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EP35 Cryoglobulinaemic vasculitis: an uncommon complication of Sjögren’s syndrome

Abstract 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.

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.

Saadia Sasha Ali and Arti Mahto
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. The patient was diagnosed with cryoglobulinaemic vasculitis and treated with pulsed intravenous cyclophosphamide and oral prednisolone, which resolved herrashand halted the progression of her symptoms. Cryoglobulinaemic vasculitis is a rare complication of Sjö gren's syndrome occurring inonly3-4% of patients with the disease. Case report -Case description: A 70-year-old female with known Sjö gren'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 virusinfection. Her Sjö gren'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 microscopiccolitis. 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 inher 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 ferritinwere unremarkable.
Nerve conduction studies showed a length-dependent, moderately severe sensory motor axonal peripheral neuropathy, which Neurology agreed was due to avasculiticprocess. The patient was diagnosed with a cryoglobulinaemic vasculitis with peripheralnerve involvement secondary to her Sjö gren'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. Shewas 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 Sjö gren'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 apositive serum monoclonal component. We suspect that her cryoglobulinaemic vasculitis was most likely due to Sjö gren'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 Sjö gren's syndrome, with cryoglobulinaemic vasculitis seen in only 3-4% of patients with the disease. Case report -Key learning points: Cryoglobulins are uncommon in Sjö gren's syndrome, occurring in 7-16% of those with the disease. Symptomatic cryoglobulinaemic vasculitis among those with Sjö gren's syndrome is rare, seen inonly 3-4% of cases. The presence of cryoglobulins in Sjö gren'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 Sjö gren'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 Sjö gren's syndrome is the mixed type, which are either formed from a monoclonal immunoglobulin (usually IgM)and apolyclonal immunoglobulin(type II),ortwo 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 remissionin cryoglobulinaemic vasculitis.

North Bristol NHS Foundation Trust, Bristol, United Kingdom
Case report -Introduction: We present the case of a patient with Primary Sjö gren'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 Azathioprinewith 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 subtotal 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.