raising the possibility of a vasculitic process. Despite her age, sex, xerostomia, and presence of Ro-52 antibodies which may be suggestive of primary Sjögren’s syndrome, she did not meet the 2016 classification criteria. Considering these findings, raised inflammatory markers and equivocal antibodies, she underwent an FDG PET scan which showed the presence of a primary ovarian malignancy with metastatic spread to her mediastinal lymph nodes and peritoneal tumour deposition. The patient has subsequently been referred to the gynae-oncology team for further grading, staging and consideration of chemotherapy. Case report - Discussion There is a well-established association between Sjögren’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. Sjögren’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 Sjögren’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 Sjögren’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 learning points Ovarian cancer can present as a mimic of Sjögren’s syndromeUp to one third of patients with primary Sjögren’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 furtherRo-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.

Case report - Introduction We present the case of a patient with Primary Sjögren’s syndrome (pSS) who presented via the general surgical take with an acute abdomen, necessitating emergency subtotal colectomy. Histology demonstrated vasculitis of the caecum, and in combination with elevated type II cryoglobulins and unmeasurable complements, a diagnosis of cryoglobulinaemic vasculitis was made. Vasculitis has a recognised association with pSS, particularly in the context of elevated cryoglobulins, but bowel involvement is rare. Clinicians involved in the care of pSS patients should be alert to the possibility of rare but severe multi-system manifestations, due to their high burden of morbidity and mortality. Case report - Case description This 54-year-old female is under the care of Rheumatology for pSS. She initially presented with sicca symptoms, fatigue, arthralgia, and parotid swelling for which she had undergone a superficial parotidectomy. She had longstanding constitutional symptoms of night sweats, weight loss and fever. She also reported chronic constipation as well as a photosensitive urticarial rash. At diagnosis, her ENA panel demonstrated SS-A, SS-B and SCLER-70 positivity with type II cryoglobulins of 0.56 and hypocomplementemia (C4 < 0.01). At this stage there were no clinical or laboratory markers of end organ damage. Initial treatments included Hydroxychloroquine and Azathioprine with recent switch to Methotrexate due to inefficacy. 2 years later, she presented emergently via the general surgical team with a one-day history of generalised abdominal pain and vomiting. On examination she had right lower quadrant peritonism. CT scan demonstrated severe caecal colitis with associated ascites, requiring emergency sub-total colectomy. Histology from the resected bowel demonstrated ischaemia with numerous foci of submucosal vasculitis. On inpatient Rheumatology review there were no cutaneous, pulmonary, musculoskeletal features of vasculitis. She had reduced pinprick sensation to her feet, associated with allodynia. Laboratory tests showed a haemoglobin of 106, platelets of 866 and albumin of 27 (all markers felt to reflect recent critical illness). Her eGFR was 71 (from a baseline of 90) with urine PCR of 11.7 but no blood. Faecal calprotectin was normal. EBV, CMV, Hepatitis B and C and HIV were negative. Repeat immunology confirmed a type II cryoglobulinemia of 0.95 and C4 of 0.01. Following MDT discussion with colleagues in both Gastroenterology and Renal medicine it was agreed that her colitis likely represented a cryoglobulinaemic vasculitis secondary to pSS. She was treated with oral prednisolone and six intravenous pulses of cyclophosphamide. After six months she is symptomatically improved with negative cryoglobulins and normal complement. Case report - Discussion pSS is an immune-mediated condition classically associated with sicca symptoms commonly affecting the eyes and mouth. These symptoms derive from immune mediated inflammation and damage of secretory glands and resultant drying of mucosal surfaces. However, extra-glandular involvement in pSS is common, both at presentation and later in the disease course. Organ systems most associated include joints, lungs, skin, and peripheral nerves. However, involvement of other organ systems, particularly gastrointestinal or pulmonary are associated with significant morbidity and mortality. Gastrointestinal involvement in pSS is well recognised and encompasses manifestations from dysphagia to pancreatitis. Symptoms related to irritable bowel syndrome, including constipation as in our patient, are common but generally follow a benign course. Our patient never experienced any symptoms suggesting inflammation of the bowel, such as diarrhoea or rectal bleeding prior to her acute presentation. Several prognostic markers have been proposed for pSS, including SS-A/ SS-B positivity, hypocomplementemia and cryoglobulinemia. These immunological markers, particularly low C4, are implicated in an increased risk of developing vasculitis. These markers were present in our patient at the time of diagnosis; at this point there were no clinical features suggestive of vasculitis. Vasculitis in pSS, when seen, is most associated with the skin and kidneys, although involvement of the small bowel has been observed. Ileal biopsies for our patient, performed prior to immunosuppression, were normal suggesting that in this case the vasculitis was limited to the large bowel. Cryoglobulinaemic vasculitis, secondary to mixed cryoglobulinemia, is seen in association with connective tissue diseases, most commonly pSS. Gastrointestinal involvement has also been recognised in this context, but again is uncommon, compared to other vasculitides. After immunosuppression, our patient’s cryoglobulins resolved and she has remained clinically stable. Her case provides an important lesson regarding the possibility of severe extra-glandular vasculitic manifestations in pSS patients. Case report - Key learning points Systemic involvement in pSS is relatively commonImmunological markers exist which can prognosticate both the risk of systemic involvement and the development of vasculitisCaecal vasculitis is rarely seen in pSS; when present it carries a large burden of morbidity and mortalityIncreasing awareness of pSS and its systemic manifestations is essential to facilitate better recognition of unusual presentations.

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 - 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 Sjögren’s syndrome (pSS) was made. There is conflicting evidence in the literature on the prevalence of gastroparesis in pSS population. The case is remarkable because abdominal symptoms and problems with swallowing rather than sicca syndrome prompted investigations and later confirmed the diagnosis. Case report - Case description A nineteen-year old woman had long-standing 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. There was 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 Sjögren’s disease. She had a trial of metoclopramide to improve gastric motility, which was not effective. Following a consultation with Gastroenterologist she had a trial of erythromycin which greatly improved her abdominal symptoms and swallowing. She remains 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-to-male 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, this high occurrence is rarely associated with clinically significant symptoms, according to one study. Nevertheless, another study of 38 patients with pSS, demonstrated a higher prevalence of self-reported 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 Sjögren’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 Sjögren’s syndrome with negative anti-Ro and anti-La antibodies, negative rheumatoid factor, and normal CRP. The patient does not meet ACR criteria for diagnosis of Sjögren’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 Sjögren’s syndrome. Case report - Key learning points 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 entire gastrointestinal system. The autonomic 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 interference with 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 exocrine gland 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.

Case report - Introduction Sjögren’s syndrome is a chronic, autoimmune condition usually characterised by reduced function of exocrine glands (mainly lacrimal and salivary) resulting in sicca symptoms. Affected patients may also have extra-glandular features including arthritis, neuropathy, and interstitial nephritis. This is a case of possible Sjögren’s syndrome without classical features like positive serology or histology. This makes the patient feel anxious about his overall health. Diagnostic criteria have been debated over the years and whilst some clinical features may be suggestive, more objective evidence can help guide discussions on long term management and prognosis to allay anxiety. Case report - Case description A 63-year-old Asian gentleman has had 6 years of intermittent cervical lymphadenopathy, dry eye and mouth symptoms without weight loss or respiratory complaints. His background includes ulcerative colitis (relatively stable), angina, hypertension, degenerative back pain (confirmed on MRI), dental extraction and diabetes. Interval FNA sampling and excision biopsy of a prominent chain of right cervical nodes on separate occasions showed “reactive changes” with negative Mycobacterium TB screening (serology and lymph nodes). Blood tests show a normal CRP ( Bilateral submandibular gland ultrasound showed hyperechoic lesions consistent with either chronic sialadenitis or Sjögren’s. FNA sampling of an intra-parotid lesion showed a “reactive” lymph node. A left lower lobe 5mm calcified granuloma seen on plain film was confirmed on CT chest imaging along with mild inflammatory changes (lingual area) and multiple soft tissue density nodules up to 1cm in the anterior mediastinum. Initially thought thymoma related, later it was agreed these were benign lymph nodes after noting bilateral, sub-centimetre axillary and pre-tracheal nodes of similar appearance. Following annual surveillance, a recent scan shows persistence of the lingular nodular focus, mediastinal lymphadenopathy and a 4mm ground glass nodule not thought suitable for PET CT or CT guided sampling. The previously seen parotid lymph node appears reduced and scattered low grade nodes are seen in the neck, chest, and porta hepatis. Ophthalmologists note a poor-quality tear film with an equivocal Schirmer’s test. He has been treated for blepharitis and diagnosed with macular oedema. He was due to have a labial gland (lip) biopsy but later declined the procedure. Case report - Discussion Sjögren’s syndrome has a female preponderance and is usually associated with sicca symptoms, a positive Schirmer’s test and autoantibodies (anti-Ro and anti-La). Extra-glandular features may exist, and secondary Sjögren’s features are seen in other autoimmune conditions. Various diagnostic criteria have been proposed using clinical, serological, and/or histological features. This patient has sicca symptoms, lymphadenopathy, and imaging findings suggestive of Sjögren’s. Though not routinely used, salivary gland imaging features include enlarged, hyperechoic lesions and later stage multi-cystic or reticular patterns within atrophic glands. Due to ethnicity, negative autoantibodies and imaging, the differential of tuberculosis (TB) was excluded. A labial gland biopsy was suggested as it may be a potentially sensitive and specific Sjögren’s biomarker. Presence of multiple, periductal, lymphocytic foci can help exclude alternative diagnoses like sarcoidosis, amyloidosis, or lymphoma. However, the patient declined the procedure due to concerns about possible post procedure hypersensitivity. This patient has mild fatigue and non-specific arthralgia but not typical of fibromyalgia which is known to mimic Sjögren’s. Reassuringly, he remains well but anxious about lymphadenopathy which he feels is unrelated to his mild ulcerative colitis managed with prednisolone enemas. In the absence of arthritis or significant organ involvement, he has only been given symptomatic treatment (e.g. eye drops). In Sjogren’s, any increased or persistent lymphadenopathy calls for further investigation. Other predictors include low complement and cryoglobulins which are absent in this patient. This case may add to the evidence of co-existence of secondary Sjögren’s or Sjogren’s like syndrome with IBD which seems uncommon and in other cases, appears to be in conjunction with immunosuppressive treatment and autoantibodies. Duration of follow up required remains uncertain and whilst the patient requires little ongoing monitoring, health anxieties can precipitate frequent contact. Case report - Key learning points Sjögren’s syndrome (SS) can be variable in presentation but in most cases is mildUnlike other autoimmune disorders, in SS there is a lack of standardised criteria for diagnosis and classificationSome features can be non- specific and like features of fibromyalgia and sarcoidosisIn unclear cases, like this, objective markers like serology or histology (labial gland biopsy) may be more helpfulIn lymphadenopathy, depending on size and appearance, further investigations require multidisciplinary discussion to check if regular imaging is more appropriate compared to invasive tests. The frequency of imaging and potential radiation exposure needs careful consideration.In this case the patient is unwilling to undergo further invasive tests like a biopsy and the lymphadenopathy seen on imaging is thought relatively stable and not amendable to sampling.The ideal duration of follow up and need for ongoing investigations in this patient remains unclear – advice on monitoring and outcome of similar cases may help guide patient management and reduce anxiety

Case report - Introduction Primary Sjögren’s syndrome (PSS) is a systemic autoimmune disease that mainly affects exocrine glands. Central nervous system (CNS) involvement in primary SS is extremely rare. In 10–20% of patients diagnosed with PSS, there are lesions in the central nervous system analogous to those presented in multiple sclerosis. We report a case of a 58-year-old female, diagnosed as PSS and multiple sclerosis (MS) (2007), but later, all neurological manifestations turned out to be related to PSS rather MS. This case illustrates how difficult it could be, distinguishing Sjögren’s with CNS involvement from MS, even to an expert clinician. Case report - Case description A 58-year-old lady presented to Rheumatology clinic in 2010 with polyarthralgia, sicca symptoms and Raynaud’s. Immunology tests (positive anti- RO & anti-LA antibodies) and lymph node biopsy were highly suggestive of primary Sjögren’s. She was commenced initially on HCQ and prednisolone. Then Methotrexate was added in because she continued to struggle with inflammatory arthritis. Her Sicca symptoms got gradually worse despite being on Acetylcysteine, Hylo Forte, cyclosporine and Dexamethasone eye drop. Therefore, autologous serum eye drops were tried with good response. Her past medical history included Hypertension and knee OA. She has been under Neurology since 2007 for MS. Her original neurological symptoms were imbalance, dizziness, headaches, and tremor of the right arm which seem to be persistent with no definite relapses. MRI brain and spine were reported as normal with a few non-specific white matter areas, but the lumbar puncture result was positive for unmatched bands in the CSF. Clinical examination revealed action tremor in the right upper limb. She had diminished vibration, pinprick, and cold temperature perception in a stocking distribution. Investigations WBC 2.0, lymphocyte 0.62, DsDNA 1, C3 0.061, C4 0.01. CRP NCS: evidence of sensory and axonal neuropathy predominantly affecting lower limbs. CTCAP 2018 – showed calcification of parotid. No evidence of lymphoproliferative disorder. The latest MRI 2019 showed two new lesions (right corpus &right striatum lesion) which according to Neuro-radiology MDT discussion were not typical of MS and more likely related to underlying CTD. Based on these MRI findings and the recent history of skin vasculitis, the deterioration in her neurological condition was put down to primary Sjögren’s. Therefore, her treatment was escalated to cyclophosphamide during the COVID-19 pandemic with a particularly good outcome. She was then switched to MMF and her condition remained stable. Case report - Discussion Neurological disorders are one of the rare manifestations of primary Sjögren’s. The first reports regarding the involvement of the nervous system in PSS were published in 1980. Distinguishing between multiple sclerosis and CNS-SS is not easy. Not only because of similarities of the MRI findings, but also the course of the disease can be like MS, either chronic or relapsing and remitting. This usually leads to missing or delaying in the diagnosis as shown in this case. However, Peripheral neuropathy is far much common in PSS rather MS which can help in differentiating these two conditions. Distal axonal sensory polyneuropathy is the most usual form of neuropathy in PSS as illustrated in this case. Furthermore, up to 75% of patients with SS and active CNS disease have been shown to have concomitant active peripheral vasculitis affecting the skin, muscles, and nerves. Our patient later developed skin vasculitis and peripheral neuropathy which made us think that all the neurological findings including the lesions on the brain are more likely to be related to PSS rather MS. Cognitive disorders are common manifestations of CNS-SS such as attention disorder and memory deficit. Dementia-related to CNS-SS seems to be reversible after immunosuppressive treatment. A second MDT discussion took place and after considering the risk-benefit ratio, the decision was made to give cyclophosphamide. Patient was given all the information to make an informed decision. Patient asked for more time to think and discuss with her partner, but eventually, she had decided to have cyclophosphamide despite all the risks and uncertainties around the COVID-19 pandemic. Our patient has noticed significant improvement regarding cognition after completing cyclophosphamide treatment and she was pleased with this outcome. Case report - Key learning points 1/ Distinguishing between multiple sclerosis and CNS-SS is difficult 2/ neurophysiological tests should be considered even in asymptomatic patients as they contribute to the detection of early and subtle damage to the nervous system. 3/ Successful outcome being achieved with intensive immunosuppression despite all the uncertainties around the COVID-19 -19 pandemic. 4/ This case highlights the importance of communication and openness in shared decisions, especially while confronting uncertainties such as in COVID-19 pandemic.

Case report - Introduction Connective tissue diseases are multisystem disorders. Diagnosis and evaluation of suspected cases is not straight forward in most of the cases. This case describes the significance of considering a broader approach when evaluating a suspected case of connective tissue disease. Case report - Case description We describe a case of 58 years old non-smoker lady, presented with acute onset livedo reticularis rash on lower limbs and background of sicca symptoms, oral ulcers, fatigue, paraesthesias in feet and arthralgias without any systemic or inflammatory joint symptoms. General examination showed livedo reticularis rash on both elbows and lower legs. There was no evidence of peripheral joint synovitis, but she had nodal osteoarthritis in her hands. Systemic examination was unremarkable. Investigations revealed anaemia, pancytopenia, ESR of 77, low C4 and urine dipstick positive for leucocytes, nitrates, protein, and blood. Schirmer’s test, ANA and ENA screen was positive with positive RNP and SMdp antibody. She also had hypergammaglobulinemia in a polyclonal pattern. Nerve Conduction and EMG studies revealed mild axonal sensory neuropathy. Case report - Discussion This lady appeared to have mixed connective tissue disease with mixed features of Sjögren’s syndrome and systemic lupus erythematosus. She was started on Hydroxychloroquine but stopped it shortly after developing floaters in her eye. She had poor response to Depomedrone injection. She had ongoing symptoms of fatigue, weight-loss, loose stools, and abdominal pain, investigated further and CT scan showed hyperdense liver lesions and mesenteric lymphadenopathy. Esophagogastroduodenoscopy showed oesophageal candidiasis. She was admitted with progressive symptoms. Further investigations showed a positive HIV test and liver biopsy came back positive for anaplastic lymphoma, later she was diagnosed with advanced HIV disease, rapidly deteriorated with neutropenic sepsis and multi-organ failure, and unfortunately died. Case report - Key learning points This lady initially presented with symptoms of connective tissue disease and investigations in keeping with this diagnosis. Unfortunately, by the time she was tested for HIV infection, it was already too late. There could be overlap of symptoms of connective tissue disease and viral infections e.g. HIV infection. Autoantibodies may be falsely positive in infections e.g. HIV and in malignancy. Risk factors of HIV infection should be considered during assessment of multisystem diseases like connective tissue diseases particularly prior to immunosuppression. Viral screening including HIV test should be considered in all high-risk patients and particularly if the symptoms are atypical and do not quite fit well with the diagnosis.