EP21 Tumour necrosis factor inhibitor for the treatment of refractory extra-pulmonary disease including sarcoid arthritis and myositis

Abstract Case report - Introduction Sarcoid myositis is a rare extrapulmonary manifestation of sarcoid, histologically characterised by non-caseating granuloma in the perimysial connective tissue. Muscle involvement is often asymptomatic but can cause weakness, myalgia, or muscle nodules. The first line treatment for sarcoid myositis is steroids. This case report details a case of sarcoid myositis and multi-system disease refractory to both steroids and mycophenolate mofetil. The use of infliximab, a Tumour Necrosis Factor α inhibitor (TNFi) resulted in drastic clinical and radiological resolution of sarcoid myositis. The patient is still on the TNFi and his sarcoid remains relatively well controlled. Case report - Case description A 33-year old Afro-Caribbean gentleman with a 10-year history of sarcoid (biopsy confirmed, affecting lymph nodes, lung) presented in May 2017 with joint pain, weakness, difficulty walking and cognitive impairment. At the time of the original diagnosis of sarcoid, he had concurrently been diagnosed with schizophrenia and steroids had been avoided. His only medication was olanzapine 5mg. Due to declining cognitive function, his psychiatrists arranged an MRI brain which showed extensive leptomeningeal disease. Lumbar puncture excluded infection and neurosarcoid was diagnosed. Prednisolone resulted in partial improvement in cognition, however joint symptoms and weakness persisted. On rheumatologic assessment there was an asymmetric inflammatory arthropathy, with small joint synovitis as well as large volume joint effusions of elbows and knees. Radiologic investigations showed characteristic lattice bony destruction, consistent with osseous sarcoid. His gait was waddling, and muscle strength was reduced symmetrically in the proximal groups. His creatinine kinase was 865, myositis specific antibody screen was negative although U1RNP was equivocal. Serum ACE was 102, CRP 17, ESR 25. CT-PET demonstrated FDG avidity in lymph nodes, lung parenchyma, bones, muscles, and testes. The muscle involvement was typical of nodular sarcoid and did not correlate with his weakness. The disease failed to respond adequately to either methotrexate or mycophenolate. He started Infliximab (5mg/kg). There was remarkable resolution of symptoms, including improvement in cognition. Follow up CT-PET confirmed response. Three years on he remains well, and no longer takes olanzapine. Case report - Discussion Muscle involvement occurs in 50-80% of sarcoidosis patients. Symptomatic myositis is rare (0.5-2.5%). There are three types of sarcoid myositis: nodular form, chronic myopathy, and acute myositis. Nodular involvement, as seen in our patient, usually occurs in young adults who experience palpable, painless nodules which may occur in any muscle. Nodules are not usually associated with weakness or limitation of movement. EMG and CK are usually normal. Chronic myopathy is rarely observed. It is characterised by a slowly progressive, symmetrical proximal myopathy with myopathic EMG changes but normal muscle enzymes, usually in women aged 50-60. Acute myositis typically affects younger patients (<40 years old) with diffuse muscle swelling, pain and proximal weakness which may progress to hypertrophy and contractures. Fatigue, fever, joint symptoms, and erythema nodosum are frequently seen. Inclusion Body Myositis is another granulomatous myopathy and should be considered as a differential, particularly in cases of treatment failure. The patient has had several episodes of psychosis and confusion which were previously diagnosed as schizophrenia and corticosteroid induced psychosis, meaning the team used steroids cautiously. MRI brain imaging revealed the presence of extensive neurosarcoidosis, and the neurocognitive improvement with treatment of a TNF inhibitor, suggested that the underlying pathology was sarcoidosis. Steroids could therefore be utilised appropriately for ongoing management. This case illustrates the difficulty of teasing out the underlying aetiology of neurocognitive dysfunction in patients with extensive sarcoidosis. TNFα released by alveolar macrophages is implicated in the induction and maintenance of sarcoid granulomas. Limited data from small randomised controlled trials and increasing data from non-randomised studies have led to consensus-based recommendations for TNFi use in pulmonary, ocular, cutaneous, neurological, and multi-system sarcoidosis. To our knowledge, this case is the first documented example of rapid clinical and radiological resolution of sarcoid myositis with an anti-TNF agent. Case report - Key learning points There are three important points to take away from this case. First, this case highlights the importance of a PET scan in demonstrating multi-system involvement in sarcoidosis. The PET scan was key in highlighting the extent of disease including sarcoid myositis. MRI scans of the brain were also important in highlighting the extent of neurosarcoidosis. Second, the patient presented with psychosis in 2013. This was thought to be corticosteroid-induced at the time. However, since treatment with the TNF inhibitor the patient experienced a significant neurocognitive improvement. The drastic improvement undermines the diagnosis of primary psychosis and suggests that the psychosis may have been due to neurosarcoidosis. In the context of patients with multi-organ sarcoidosis, psychosis secondary to neurosarcoid should be considered as a differential, even in the context of an earlier diagnosis of schizophrenia pre-dating the diagnosis of sarcoid. Third, the drastic resolution of sarcoid myositis and arthritis with a TNF inhibitor suggests that TNF inhibitors should be considered as treatment for cases of sarcoid myositis or sarcoid arthritis refractory to steroids. Whilst TNF inhibitors are currently unlicensed for this use in the UK, there is a growing body of evidence for their effectiveness in treating refractory extra-pulmonary sarcoidosis.

Given the constellation of hypercalcaemia, raised serum ACE level and anklesynovitisonMRIscan, hewas treatedforsarcoidosis with prednisolone 20mg. This led to a rapid improvement in his symptoms and normalisation of serum ACE. He was started on azathioprine as a steroid-sparing agent. Case report -Discussion: In cases series, hypercalcaemia due to sarcoidosis accounts for only 6% of all hypercalcaemic patients. The mechanism of hypercalcaemia in sarcoidosis is thought to be via activated pulmonary macrophages and sarcoid lymph node granulomas which upregulate the enzyme 1-alpha hydroxylase, resulting in the increased formation of calcitriol (1,25(OH) 2 D 3 ). This increases calcium absorption from the gastrointestinal tract, stimulates renal calcium reabsorption and promotes calcium release from skeletal stores,causing hypercalcaemia. This case was particularly unusual as earlier literature suggests that sarcoidosis-associated hypercalcaemia is a result of activated pulmonary macrophages and sarcoid granulomas. However, this patient had significant hypercalcaemia without any radiological lung involvement or granulomata, posing the question whether there are other pathways causing hypercalcaemia in sarcoidosis. Hypercalcaemia without pulmonary involvement may be due to the presence of small amounts of sarcoid granulomata in extra-pulmonary locations such as the porta hepatis. These may not be as easily detectable on radiological investigations but may contribute to the upregulation of 1alpha hydroxylase and subsequent hypercalcaemia. Another explanation for the significant hypercalcaemia in this patient may be due to the productionof parathyroid hormone-related peptide (PTHrP) from sarcoid granulomas and bone marrow, which upregulates renal 1-alpha hydroxylase enzymesand increases the formation of calcitriol. There was no area to obtain a tissue biopsy given the normal CT and PET CTscans,resultinginagreaterrelianceonhistory, examination,andserological investigations.
In addition, 30-50% of all patients with sarcoidosis have hypercalciuria, yet this patient interestingly had only an isolated hypercalcaemia with a normal urinarycalcium.

Case report -Key learningpoints
Hypercalcaemia is rare in the absence of pulmonary involvement with only 10 cases reported in literature. Although non-specific, an elevated serum ACE level may be a useful pointer to the diagnosis of sarcoidosis in the absence of other classical signs. In this case, granulomatous tissue responsible to produce 1,25(OH) 2 D3 might be below the limits of radiological detection. Production may originate from extra-pulmonary sarcoid granulomatous tissue such as in the porta hepatis. Another possible mechanism for hypercalcaemia may be the production of PTHrP which has been reported in sarcoid tissue specimens and in the bone marrow. Case report -Introduction: Sarcoid myositis is a rare extrapulmonary manifestation of sarcoid, histologically characterised by non-caseating granuloma in the perimysial connective tissue. Muscle involvement is often asymptomatic but can cause weakness, myalgia, or muscle nodules. The first line treatment for sarcoid myositis is steroids. This case report details a case of sarcoid myositis and multi-system disease refractory to both steroids and mycophenolate mofetil. The use of infliximab, a Tumour Necrosis Factor a inhibitor (TNFi) resulted in drastic clinical and radiological resolution of sarcoid myositis. The patient is still on the TNFi and his sarcoid remainsrelatively well controlled. Case report -Case description: A 33-year old Afro-Caribbean gentleman with a 10-year history of sarcoid (biopsy confirmed, affecting lymph nodes, lung) presented in May 2017 with joint pain, weakness, difficulty walking and cognitive impairment. At the time of the original diagnosis of sarcoid, hehadconcurrentlybeen diagnosed withschizophreniaandsteroids had been avoided.His only medication was olanzapine 5mg. Due to declining cognitive function, his psychiatrists arranged an MRI brain which showed extensive leptomeningeal disease. Lumbar puncture excluded infection and neurosarcoid was diagnosed. Prednisolone resulted in partial improvement in cognition, however joint symptoms and weaknesspersisted. On rheumatologic assessment there was an asymmetric inflammatory arthropathy, with small joint synovitis as well as large volume joint effusions of elbows and knees. Radiologic investigations showed characteristic lattice bony destruction, consistent with osseous sarcoid. His gait was waddling, and muscle strength was reduced symmetrically in the proximalgroups. His creatinine kinase was 865, myositis specific antibody screen was negative although U1RNP was equivocal. Serum ACE was 102, CRP 17, ESR 25. CT-PET demonstrated FDG avidity in lymph nodes, lung parenchyma, bones, muscles, and testes. The muscle involvement was typical of nodular sarcoid and did not correlate with his weakness. The disease failed to respond adequately to either methotrexate or mycophenolate. HestartedInfliximab (5mg/kg).Therewasremarkable resolution of symptoms, including improvement in cognition. Follow up CT-PET confirmed response. Three years on he remains well, and no longer takes olanzapine.
Case report -Discussion: Muscle involvement occurs in 50-80% of sarcoidosis patients. Symptomatic myositis is rare (0.5-2.5%). There are three types of sarcoid myositis: nodular form, chronic myopathy, and acute myositis. Nodular involvement, as seen in our patient, usually occurs in young adults who experience palpable, painless nodules which may occur in any muscle. Nodules are not usually associated with weakness or limitation of movement. EMG and CK are usually normal. Chronic myopathy is rarely observed. It is characterised by a slowly progressive, symmetrical proximal myopathy with myopathic EMG changes but normal muscle enzymes, usually in women aged 50-60. Acute myositis typically affects younger patients (<40 years old) with diffuse muscle swelling, pain and proximal weakness which may progress to hypertrophy and contractures. Fatigue, fever, joint symptoms, and erythema nodosum are frequently seen. Inclusion Body Myositis is another granulomatous myopathy and should be considered as a differential, particularly incases of treatment failure.
The patient has had several episodes of psychosis and confusion which were previously diagnosed as schizophrenia and corticosteroid induced psychosis, meaning the team used steroids cautiously. MRI brain imaging revealed the presence of extensive neurosarcoidosis, and the neurocognitive improvement with treatment of a TNF inhibitor, suggested that the underlying pathology was sarcoidosis. Steroids could therefore be utilised appropriately for ongoing management. This case illustrates the difficulty of teasing out the underlying aetiology of neurocognitive dysfunction in patients with extensive sarcoidosis. TNFa released by alveolar macrophages is implicated in the induction and maintenance of sarcoid granulomas. Limited data from small randomised controlled trials and increasing data from non-randomised studies have led to consensus-based recommendations for TNFi use in pulmonary, ocular, cutaneous, neurological, and multi-system sarcoidosis. To our knowledge, this case is the first documented example of rapid clinical and radiological resolution of sarcoid myositis with an anti-TNF agent.
Case report -Key learning points: There are three important points to take away from this case. First, this case highlights the importance of a PET scan in demonstrating multi-system involvement in sarcoidosis. The PET scan was key in highlighting the extent of disease including sarcoid myositis. MRI scans of the brain were also important in highlighting the extent of neurosarcoidosis. Second, thepatientpresentedwithpsychosisin2013.Thiswasthoughtto be corticosteroid-induced at the time. However, since treatment with the TNF inhibitor the patient experienced a significant neurocognitive improvement. Thedrasticimprovementunderminesthediagnosisofprimarypsychosisand suggests that the psychosis may have been due to neurosarcoidosis. In the context of patients with multi-organ sarcoidosis, psychosis secondary to neurosarcoid should be considered as a differential, even in the context of an earlierdiagnosisofschizophreniapre-datingthediagnosisofsarcoid. Third, the drastic resolution of sarcoid myositis and arthritis with a TNF inhibitor suggests that TNF inhibitors should be considered as treatment for cases of sarcoid myositis or sarcoid arthritis refractory to steroids. Whilst TNF inhibitors are currently unlicensed for this use in the UK, there is a growing body of evidence for their effectiveness in treating refractory extra-pulmonary sarcoidosis.

Rajiv Ark Royal Lancaster Infirmary, Lancaster, United Kingdom
Case report -Introduction: In 2011 a gentleman in his 50s presented with nasal blockage and bloody discharge. He was diagnosed with sarcoidosis and after 9 years of failed strategies to control his disease, he developeddactylitis. X-ray of the hands showed severe arthropathy in the distal interphalangeal joints. This case demonstrates an uncommon extrapulmonary manifestation of sarcoidosis. Although most of his follow up was with a respiratory clinic, his main symptoms were not due to interstitial lung disease, highlighting the importance of a multidisciplinary approach. To reduce the need for steroids, several DMARDs were tried illustrating that there arelimited treatment options. Case report -Case description: This gentleman presented in June 2011 with left epiphora, bloody nasal discharge and fatigue. He had no family history of sarcoidosis and was of Caucasian ethnicity. He was referred by his GP to Ophthalmology and ENT. Septoplasty showed a 95% blockage at the lacrimal sac. A biopsy was performed, and histology showed a nasal sarcoid granuloma. He was referred to the respiratory team who requested a high-resolution CT scan showing sizeable lymph nodes. One inguinal node was biopsied confirming sarcoid granulomas before starting treatment. Calcium was briefly raised, and serum ACE was initially 123. He was started on 40mg of prednisolone for 6 weeks, which was tapered to 20/25mg on alternating days. There was a recurrence of his nasal discharge; steroids were increased again but he developed symptoms of muscle weakness from long term steroid use. He was referred to an interstitial lung disease clinic at a tertiary centre where he was investigated for cardiac sarcoidosis with MRI due to ventricular ectopics. Hydroxychloroquine was started to reduce the steroid use however he developed symptoms of tinnitus, so it was stopped. Methotrexate, Azathioprine and Leflunomide were all trialled to however they did not have any impact on controlling his disease. His Prednisolone was slowly reduced by 1mg a month. When he had recurrence of his symptoms, he was given IVmethylprednisolone. Nine years after his first presentation he presented with stiffness of the right thumb base. This progressed to dactylitis and slight fixed flexion deformity of rightindex fingerand left little finger. An x-ray of his hands showed disease in the distal interphalangeal joints bilaterally with severe changes in the left little finger. The effects of longterm steroids led him to request aletterto support early retirement.
Case report -Discussion: The main rationale for changing treatment options was to reduce the prednisolone dose. Steroids were the only treatment option that showed evidence of controlling his disease when the dose was between 25mg and 40mg a day. Each of the DMARDs that were trialled had a different side effect profile and did not show any evidence of suppressing disease as symptoms recurred. Dose changes later in treatment fluctuated, reflecting a balancing act between disease recurrence and sideeffects of long-term steroids. There are many extra pulmonary manifestations of sarcoidosis that were investigated in this case. The first being the nasal granuloma, which can occur in sarcoid patients with symptoms of epistaxis, crusting, congestion, and pain. There were granulomatous changes seen in the hila as wellas other lymph nodes such as the inguinal region; inguinal lymphadenopathy can lead to pain in the groin area. In addition to this it was important to exclude uveitis with ophthalmology review as he had symptoms of epiphora. Uveitis can be diagnosed in ophthalmological assessment of sarcoid patients in the absence of ocular complaints. Cardiac sarcoidosis was excluded with an MRI at a specialist heart and lung centre due to ventricular ectopics. Cardiac sarcoidosis can lead to heart block, arrhythmias, and congestive cardiacfailure. Finally, he developed sarcoid arthropathy, review of his radiological imagesover time showed extensive damage to the jointsof the hand. This gentleman had poor outcomes due to limited treatment options for his disease. Being restricted to long term steroid as the mainstay of treatment led to early retirement due to fatigue and muscle weakness.
Conversely, under dosing steroids led to recurrence in symptoms. His disease is still not controlled as shown by an evolving sarcoid arthropathy.
Case report -Key learning points: An illustration of sarcoid arthropathy is also shown in this case. Sarcoid arthropathy is an uncommon manifestation of the disease primarily affecting joints in the hands and feet. In this case the distal interphalangeal joints and proximal interphalangeal joints were affected. The first symptom of arthropathy was stiffness of the base of the right thumb in 2017, this could fit with an osteoarthritic picture and could be mistaken for it in undiagnosed sarcoidosis. The most severe disease was in the DIP of the left little finger, which is not commonly affected. An oligoarthritic pattern with involvement of the ankle is seen more often. This is also an unusual case of sarcoidosis as there was no family history of the disease and his ethnicity did not predispose him to the condition. He also had a few uncommon extra pulmonary manifestations of sarcoidosis.
The importance of a multidisciplinary approach in managing sarcoidosis wasdemonstratedinthiscase.Mostofhisfollowupwaswitharespiratory clinic. However, respiratory symptoms were not the main issue during the patient journey; early ENT and rheumatology input was significant inmanaging his disease. Although pulmonary lymph nodes were enlarged, they did not affect hislung function.

Saadia Sasha Ali, Mark Russell, James Galloway and Ioana Onac
King's College Hospital, London, United Kingdom Case report -Introduction: Sarcoidosis is a multisystem disorder of unknown aetiology that is characterised pathologically by the presence of non-caseating granulomata. The disease is known for its multitude of presentations and can affect almost any organ system. Symptomatic skeletal muscle involvement in sarcoidosis is infrequent and occurs in < 3% of all sarcoidosis patients. We present the case of a 47-year-old male with multisystem sarcoidosis involving his lungs, eyes, and liver, who presented to our tertiary sarcoid centre with proximal muscle weakness. This case is significant as it highlights the diagnostic challenges that can arise when muscle weakness occurs on a background of sarcoidosis.
Case report -Case description: A 47-year-old gentleman presented to Rheumatology with a ten-year history of progressive lower extremity muscle weakness. He was known to have multisystem sarcoidosis affecting his lungs (diffuse interstitial lung disease), eyes (anterior uveitis) and liver (liver fibrosis). His sarcoidosis was initially diagnosed ten years beforehand, from confirmatory histology obtained via Endobronchial Ultrasound sampling. He was previously a keen runner; however, he had observed a gradual decline in his ability to run. Over a period of two years his mobility further deteriorated,and herequiredtwo sticks to walk. Physical examination revealed a waddling gait with wasting to his quadriceps bilaterally. He had reduced power of 2/5 on hip flexion on the Medical Research Council (MRC) muscle grading scale. There was no bulbar involvement and facial and upper extremitystrength was normal.