EP25 Blau syndrome: a lifetime of sarcoid

Abstract Case report - Introduction Here we explore a case of a 31-year-old female treated with juvenile arthritis rebranded as Blau syndrome. This is characterised by sarcoid involvement principally of her eyes as well as skin, kidneys, and joints. We aim to explore her management challenges and complications. Case report - Case description 31 MS of Afro-Caribbean descent was diagnosed with early onset sarcoidosis at the age of 18 months. She was later found to be NOD2 gene positive but has no significant family history. Her health has been further complicated by her diagnoses of growth hormone deficiency and hyperthyroidism secondary to multinodular goitre. Clinically MS has a short stature and profound deafness. A legacy of the ophthalmic morbidity, panuveitis, has led to a visual acuity is 6/15 in her left eye and her right reduced to counting fingers due to developing endophthalmitis in 2019. Her arthritis is stable, but there are flexion deformities primarily involving her proximal interphalangeal joints reducing her grip function. In adulthood she does not have significant cutaneous changes. Investigations have revealed her to be anti-nuclear and anti-neutrophil cytoplasmic antibody negative. Radiologically, hand films show sparing of erosive changes, radiocarpal subluxation, and deformity of carpi in keeping with bilateral Madelung deformity. MRI has never suggested synovial enhancement of sacroiliac joints. Therapeutically she has trialled conventional disease modifying therapy including azathioprine, mycophenolate, and methotrexate. Disease activity continues to be high despite anti-TNF biologic DMARDs (adalimumab, infliximab and golimumab). Use of anti-TNF therapy has been complicated by development of CMV disease and identification of anti-infliximab antibodies following interruption. Ongoing steroid use from 18 months, hyperthyroidism and a chronic inflammatory state has led to osteoporosis. DEXA Z-scores reveal lumbar -2.7, right femoral neck -3.2 and left femoral neck -4.7. Systemic corticosteroid has tried to be offset through dexamethasone intravitreal implants. Consequentially, uncontrolled disease burden has also led to significant input from orthopaedics, including bilateral total knee replacements by age 28. However, with MS, we are hopeful with the commencement of anti-IL6 receptor therapy (Tocilizumab) that this may represent a new line of effective treatment. Case report - Discussion Blau syndrome is a juvenile sarcoidosis characterised by the triad of granulomatous arthritis, recurrent uveitis, and dermatitis. It is inherited in an autosomal dominant pattern due to a missense mutation in the gene encoding for nucleotide-binding oligomerisation domain containing protein 2 (NOD2/CARD15). It is proposed that NOD2 as intracellular receptors, for antigen such as lipopolysaccharide, may subsequently act like toll-like receptors to cascade NF-kappa B and downstream inflammatory pathways. Its role is also implicated in other inflammatory conditions such as Crohn’s disease. As represented in our case, uveitis presents the highest morbidity, with median age of eye disease presenting at 60 months and remains persistent despite topical or systemic therapy in more than 50% of patients. In comparison to Juvenile idiopathic arthritis, Blau often leads to a pan rather than anterior segment only uveitis and in a greater proportion of cases. In addition to biological factors, much of MS’s treatment decisions have been guided by her and her psychology. In attempting to address the difficulties of her condition, including coordinating several specialities clinics whilst developing as a young woman, she has frequently discontinued therapy which may represent an area that she can exact control given little perceived benefit. TNF-alpha inhibitors have been validated through randomised controlled trials for the use of refractory sarcoidosis. However recent literature has highlighted the use of targeting the IL-6 pathway in multisystem chronic sarcoidosis. It is believed this may represent a key cytokine in promoting Th17 effector cells that have been implicated in sarcoidosis bio-pathology. However ongoing case reports and ideally large-scale studies are needed. Case report - Key learning points Blau syndrome as a rare lifelong form of early onset sarcoidosis offers insight into challenging therapeutic decision making where limited clinical trial data is available.

His past medical history was also remarkable for anxiety and depression. There was nofamilyhistory of muscle disease. Serology revealed a Creatine Kinase (CK) of 773 IU/L (32-294 IU/L). He had an equivocal signal recognition particle (SRP) antibody result, which was later repeated and found to be negative. His EMG showed myopathic changes in his distal and proximal lower limb muscles with profuse spontaneous activity,indicating anactive myopathicprocess. MRI of his lower limbs showed symmetrical fatty infiltration in the distal semimembranosus and short head of biceps femoris muscles with no clear oedema. A muscle biopsy showed diffuse MHC Class 1 upregulation with nemaline rods. Treatment with pulsed IV methylprednisolone was started, in addition to Mycophenolate Mofetil (MMF) as steroid therapy was not sufficient to suppress his disease. He had a reduction in his CK to 205 IU/L and no activity in his skeletal muscle on FDG-PET CT. His power improved to 3/5 onMRCgrading. Case report -Discussion: Three distinct patterns of muscle involvement in sarcoidosis are recognised: chronicmyopathy, nodular myopathy, and acute myopathy. Symptomatic muscle disease in sarcoidosis is rare and it is important to consider other potential aetiologies of a progressive myopathy, even in a patient with established multisystem sarcoidosis. This case is interesting as there was diagnostic difficulty in ascertaining the diagnosis, which potentially included a corticosteroid-induced myopathy, SRP necrotising myopathy, oreven anemaline myopathy. Corticosteroid myopathy has a similar distribution to a sarcoid myopathy. However, the patient's clinical phenotype, elevated muscle enzymes, EMG findings, and histological data favoured an inflammatorymyositis. SRP necrotising myopathy is characterised by rapidly progressive proximal muscle weakness with necrotic muscle fibres, scant inflammation, and a significant elevation in muscle enzymes, which were not seen in this patient. The patient's weakness was more insidious in onset, with diffuse inflammation on muscle biopsy. Nemaline rods were seen on biopsy, however these were only present in one area, which is atypical of a nemaline myopathy. Furthermore, the presence of many loculated fibres on biopsy and upregulation of MHC class 1 was more in keeping with a diagnosis of an inflammatory myopathy secondary to sarcoidosis, even in the absence of non-caseating granulomas onmuscle biopsy. There are norandomised controlled trials of treatments insarcoid myopathy. While methotrexate is most used in steroid-recalcitrant myositis, the patient's liver fibrosis preluded this therapy, thus MMF was trialled instead. Co-existing inflammatory muscle disease with sarcoidosis has been documented infrequently in the literature. They both have overlapping symptoms with contrasting treatment strategies. In this patient, the musclebiopsy pointed toanidiopathic inflammatorymyopathy (IIM)without granulomatous infiltration, it is intriguing to consider whether treatment of an IIM with intravenous immunoglobulin or rituximab would have resulted in better clinical outcomes. Case report -Key learningpoints: Keypoints: Even though symptomatic muscle involvement in sarcoidosis is uncommon, a sarcoid myopathy should be suspected in symptomatic patients with known or suspected pulmonary or extrapulmonary sarcoidosis. In patients without known sarcoidosis but with unexplained muscle symptoms, particularly in the setting of a multisystem illness, sarcoid myopathy should be considered in the differential diagnosis. MRI and muscle biopsy are useful in distinguishing a sarcoid myopathy from a corticosteroid-induced myopathy as illustrated in this case. Fluorine 18 fluorodeoxyglucose (FDG) PET/CT is sensitive for assessment of the inflammatory activity of sarcoidosis in any organ. In this patient, FDG-PET was useful in evaluating active sarcoid lesions and evaluating the therapeutic effects of Mycophenolate Mofetil on his sarcoid myopathy. Although there is limited data to guide treatment in a sarcoid myopathy, Mycophenolate Mofetil can be used as an alternative to Methotrexate.

Ritsuko Saito and Ernest Wong
Queen Alexandra Hospital, Portsmouth, United Kingdom Casereport-Introduction:Granulomatousdisordersarediverseintheir aetiologies and presentations. We present an unusual case of severe psoriatic arthritis patient who subsequently developed multiple granulomatous diseases over time, granulomatous interstitial nephritis, granulomatous sarcoidosis with hilar lymphadenopathy and localised laryngeal granulomatous inflammation secondary to lambda type amyloidosis.
Case report -Case description: 52-year-old gentleman with arthritis mutilans secondary to severe poorly controlled psoriatic arthritis was followed up in Rheumatology clinic. Earlier therapy with leflunomide and methotrexate provided inadequate control. Golimumab, despite giving a good response, was stopped in 2013 after 5 months of treatment due to acute kidney injury. Renal biopsy revealed granulomatous interstitial nephritis, thought to be Golimumab-induced based on the timing of usage and reversibility with discontinuation. He was then trialled on UstekinumabandSecukinumabin2016 and2017respectively with variable response.
He also had a few-years history of voice change (high pitched) and sore throat which he attributed to recurrent colds. He denied dysphagia or breathlessness, and he did not have stridor. He has never smoked and only drank alcohol occasionally. ENT team noted white deposits on erythematous and thickened false vocal cords and posterior glottis with a thin web on microlaryngoscopy, which histologically proved to show granulomatous inflammation, potentially consisting of amyloid, although congo red stain was negative. On further investigation, including SAP scan, he was diagnosed with localised lambda type amyloid. Increasing throat pain and worsening dysphonia prompted change of management from conservative to a surgery at a specialist centre and an input from speech and language therapy team. During thistime,considerationforEtanerceptforhisjointandskindisease was put on hold, pending further management of laryngeal amyloidosis. Furthermore, he presented to hospital with breathlessness in 2019, where his chest X-ray showed bulky right hilum and a follow-up CT chest revealed calcified right hilar and mediastinal lymphadenopathy, ground glass opacification and consolidation. Histology from hilar node was suggestive of sarcoidosis,with stain negative foramyloid. He underwent removal of false vocal cords for his symptomatic laryngeal amyloidosis. He continues to be followed up at the local Rheumatology, Dermatology and ENT team.
Case report -Discussion: Granulomatous diseases have vast aetiologies, including infectious, immunological, neoplastic, and chemicalinduced processes. The age at which they affect patients and tissue they involve also vary hugely. This is the first reported case of three seemingly unrelated granulomatous diseases occurring in a single patient with severe refractory psoriatic arthritis. Retrospective reassessment of the histology samples supported that these are three separate pathologies. It is very unusual for one patient to acquire multiple separate granulomatous diseases, which was why the diagnostic process of this patient was challenging. In this case, managing the original underlying psoriatic arthritis was particularly difficult due to interruptions of treatment for adverse drug effects and investigations and treatment of subsequent granulomatous diseases. The case also raises questions about possible currently unknown association between the pathologies. Case report -Key learning points: Key points are the uniqueness of this case and that it highlighted the possibility of currently under-reported association between these three granulomatous conditions. As ever, a multidisciplinary approach to managing such a complex patient is important forthe provision of good care. Case report -Introduction: Here we explore a case of a 31-year-old female treated with juvenile arthritis rebranded as Blau syndrome. This is characterised by sarcoid involvement principally of her eyes as well as skin, kidneys, and joints. We aim to explore her management challenges and complications. Case report -Case description: 31 MS of Afro-Caribbean descent was diagnosed with early onset sarcoidosis at the age of 18 months. She was later found to be NOD2 gene positive but has no significant family history. Her health has been further complicated by her diagnoses of growth hormone deficiencyand hyperthyroidism secondary to multinodulargoitre. Clinically MS has a short stature and profound deafness. A legacy of the ophthalmic morbidity, panuveitis, has led to a visual acuity is 6/15 in her left eye and her right reduced to counting fingers due to developing endophthalmitis in 2019. Her arthritis is stable, but there are flexion deformities primarily involving her proximal interphalangeal joints reducing her grip function. In adulthood she does not have significant cutaneous changes.

EP25 BLAU SYNDROME: A LIFETIME OF SARCOID
Investigations have revealed her to be anti-nuclear and anti-neutrophil cytoplasmic antibody negative. Radiologically, hand films show sparing of erosive changes, radiocarpal subluxation, and deformity of carpi in keeping with bilateral Madelung deformity. MRI has never suggested synovialenhancement of sacroiliac joints. Therapeutically she has trialled conventional disease modifying therapy including azathioprine, mycophenolate, and methotrexate. Disease activity continues to be high despite anti-TNF biologic DMARDs (adalimumab, infliximab and golimumab). Use of anti-TNF therapy has been complicated by development of CMV disease and identification of antiinfliximabantibodies following interruption. Ongoing steroid use from 18 months, hyperthyroidism and a chronic inflammatorystatehas ledto osteoporosis. DEXA Z-scores reveal lumbar -2.7, right femoral neck -3.2 and left femoral neck -4.7. Systemic corticosteroid has tried to be offset through dexamethasone intravitreal implants. Consequentially, uncontrolled disease burden has also led to significant input from orthopaedics, including bilateral total knee replacements by age 28. However, with MS, we are hopeful with the commencement of anti-IL6 receptor therapy (Tocilizumab) that this may represent a new line of effective treatment.
Case report -Discussion: Blau syndrome is a juvenile sarcoidosis characterised by the triad of granulomatous arthritis, recurrent uveitis, and dermatitis. It is inherited in an autosomal dominant pattern due to a missense mutation in the gene encoding for nucleotide-binding oligomerisation domain containing protein 2 (NOD2/CARD15). It is proposed that NOD2 as intracellular receptors, for antigen such as lipopolysaccharide, may subsequently act like toll-like receptors to cascade NF-kappa B and downstream inflammatory pathways. Its role is also implicated in other inflammatory conditions such as Crohn's disease.
As represented in our case, uveitis presents the highest morbidity, with median age of eye disease presenting at 60 months and remains persistent despite topical or systemic therapy in more than 50% of patients. In comparison to Juvenile idiopathic arthritis, Blau often leads to a pan rather than anterior segment only uveitis and in a greater proportion of cases.
In addition to biological factors, much of MS's treatment decisions have been guided by her and her psychology. In attempting to address the difficulties of her condition, including coordinating several specialities clinics whilst developing as a young woman, she has frequently discontinued therapywhich may represent an area that she can exact control given little perceivedbenefit. TNF-alpha inhibitors have been validated through randomised controlled trials for the use of refractory sarcoidosis. However recent literature has highlighted the use of targeting the IL-6 pathway in multisystem chronic sarcoidosis. It is believed this may represent a key cytokine in promoting Th17 effector cells that have been implicated in sarcoidosis bio-pathology. However ongoing case reports and ideally large-scale studies are needed.
Case report -Key learning points: Blau syndrome as a rare lifelong form of early onset sarcoidosis offers insight into challenging therapeutic decision makingwhere limited clinicaltrial data is available.
Zeeshan Javaid 1,2 , Babitha Mekkayil 2 and Anupam Paul 2 1 Darlington Memorial Hospital, Darlington, United Kingdom, and 2 The James Cook University Hospital, Middlesbrough, United Kingdom 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 nonsmoker 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 Sjö gren'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 investigationsshowed apositiveHIVtest andliver biopsy camebackpositive for anaplastic lymphoma, later she was diagnosed with advanced HIV disease, rapidly deteriorated with neutropenic sepsis and multiorgan failure, and unfortunately died. Case report -Introduction: Sjö gren'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 Sjö gren'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 gentlemanhas had 6 years of intermittent cervical lymphadenopathy, dry eye and mouth symptoms withoutweightlossorrespiratorycomplaints.Hisbackground 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 negativeMycobacterium TB screening (serology and lymph nodes). Blood tests show a normal CRP (<5 mg/L), ESR 36 mm/h, raised polyclonal IgG 28.6 g/L (IgG subclass 1, 20.40 g/L, subclass 2, 9.36g/L, subclass 3, 0.954g/L, subclass 4, 9.430g/L) , normal complement and negative results for ANA, HLA B27, Anti CCP and ANCA. Bilateral submandibular gland ultrasound showed hyperechoic lesions consistent with either chronic sialadenitis or Sjö gren'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 onCT 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 areseen inthe neck, chest,and portahepatis.
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: Sjö gren's syndrome has a female preponderance and is usually associated with sicca symptoms, a positive Schirmer's test andautoantibodies (anti-Ro and anti-La). Extra-glandular