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Objectives Although the painful and disabling features of early diffuse cutaneous SSc (dcSSc) have an inflammatory basis and could respond to corticosteroids, corticosteroids are a risk factor for scleroderma renal crisis. Whether or not they should be prescribed is therefore highly contentious. Our aim was to examine safety and efficacy of moderate-dose prednisolone in early dcSSc. Methods PRedSS set out as a Phase II, multicentre, double-blind randomized controlled trial, converted to open-label during the Covid-19 pandemic. Patients were randomized to receive either prednisolone (∼0.3 mg/kg) or matching placebo (or no treatment during open-label) for 6 months. Co-primary endpoints were the HAQ Disability Index (HAQ-DI) and modified Rodnan skin score (mRSS) at 3 months. Over 20 secondary endpoints included patient reported outcome measures reflecting pain, itch, fatigue, anxiety and depression, and helplessness. Target recruitment was 72 patients. Results Thirty-five patients were randomized (17 prednisolone, 18 placebo/control). The adjusted mean difference between treatment groups at 3 months in HAQ-DI score was −0.10 (97.5% CI: −0.29, 0.10), P = 0.254, and in mRSS −3.90 (97.5% CI: −8.83, 1.03), P = 0.070, both favouring prednisolone but not significantly. Patients in the prednisolone group experienced significantly less pain (P = 0.027), anxiety (P = 0.018) and helplessness (P = 0.040) than control patients at 3 months. There were no renal crises, but sample size was small. Conclusion PRedSS was terminated early primarily due to the Covid-19 pandemic, and so was underpowered. Therefore, interpretation must be cautious and results considered inconclusive, indicating the need for a further randomized trial. Trial registration ClinicalTrials.gov, https://clinicaltrials.gov, NCT03708718.

Inflammatory myopathies are heterogeneous clinico-serological syndromes, with variable clinical manifestations. Interstitial lung disease (ILD) is a major cause of morbidity and mortality in patients with myositis. The clinical manifestation of myositis-ILD is heterogeneous, e.g., with acute-on-chronic presentations, as well as the chronic aftermath of acute disease. Here, we have largely divided myositis-ILD into three main prognostic groups which require different treatment approaches: mild-moderate (subacute), severe or progressive (acute or subacute) and rapidly progressive, life-threatening. In current clinical practice, the treatment of myositis-ILD involves immunomodulation in an induction-maintenance treatment paradigm. There is now an option to add antifibrotics to slow the progression of established fibrosis in selected cases with chronic progressive phenotype. Here, we describe current concepts in myositis-ILD and aim to provide a practical guide for clinicians on how to approach assessment, including early identification of ILD, phenotyping of patients according to clinical trajectory and likely prognosis and stratified management adopting multi-disciplinary cross-speciality expertise, with close collaboration between rheumatology and respiratory physicians.

Background/Aims Giant cell arteritis (GCA) is a systemic vasculitis involving large and medium-sized blood vessels. Patients can present with cranial, ocular or large vessel (LVV-GCA) involvement. Treatment is with high dose glucocorticoids. Steroid-sparing agents and tocilizumab (TCZ) are used for refractory or relapsing cases. NHS England requires all GCA patients to be discussed in a regional multidisciplinary team meeting (MDT) prior to commencing TCZ. We reviewed the case mixture of patients referred to the Bristol and Bath regional MDT. Methods The Bristol and Bath regional MDT started in November 2018 and runs monthly. A referral proforma was designed, adapted from the NHS England Blueteq approval form for TCZ in GCA (definitions of refractory and relapsing disease), with tick boxes for clinical features, investigations, treatment, glucocorticoid adverse events and a free text clinical vignette. All referral proformas were reviewed. Results Audit data from all cases referred, between November 2018 and September 2021, were analysed. 38 cases of GCA were discussed with 31 cases approved for TCZ usage. Of the approved, 100% fulfilled the criteria for either refractory (n = 11) or relapsing (n = 20) disease. Mean age of approved cases was 74 years with three quarters being female (74.2%). Average disease duration was 161.5 days for the refractory group and 827.3 days for the relapsing group. Over three quarters of cases (77.4%) had cranial GCA, 48.4% had LVV-GCA, 45.2% had visual symptoms (reduction in visual acuity, blurring or diplopia) and 25.8% had ischaemic visual loss. The positive investigations were PET-CT (48.4%), temporal artery ultrasound (41.9%) and temporal artery biopsy (32.3%). Almost two-thirds (64.5%) had previously had a steroid-sparing agent (61.3 % methotrexate, 9.7% azathioprine, 6.5% leflunomide), one third (35.5%) had received intravenous methylprednisolone and more than half (58%) were receiving greater than 40mg prednisolone at the time of referral. Common glucocorticoid adverse effects (each seen in 19.4% of cases) included osteoporosis, weight gain, cataracts or hypertension, whilst diabetes, neuropsychiatric symptoms or sleep disturbance were each reported in 16.1% of cases. The majority of patients with ocular involvement had cranial symptoms (71%). Patients with ocular involvement tended to be referred earlier than those with no ocular involvement (478.2 days vs 648.1 days), were on a higher dose of glucocorticoids at time of referral (71.4% vs 47.1% on more than 40mg) and had fewer steroid-sparing agents prior to referral. Conclusion All patients approved for TCZ in the GCA MDT fulfilled NHS England criteria for either relapsing or refractory disease. The majority of cases had cranial disease, but almost half had either ocular or large vessel vasculitis involvement, reflecting a severe spectrum of disease. Cases showed a high burden of glucocorticoid toxicity. Patients with ocular involvement were referred slightly earlier with less use of other steroid sparing treatments prior to TCZ in our cohort. Disclosure C. Jayatilleke: None. S. Janagan: None. R. Marshall: Other; Has received sponsorship from UCB Pharma to attend educational conferences in the last 2 years. S. Skeoch: None. C.M. Guly: None. F. En Sin: None. L. AL Sweedan: None. A. Anilkumar: None. K. Austin: None. A. Bourn: None. L. Clarke: None. H. Gunawardena: None. A. Johnson: None. S. Knights: None. J.D. Pauling: None. E. Reilly: None. T.D. Reynolds: None. S. Villar: None. J.C. Robson: None.

Interstitial lung disease is a known complication of rheumatoid arthritis, with a lifetime risk of developing the disease in any individual of 7·7%. We aimed to assess the safety, tolerability, and efficacy of pirfenidone for the treatment of patients with rheumatoid arthritis-associated interstitial lung disease (RA-ILD).TRAIL1 was a randomised, double-blind, placebo-controlled, phase 2 trial done in 34 academic centres specialising in interstitial lung disease in four countries (the UK, the USA, Australia, and Canada). Adults aged 18-85 years were eligible for inclusion if they met the 2010 American College of Rheumatology and European Alliance of Associations for Rheumatology criteria for rheumatoid arthritis and had interstitial lung disease on a high-resolution CT scan imaging and, when available, lung biopsy. Exclusion criteria include smoking, clinical history of other known causes of interstitial lung disease, and coexistant clinically significant COPD or asthma. Patients were randomly assigned (1:1) to receive 2403 mg oral pirfenidone (pirfenidone group) or placebo (placebo group) daily. The primary endpoint was the incidence of the composite endpoint of a decline from baseline in percent predicted forced vital capacity (FVC%) of 10% or more or death during the 52-week treatment period assessed in the intention-to-treat population. Key secondary endpoints included change in absolute and FVC% over 52 weeks, the proportion of patients with a decline in FVC% of 10% or more, and the frequency of progression as defined by Outcome Measures in Rheumatoid Arthritis Clinical Trials (OMERACT) in the intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT02808871.From May 15, 2017, to March 31, 2020, 231 patients were assessed for inclusion, of whom 123 patients were randomly assigned (63 [51%] to the pirfenidone group and 60 [49%] to the placebo group). The trial was stopped early (March 31, 2020) due to slow recruitment and the COVID-19 pandemic. The difference in the proportion of patients who met the composite primary endpoint (decline in FVC% from baseline of 10% or more or death) between the two groups was not significant (seven [11%] of 63 patients in the pirfenidone group vs nine [15%] of 60 patients in the placebo group; OR 0·67 [95% CI 0·22 to 2·03]; p=0·48). Compared with the placebo group, patients in the pirfenidone group had a slower rate of decline in lung function, measured by estimated annual change in absolute FVC (-66 vs -146; p=0·0082) and FVC% (-1·02 vs -3·21; p=0·0028). The groups were similar with regards to the decline in FVC% by 10% or more (five [8%] participants in the pirfenidone group vs seven [12%] in the placebo group; OR 0·52 [95% CI 0·14-1·90]; p=0·32) and the frequency of progression as defined by OMERACT (16 [25%] in the pirfenidone group vs 19 [32%] in the placebo group; OR 0·68 [0·30-1·54]; p=0·35). There was no significant difference in the rate of treatment-emergent serious adverse events between the two groups, and there were no treatment-related deaths.Due to early termination of the study and underpowering, the results should be interpreted with caution. Despite not meeting the composite primary endpoint, pirfenidone slowed the rate of decline of FVC over time in patients with RA-ILD. Safety in patients with RA-ILD was similar to that seen in other pirfenidone trials.Genentech.

Sneddon syndrome (SS) is a rare medium-vessel vasculopathy which characteristically presents with livedo racemosa (LR) and complications such as strokes. This case report describes a female presenting acutely with a stroke and, initially, no evidence of LR. Her antiphospholipid antibodies were negative, and her neuroimaging revealed multiple territory strokes with extensive vasculopathy and fragile neo-formed vessel collateralisation. She had progressive memory loss and multiple transient ischaemic attacks on a background of established infarctions. SS should be considered in any idiopathic medium-vessel vasculopathy despite the absence of LR. Medical therapy can be challenging and the importance of antiphospholipid status in risk stratifying anticoagulation against antiplatelet therapy is discussed with a proposed rheumatology management strategy. The medical option of hydroxychloroquine should be considered in all patients in view of its anti-thrombotic properties and efficacy in diseases such as systemic lupus erythematosus and antiphospholipid syndrome with the suggestion that SS may be a forme fruste of these diseases. Neurosurgical options should be considered for recurrent transient neurological symptoms. For our patient, this included an extracranial to intracranial bypass via a radial artery graft for haemodynamic stroke management confirmed on SPECT imaging. The traditional hallmark of SS has previously been LR. This case highlights an atypical presentation stressing the importance of diagnostic vigilance in a patient with an idiopathic medium-vessel vasculopathy, together with balancing the medical risk of antiplatelet therapy, anticoagulation and thrombolysis whilst revealing possible neurosurgical options in select SS patients.

We describe the case of a 61-year-old woman who presented with progressive respiratory symptoms and imaging demonstrating multiple opacities in the right lung with hilar and mediastinal lymphadenopathy suggestive of multifocal adenocarcinoma. Subsequent biopsies were consistent with focal changes of organising pneumonia (OP) and no evidence of malignancy. She was treated with steroids for cryptogenic OP with limited response. There was clinical and radiological progression with new lung nodules, mediastinal and thoracic spinal canal infiltration. There was ongoing concern that clinical findings represented disseminated malignancy. Following further investigation and multidisciplinary respiratory and rheumatology review, a diagnosis of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) - granulomatosis with polyangiitis (GPA) was confirmed. The case highlighted the multisystem nature of GPA with unusual dural and large vessel aortic and pulmonary trunk involvement.

IntroductionAntisynthetase syndrome (ASyS) is a rare autoimmune connective tissue disease (CTD), associated with autoantibodies targeting tRNA synthetase enzymes, that can present to respiratory (interstitial lung disease (ILD)) or rheumatology (myositis, inflammatory arthritis and systemic features) services. The therapeutic management of CTD-associated ILD and idiopathic pulmonary fibrosis (IPF) differs widely, thus accurate diagnosis is essential.MethodsWe undertook a retrospective, multicentre observational cohort study designed to (1) evaluate differences between ASyS-associated ILD with IPF, (2) phenotypic differences in patients with ASyS-ILD presenting to respiratory versus rheumatology services, (3) differences in outcomes between ASySassociated with Jo-1 versus non-Jo-1 autoantibodies and (4) compare long-term outcomes between these groups.ResultsWe identified 76 patients with ASyS-ILD and 78 with IPF. Patients with ASyS were younger at presentation (57 vs 77 years, pConclusionsExtended autoimmune serology is needed to evaluate for ASyS autoantibodies in patients presenting with ILD, particularly in younger female patients. Musculoskeletal involvement is common in ASyS (typically Jo-1 autoantibodies) presenting to rheumatology but the burden of ILD is similar to those presenting to respiratory medicine.

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.

Objectives It has been over 10 years since the first report of autoantibodies directed against phenylalanyl tRNA synthetase (anti-Zo) in a patient with features of the anti-synthetase syndrome. In that time no further cases have been published. Here we aim to characterize more fully the clinical phenotype of anti-Zo–associated myositis by describing the clinical features of nine patients. Methods Anti-Zo was identified by protein-immunoprecipitation in patients referred for extended spectrum myositis autoantibody testing at our laboratory. Results were confirmed by immunodepletion using a reference serum. Medical records were retrospectively reviewed to provide detailed information of the associated clinical phenotype for all identified patients. Where possible, HLA genotype was imputed using Illumina protocols. Results Nine patients with anti-Zo were identified. The median age at disease onset was 51 years, and six patients were female. Seven patients had evidence of inflammatory muscle disease, seven of interstitial lung disease and six of arthritis. The reported pattern of interstitial lung disease varied with usual interstitial pneumonia, non-specific interstitial pneumonia and organizing pneumonia all described. Other features of the anti-synthetase syndrome such as RP and mechanics hands were common. HLA data was available for three patients, all of whom had at least one copy of the HLA 8.1 ancestral haplotype. Conclusion Patients with anti-Zo presenting with features of the anti-synthetase syndrome and interstitial lung disease is a common finding. Like other myositis autoantibodies, there is likely to be a genetic association with the HLA 8.1 ancestral haplotype.

Dr Andrew W Creamer (AWC), Respiratory Registrar : A 70-year-old retired teacher was referred to the respiratory clinic with a 12-month history of progressive exertional dyspnoea and dry cough. He denied haemoptysis, constitutional symptoms or diurnal variation. He took omeprazole, amlodipine and ezetimibe for a long-standing history of dyspepsia, hypertension and hypercholesterolaemia. He was an ex-smoker with a 30 pack-year history. He reported monophasic colour change in his fingers in the cold, but denied any other connective tissue disease (CTD) symptoms. He denied any significant environmental exposures such as organic dusts or moulds. His vital signs were normal. There was evidence of mechanic’s hands (a hyperkeratotic eruption with fissuring and cracking on the palmar and radial aspects of the fingers, strongly associated with idiopathic inflammatory myopathies) but no other features of CTD or clubbing. Bibasal fine inspiratory crepitations were audible on chest auscultation. Cardiovascular examination was normal. Initial investigations revealed pancytopenia (figure 1) with unremarkable liver and renal function, prompting referral to local haematology services for further assessment. Figure 1 Baseline blood tests at presentation. Abnormal values are highlighted in bold. Pancytopenia was evident, in the context of normal B12, folate and ferritin. Lung function testing revealed a restrictive pattern with significantly reduced gas transfer (figure 2), while 6 min walk test demonstrated baseline saturations of 95% on air dropping to 77% on exertion, achieving 260 m (48% of theoretical distance). Figure 2 Lung function tests at baseline and 4-month follow-up. Spirometry demonstrated a restrictive pattern with reduction in gas transfer factor. KCO, carbon monoxide transfer coefficient; TLCO, transfer factor for carbon monoxide. Chest X-ray showed prominent interstitial lung markings in the mid and lower zones (figure 3). High-resolution CT thorax (HRCT) demonstrated centrilobular emphysema throughout the lungs and a basally predominant interstitial process with features suggestive of non-specific interstitial pneumonia (NSIP) (figure …

Introduction The anti-neutrophil cytoplasmic antibody (ANCA) - associated vasculitides are a heterogeneous group of rare multisystem disorders characterised by inflammation and necrosis of small and medium blood vessels. Early diagnosis and prompt initiation of immunosuppressive treatment are essential to induce and maintain remission of disease, and thereby prevent severe life- or organ-threatening complications. We present a challenging case of a patient presenting with progressive lung lesions in the context of known ANCA-associated vasculitis (AAV), despite escalating immunosuppressive treatment. Case description A 66-year old-female was diagnosed in 2010 with cANCA (PR3) positive vasculitis with lung involvement. Remission was induced with high dose steroids and cyclophosphamide. Methotrexate was given as maintenance treatment until 2013 when she had a significant renal relapse treated with plasma exchange, steroids and cyclophosphamide. Her maintenance treatment was changed to mycophenolate. She had a further lung relapse in 2014, treated successfully with high dose steroids and rituximab. She was eventually weaned off all treatment in 2017. She was admitted to hospital in 2019 with dry cough, dyspnoea and sinus congestion. She was noted to have several purpuric lesions on her limbs. Her CRP was elevated at 123 with a stable eGFR of 77. ANCA screen was negative. Chest Xray revealed bilateral consolidation. She was initially treated with six pulses of 500mg of IV methylprednisolone and one pulse of rituximab as an inpatient over the course of 2 weeks, with broad spectrum antibiotic cover. Despite this, she continued to deteriorate with a worsening purpuric rash and increasing oxygen requirement. She underwent plasma exchange with little improvement. CT of her chest revealed multiple progressive bilateral cavitating lesions. It was noted that her IgG levels were low (3.72) following rituximab, increasing her risk of infection. An atypical infection screen was performed and she was discovered to have cytomegalovirus (CMV) reactivation with high viral titres of 56889. She underwent bronchoscopic alveolar lavage which was positive for CMV on PCR. CT guided lung biopsy revealed necrotising granulomatous inflammation with occasional CMV positive nuclei. She was given valganciclovir and IV immunoglobulin, and her prednisolone dose was reduced to 10mg. This resulted in her viral load reducing to undetectable levels, her CRP improving to 23 and immunoglobulins normalising. This correlated with a clinical improvement allowing the patient to be discharged home. Discussion The patient in this case appeared in the first instance to have another flare of her AAV. However the flare was atypical in that it was not associated with an increase in her cANCA titre and it did not respond quickly to steroids as had been the case on each previous occasion. This prompted a reassessment of her case and investigation into other potential causes for her deterioration. CMV is a persistent herpesvirus which can affect up to 75% of healthy individuals. The primary infection is rarely symptomatic but can be associated with significant morbidity and mortality in immunocompromised patients. Pulmonary CMV disease can mimic pulmonary disease associated with vasculitis. CMV can also directly damage endothelial cells and cause an occlusive vasculitis itself. The patient was immunosuppressed, increasing her risk of acquiring primary CMV infection or developing CMV reactivation. She was given further potent immunosuppression during her admission. Serology is often unreliable in immunosuppressed patients and in this case her CMV IgG was positive with a negative IgM, indicating past CMV infection only. It is important to send samples for viral PCR to detect and diagnose active infection, and allow treatment to be initiated promptly. The lung biopsy was felt to be more in keeping with active AAV, although occasional CMV positive nuclei were present. The patient was therefore managed as having CMV reactivation in the context of active AAV. Treatment of viral infection can pose further challenges when trying to manage coexistent active vasculitis as highlighted in this case. Close monitoring of the patient was required, together with a multidisciplinary approach involving input from colleagues in infectious diseases and immunology, to allow the patient to be managed safely and effectively. Prophylactic antiviral therapy may need to be considered if further immunosuppression is required in future. Key learning points CMV reactivation can complicate treatment of ANCA associated vasculitis. Clinicians should have a low threshold to test for CMV in immunocompromised patients with vasculitis, particularly in cases which are atypical or refractory to standard treatment. Viral PCR should be tested, as serology can often be unreliable in immunosuppressed patients. Conflict of interest The authors declare no conflicts of interest.

Introduction Myositis can be infective, metabolic or immune-mediated. Idiopathic inflammatory myopathy, which is immune-mediated, tends to be subacute, with symmetrical symptoms, overlap clinical features and positive autoimmune serology. We present a case of acute onset lower limb seronegative inflammatory myopathy with a normal creatinine kinase (CK), a marked acute phase response that responded promptly to immunomodulatory therapy. Case description A 68-year-old man presented with a 2-week history of lower limb pain with subjective weakness, on a background of well-controlled type 2 diabetes mellitus and hypertension. He was admitted with worsening symptoms of marked left thigh pain, night sweats, and fevers. On admission, he had swinging pyrexia (above >39 °C) while remaining haemodynamically stable. He had focal tenderness over the left anterolateral thigh, with a good range of movement, normal power and no signs of focal collection or cellulitis. There were no extra-muscular features to suggest systemic infection or overlap connective tissue disease. Bloods showed C-reactive protein (CRP) 225, normal CK 212 and negative blood cultures. X-rays knee, femur and pelvis were normal. Magnetic resonance imaging (MRI) on T2, fat-suppressed STIR sequences demonstrated increased signal/oedema both thighs throughout the anterior muscle compartment and along the fascial plane, notably most severe in the left vastus lateralis. He was treated empirically for infective myositis. Despite 14 days of broad-spectrum antibiotics, he remained febrile with persistently elevated CRP. There was no focal collection, lymphadenopathy or occult malignancy on CT abdomen and pelvis. Trans-oesophageal echocardiogram showed no evidence of infective endocarditis but revealed incidental moderate aortic stenosis. The patient described persistent now bilateral thigh pain with continued normal CK and high CRP. Full autoimmune screen (ANA, ANCA, ACE and complement studies) was negative. Despite negative nuclear and cytoplasmic HEp-2 immunofluorence, extended myositis immunoblot was negative. Muscle biopsy from the left vastus lateralis demonstrated inflammation within the perimysium and perivasculature. In view of biopsy findings and no response to anti-microbial therapy, prednisolone (0.5mg/kg) with significant clinical response (resolution of fever and pain) with concurrent normalisation in CRP. The patient remains in remission following steroid reduction with no additional immunomodulatory therapy required. Discussion We report a case of idiopathic inflammatory myopathy presenting with predominantly asymmetrical symptoms, normal CK, marked inflammatory response and negative myositis autoantibodies. Diagnosis was confirmed on MRI and muscle biopsy. The normal CK can be explained by the histology demonstrating inflammation in perivascular regions and around muscle fibres, rather than inflammation or necrosis in the muscle fascicles and fibres themselves. Idiopathic inflammatory myopathy including sporadic inclusion-body myositis, dermatomyositis, overlap CTD myositis and polymyositis/necrotising myopathy subsets are distinguishable based on clinical features, autoantibodies, MRI and biopsy features. The table below summarises the atypical aspects of this case. Differential diagnoses for this case include atypical infection, sarcoid myopathy and amyloid myonecrosis secondary to diabetes. Table: Features of typical idiopathic inflammatory myopathy compared with this atypical case.Idiopathic inflammatory myopathiesOur patient- typical featuresOur patient- atypical featuresSymptomsPain, fever, weakness.Pain and fever.Normal power.Clinical distributionSymmetrical, proximal muscle groups.Predominantly asymmetrical (worse on left), only in thighs.AntibodiesMyositis associated autoantibodiesSeronegativeMuscle enzymesElevated CKNormal CK.Inflammatory markersNormal to slightly elevated CRPMarkedly raised CRP and WCC.MR imaging resultsFocal muscle oedema in affected musclesDiffuse and speckled muscle oedema Key learning points Early idiopathic inflammatory myopathy can have inflammation around the muscle fascicles in the perimysium. Normal CK does not rule out a diagnosis of idiopathic inflammatory myopathy. Idiopathic inflammatory myopathies can present atypically with fevers >39 °C, significantly raised inflammatory markers, and asymmetrical symptoms and MRI findings. In the absence of overlap features, normal CK and negative serology, MRI and biopsy can delineate the type of myositis and direct management. Conflicts of interest The authors have declared no conflicts of interest.

We present the case of a patient with relapsing anti-synthetase syndrome (ASS) that may have been triggered by monoclonal antibody trastuzumab therapy given for breast cancer. A 52-year-old female with a history of anti-Jo1-associated ASS went into remission with glucocorticoids and mycophenolate mofetil. Her past history included invasive ductal carcinoma of the right breast that was fully treated six years prior to the onset of ASS. She subsequently developed recurrent right-sided breast cancer that was treated with right mastectomy and six cycles of cyclophosphamide-docetaxel chemotherapy. She commenced adjuvant trastuzumab and letrozole therapy, and following the sixth injection of trastuzumab, she was admitted with clinical features consistent with a flare of ASS, which included swinging fever, interstitial lung disease, myositis, and possible subclinical myocarditis, despite recent treatment with cyclophosphamide. She responded to intravenous IV methylprednisolone followed by increased doses of oral glucocorticoids, and she remains stable on immunomodulatory treatment and letrozole monotherapy given for breast cancer. This report provides a concise overview of ASS along with other cases of cardiac and pulmonary diseases attributed to trastuzumab therapy reported in the medical literature.

Eosinophilic fasciitis (EF) is a syndrome of unknown aetiology characterised by progressive collagenous thickening of the subcutaneous fascia. Limb oedema can precede the skin thickening and induration classically associated with EF. We describe a case of EF in a 31-year-old woman who presented to her general practitioner with lower limb oedema and stiffness. Blood tests in primary care showed a persistently raised alanine transferase (ALT). No hepatic cause for her raised ALT was found despite investigation. The unusual manner of her presentation led to delay in her referral to the autoimmune connective tissue disease (CTD) clinic. This case illustrates the importance of considering autoimmune CTD such as EF in young patients presenting with limb oedema and raised ALT, as early treatment influences prognosis and functional recovery.

Introduction Dashboards are considered an effective way to monitor key performance indicators (KPIs) in management practice. Publicly available NICE quality standards for the management of Idiopathic Pulmonary Fibrosis (IPF) and statutory requirements to submit quarterly specialised service quality dashboard information (SSQD) for commissioned ILD centres is driving the need to have readily available data on KPIs of service delivery. Our objective was to develop an electronic dashboard to capture ILD activity using recognised ‘model for improvement’ frameworks. Methods In conjunction with our business intelligence department we undertook a quality improvement project (QIP) using data stored in our ILD MDT database and patient administration system (Lorenzo), to develop an electronic ILD dashboard. The eMeasures were: 1) capture of outpatient ILD activity (something poorly assessed by HES data) 2) ILD population demographics 3) NICE quality standards for IPF and 4) the SSQD ’metric definition set’. Prototype electronic queries were built using numerator and denominator populations of ILD patients using standardised, ICD-10 coded terminology (inpatients) and named ILD clinics (outpatients) to enable automatic extraction of data. We adjusted clinical workflows, documentation and electronic queries through Plan-Do-Study-Act cycles to enable standardised information collection. Results The dashboard was conceptualised in June 2017, producing monthly reports to all our stakeholders. Between July 2017 to June 2018, 1200 patients were reviewed in outpatients. For the month of June 2018, 27 new(N) and 118 follow-up(F-up) ILD appointments were undertaken (N:F-up ratio of 1:4.4). The ‘did not attend’ rate was 3.3%. With regards to the NICE quality standards for IPF, data from the last quarter suggests that 100% ILD patients were discussed in our MDT, with 82.4% patients receiving lung function within 3 months of assessment. 90% of IPF patients had lung function testing on an annual basis. Emergency admission rate for respiratory deterioration of IPF patients was 2.2%, with an annual ILD mortality rate of 6.2%. Conclusion The development of an electronic dashboard has increased the accessibility of useful data to understand service quality and delivery. It enables us to fulfil statutory requirements for SSQD submission easily, providing a platform for future benchmarking of QIPs in service delivery.

Introduction and objectives Initial manifestations of lung disease in rheumatoid arthritis often occur in the small airways which can be challenging to measure using traditional lung function tests. The lung clearance index (LCI), measured by the nitrogen multiple breath washout (MBW) is a non-invasive measure of ventilation inhomogeneity and has been shown to be elevated in patients with primary lung disease. This study aimed to assess whether LCI, Scond (convection-dependent ventilation inhomogeneity) and Sacin (diffusion-convection dependent inhomogeneity) were elevated in patients with rheumatoid arthritis related lung disease and to assess whether MBW is feasible in this patient population. Methods 19 patients with rheumatoid arthritis (5 without lung disease and 14 with associated lung disease) were recruited from the respiratory and rheumatology clinics at North Bristol NHS Trust. Each patient participant completed spirometry, MBW and health-related quality of life (HRQoL) questionnaires at a single study visit. A separate group of 8 healthy controls also completed spirometry and MBW at a single visit. MBW was completed using the EasyOne proLAB™ (ndd Medizntechnik AG, Zurich, Switzerland). Results The mean time to perform a single test was 214 s and the mean number of tests required to achieve 3 acceptable efforts was 3.5 tests. All MBW parameters were repeatable (intra-class correlation coefficient >0.8). LCI and Sacin were significantly increased in patients with associated lung disease compared to healthy controls (p=0.008, p=0.004). No significant difference was seen in LCI and Sacin between patients without lung disease and healthy controls (p=0.171, p=0.083). There was no significant difference in spirometry z-scores. There was a significant correlation between LCI and HRQoL as measured by K-BILD and SGRQ. Conclusion MBW is a repeatable and feasible technique in patients with rheumatoid arthritis. The data from this pilot study suggests that N2 MBW may be a promising technique in the assessment of lung disease in patients with rheumatoid arthritis, with LCI and Sacin appearing to be the most useful parameters. The findings support the further investigation of MBW in patients with rheumatoid arthritis in a longitudinal cohort study to assess the variability over time and the relationship with HRQoL.

Introduction The therapeutic management of CTD-ILD and idiopathic forms differs widely, thus accurate diagnosis is essential. Several myositis-specific and myositis-associated antibodies (MSA/MAA) are now detectable that may associate with ILD. We wished to: 1) evaluate the use of comprehensive autoantibody testing to help differentiate idiopathic ILD from anti-synthetase syndrome (ASS) associated-ILD and 2) determine if there were differences in clinical characteristics of ASS-ILD patients presenting to respiratory versus rheumatology services. Method We retrospectively analysed the clinical characteristics and antibody profiles of ILD patients referred between Jan 2015 and July 2017. The clinical characteristics of all ASS-ILD patients were collated. Results Twenty-five patients (11 M: 14 F), referred initially to respiratory services as ILD of unknown cause, were diagnosed with ASS, representing 3.1% of new ILD referrals received (based on 27 new referrals/month). Patients were significantly younger than randomly selected comparator cohorts of IPF and unclassifiable (u) ILD patients (ASS patients median age 59 years (IQR 50–69.5) vs IPF 78 years (IQR 73.5–82) (p Although 76% of the ASS cohort were ANA negative (19/25), co-existent cytoplasmic staining was detected using cell immunofluorescence in 84% (21/25). For comparison, homogenous ANA positivity was detected in 13/25 IPF and in 7/25 uILD cohorts, in the absence of cytoplasmic staining. Anti Jo-1 antibodies were identified in 40% (10/25) of ASS patients (ENA positive). Specific MSAs were detected in a further 11 patients (2 EJ, 4 PL7, 1 KS, 3 PL12, 1 OJ – ENA negative) using immunoblot techniques. ASS patients with ILD who initially presented to respiratory services were more likely to express non-Jo-1 MSAs (p 0.06). Conclusions A negative ANA screen does not necessarily indicate autoantibody negativity. Despite the presence of MSAs, ASS-ILD patients presenting to respiratory services were more likely to have an amyopathic phenotype. Comprehensive serological testing, including cell immunofluorescence, should be routinely considered in initial assessments of ILD patients.

Objectives: Our aim was to describe the burden of early dcSSc in terms of disability, fatigue and pain in the European Scleroderma Observational Study cohort, and to explore associated clinical features.Methods: Patients completed questionnaires at study entry, 12 and 24 months, including the HAQ disability index (HAQ-DI), the Cochin Hand Function Scale (CHFS), the Functional Assessment of Chronic Illness Therapy-fatigue and the Short Form 36 (SF36). Associates examined included the modified Rodnan skin score (mRSS), current digital ulcers and internal organ involvement. Correlations between 12-month changes were also examined.Results: The 326 patients recruited (median disease duration 11.9 months) displayed high levels of disability [mean (S.D.) HAQ-DI 1.1 (0.83)], with ‘grip’ and ‘activity’ being most affected. Of the 18 activities assessed in the CHFS, those involving fine finger movements were most affected. High HAQ-DI and CHFS scores were both associated with high mRSS (ρ = 0.34, P < 0.0001 and ρ = 0.35, P < 0.0001, respectively). HAQ-DI was higher in patients with digital ulcers (P = 0.004), pulmonary fibrosis (P = 0.005), cardiac (P = 0.005) and muscle involvement (P = 0.002). As anticipated, HAQ-DI, CHFS, the Functional Assessment of Chronic Illness Therapy and SF36 scores were all highly correlated, in particular the HAQ-DI with the CHFS (ρ = 0.84, P < 0.0001). Worsening HAQ-DI over 12 months was strongly associated with increasing mRSS (ρ = 0.40, P < 0.0001), decreasing hand function (ρ = 0.57, P < 0.0001) and increasing fatigue (ρ = −0.53, P < 0.0001).Conclusion: The European Scleroderma Observational Study highlights the burden of disability in early dcSSc, with high levels of disability and fatigue, associating with the degree of skin thickening (mRSS). Impaired hand function is a major contributor to overall disability.

The idiopathic inflammatory myopathies (IIM) are a group of autoimmune diseases traditionally defined by clinical manifestations including skeletal muscle weakness, skin rashes, elevated skeletal muscle enzymes, and neurophysiological and/or histological evidence of muscle inflammation. Patients with myositis overlap can develop other features including parenchymal lung disease, inflammatory arthritis, gastrointestinal manifestations and marked constitutional symptoms. Although patients may be diagnosed as having polymyositis (PM) or dermatomyositis (DM) under the IIM spectrum, it is quite clear that disease course between subgroups of patients is different. For example, interstitial lung disease may predominate in some, whereas cutaneous complications, cancer risk, or severe refractory myopathy may be a significant feature in others. Therefore, tools that facilitate diagnosis and indicate which patients require more detailed investigation for disease complications are invaluable in clinical practice. The expanding field of autoantibodies (autoAbs) associated with connective tissue disease (CTD)-myositis overlap has generated considerable interest over the last few years. Using an immunological diagnostic approach, this group of heterogeneous conditions can be separated into a number of distinct clinical phenotypes. Rather than diagnose a patient as simply having PM, DM or overlap CTD, we can define syndromes to differentiate disease subsets that emphasise clinical outcomes and guide management. There are now over 15 CTD-myositis overlap autoAbs found in patients with a range of clinical manifestations including interstitial pneumonia, cutaneous disease, cancer-associated myositis and autoimmune-mediated necrotising myopathy. This review describes their diagnostic utility, potential role in disease monitoring and response to treatment. In the future, routine use of these autoAb will allow a stratified approach to managing this complex set of conditions.

With an increased understanding of the molecular pathways of inflammation and autoimmunity, the development of targeted biological agents has revolutionized the management of connective tissue diseases (CTDs). There has been an explosion in the development of these drugs in the last decade, targeting diseases in diverse fields including: allergic disorders, oncology, neuroinflammatory disorders, inflammatory bowel disease, macular degeneration and CTDs. In this last field, commonly applied biologics fall into two categories: cytokine inhibitors and lymphocyte-targeted therapies. The former group includes the antitumour necrosis factor alpha (TNF-α), anti-interleukin (IL)-6 receptor monoclonal antibodies and IL-1 receptor antagonists, whilst the latter encompasses the anti-CD20, B-cell depleting, monoclonal antibody (mAb), Rituximab and the anti-T-cell activation agent, Abatacept. This review will examine our developing experience in the use of these agents in the treatment of CTD-related interstitial lung diseases, with a particular focus on B-cell depletion.

Interstitial lung disease (ILD) is a common clinical problem, representing a group of diseases consisting of inflammation and progressive fibrosis of the lung. In some cases, an underlying cause is not identified; however, a significant proportion of ILD is associated with connective tissue disease (CTD). A detailed history and examination is the most important part of the assessment of patients with suspected ILD and will direct further investigation. This case illustrates the importance of identifying the symptoms and signs of CTD when assessing a patient with ILD. In addition, we describe an unusual presenting manifestation of yellow nails, which is not a recognised feature of CTD-ILD, but improved following immunomodulatory treatment for the overall condition.

Opinion statement IgG4-related disease (IgG4-RD) is a multisystem inflammatory disorder. Early recognition of IgG4-RD is important to avoid permanent organ dysfunction and disability. Neurological involvement by IgG4-RD is relatively uncommon, but well recognised—hypertrophic pachymeningitis and hypophysitis are the most frequent manifestations. Although the nervous system may be involved in isolation, this more frequently occurs in conjunction with involvement of other systems. Elevated circulating levels of IgG4 are suggestive of the condition, but these are not pathognomonic and exclusion of other inflammatory disorders including vasculitis is required. Wherever possible, a tissue diagnosis should be established. The characteristic histopathological changes include a lymphoplasmacytoid infiltrate, storiform fibrosis and obliterative phlebitis. IgG4-RD typically responds well to treatment with glucocorticoids, although relapse is relatively common and treatment with a steroid-sparing agent or rituximab may be required. Improved understanding of the pathogenesis of IgG4-RD is likely to lead to the development of more specific disease treatments in the future.

The idiopathic inflammatory myopathies: polymyositis (PM) and dermatomyositis (DM) have been historically defined by broad clinical and pathological criteria. These conditions affect both adults and children with clinical features including muscle weakness, skin disease and internal organ involvement. Over the last few years, it has become increasingly apparent that using a clinico-serological approach, both DM and PM can be defined into more homogeneous subsets. A large number of antibodies are directed against cytoplasmic or nuclear components involved in key regulatory intra-cellular processes including protein synthesis, translocation and gene transcription within this disease spectrum. In addition, these autoantibodies are found in patients with clinical features other than myositis, in particular 'idiopathic' interstitial pneumonia emphasizing that these patients may in fact be a formes-frustes of autoimmune connective tissue disease. Other important findings are the identification of specific autoantibodies in both cancer-associated dermatomyositis, clinically amyopathic dermatomyositis and juvenile dermatomyositis, which previously were classically described as antibody-negative clinical subsets. Finally, work has highlighted how target autoantigens identified in the myositis-connective tissue disease overlap share common cellular mechanisms, which provides us with further insights into disease pathogenesis.