EP19 Renal sarcoidosis associated with certolizumab pegol treatment for psoriatic arthritis: a case report

Abstract Case report - Introduction Sarcoidosis is a systemic granulomatous disease without a known aetiology. Patients can be asymptomatic and do not require treatment. However, for the severe cases of sarcoidosis, anti-tumour necrosis factor-α (TNF-α) agents have been used in addition to corticosteroids and disease modifying anti-rheumatic drugs (DMARDs). Paradoxically, anti-TNF-α treatment has also been shown to induce sarcoidosis in patients with autoimmune diseases, though what is known about the pathogenesis of this phenomenon is limited. We present a case of renal sarcoidosis occurring following Certolizumab Pegol (CZP) treatment in a patient with psoriatic arthritis. Case report - Case description A 55-year-old Caucasian man presented to the emergency department in Jan 2020 with a seizure and was found to have a stage 3 acute kidney injury. He was diagnosed with psoriatic arthritis (PsA) at age 47 and plaque psoriasis at 20. He has no other past medical history. For PsA, he was initially treated with Methotrexate, but this was stopped due to nausea. After failing on sulfasalazine, he was started on Humira (Adalimumab) and low dose Methotrexate, 10mg weekly. Due to lack of efficacy, he switched to Benepali (Etanercept) monotherapy. One year later, he was switched to Cimzia (Certolizumab Pegol) due to worsening disease activity. He was on the treatment for 7 months before presenting with seizures and renal failure. His seizure was caused by uraemia and hypertension secondary to renal failure. He has severe renal dysfunction (eGFR of 8ml/min/1.73m2), but low-level proteinuria (uPCR of 47mg/mmol). A renal biopsy was performed which showed features of non-necrotising interstitial nephritis, with well-formed granulomas & multiple giant cells, consistent with renal sarcoidosis. Infections were excluded including TB. He was started on high dose prednisolone 80mg daily, a modest improvement in creatinine was observed from 636µmol/L (eGFR 8ml/min/1.73m2) on admission to 526µmol/L (eGFR 10ml/min/1.73m2) on discharge a week later. He did not require renal replacement therapy during admission. The dose of prednisolone was tapered over time, he is now on 10mg per day and his creatinine in April 2020 was 344 µmol/L, (eGFR 16 ml/min/1.73m2). Currently, his psoriatic arthritis is under control, and his latest creatinine in July was 293 µmol/L (eGFR 20ml/min/1.73m2), his prednisolone was reduced further to 5mg daily. In this case report, we reviewed the evidence on anti-TNF-α induced sarcoidosis and options for future biologic agent therapy if there were to be deterioration of psoriatic arthritis or flare of psoriasis. Case report - Discussion Certolizumab-induced sarcoidosis is still a rare, but emerging phenomenon, with an unclear pathogenesis. Of the 87 published case reports of anti-TNF-α agent-induced sarcoidosis, 85 were in patients receiving Etanercept, Adalimumab, and infliximab. In terms of Certolizumab-induced sarcoidosis, a PubMed search using the terms “sarcoidosis, and Certolizumab”, found only two previously reported cases. In the first case, a 45-year-old Caucasian woman with HLA-B27-positive non-radiographic axial spondyloarthritis developed severe renal insufficiency and mediastinal lymphadenopathy following 6 months of Certolizumab therapy. Renal biopsy showed granulomatous interstitial nephritis consistent with renal sarcoidosis, and bronchial biopsies showed non-caseating granulomas. The patient was treated with prednisolone 60mg daily, which was weaned over 6 months along with the initiation of Methotrexate and Secukinumab. This combination led to a minor improvement in her axial symptoms and stabilisation of her renal disease. In the second case, a 69-year-old woman with rheumatoid arthritis developed fatigue, appetite loss and low-grade fever after 6 years of Certolizumab Pegol therapy. She was found to have granulomatous uveitis, bilateral hilar and mediastinal lymphadenopathy, a subcutaneous nodule on her right knee, and micronodules in the upper lobes of both lungs. A video-assisted thoracoscopic biopsy showed noncaseous epithelioid cell granulomas consistent with sarcoidosis. Furthermore, a biopsy of the nodule on her knee showed noncaseous epithelioid cell granulomas. She received 20mg of prednisolone daily to advantageous effect, which was then tapered to 10mg daily without recurrence of sarcoidosis. She was then started on abatacept treatment while further tapering her prednisolone. Case report - Key learning points In these two cases plus this current case, discontinuation of anti-TNF-α agents with systemic corticosteroid treatment resulted in the regression of sarcoidosis. One proposed mechanism of Certolizumab-induced sarcoidosis involves neutralising antibodies, though data on the impact and frequency of anti-drug antibodies in Certolizumab therapy is still unclear. Even the frequency of anti-drug antibodies in Certolizumab therapy is still unclear, with reported percentages ranging from 3.3% to 25.3%. Anti-drug antibodies with Adalimumab is thought to be more common with reported frequency as high as 38.0%, with 21 case reports published about Adalimumab-induced sarcoidosis. There are also case reports on Secukinumab (anti-IL17) associated with onset of sarcoidosis, this is one of the treatment options for psoriatic arthritis and psoriasis as per NICE guidance (TA445). Tofacitinib has been approved by NICE recently (TA543) for PsA, so far, there are no case reports associated with the onset of sarcoidosis, rather, it has been used to treat sarcoidosis successfully. Therefore, Tofacitinib seems to be a potential treatment option for this patient. Key learning points therefore include: Certolizumab-induced sarcoidosis is a rare but increasingly recognised phenomenon. The role of anti-drug antibodies in the pathogenesis of anti-TNF-α agent-induced sarcoidosis remains unclear. Systemic corticosteroid treatment seems to be an effective treatment for anti-TNF-α agent-induced sarcoidosis. Tofacitinib has not been reported to cause drug-induced sarcoidosis and is a viable alternative treatment option.

an MRI brain showed neurosarcoid in the superior sagittal sinus tracking along the right transverse sinus. Currently the patient is maintained on subcutaneous methotrexate 25mg disease modifying anti-rheumatic drug (DMARD) monotherapy. He has diabetes attributed to prolonged corticosteroid use over the last three years. As a result of his testicular involvement, the patient suffers from erectile dysfunction and hypogonadism with low testosterone production. Chronic pain and neuro-sagittal involvement have contributed to difficulties in achieving treatment targets with increased malaise, fatigue and poor cognition all compounding his disease further. This has posed a challenge as to whether this is due to the disease or the patients use of cannabisor acombinationof the two. Case report -Discussion: Testicular sarcoid is a rare presentation in which only around 0.2% of all sarcoidosis cases are diagnosed. The epididymis, vas deferens and testis can all be involved. Presentation can mimic that of infections such as tuberculosis mycobacterium and malignancy with uni-or bilateral testicular involvement. Challenges arise, as in this case, when the patient presents with genito-urinary involvement in the absence of more systemic features which may favour extra-pulmonary manifestations. The diagnosis and treatment can be difficult, as corticosteroid response tends to be most effective at high doses and disease modifying anti-rheumatic drugs (DMARDs) such as methotrexate have evidence for pulmonary and extra-pulmonary sites. Our patient developed more systemic features at a later stage. The diagnosis was challenging and there was an interval of a year between the orchidectomy and commencement of steroids. This shows the ongoing difficulties in diagnosing patients with sarcoidosis and the delays that occur in treatment initiation. Testicular involvement has created debilitating symptoms for the patient with chronic pain affecting his ability to sit and ride his bike for extended periods. Involvement of the other testicle, ongoing low testosterone production and erectile dysfunction have posed difficult discussions around future fertility. It is encouraging that he has managed to wean from corticosteroid and methotrexate seems to be controlling the disease quite well. The evidence relating to best possible DMARD treatment in testicular sarcoid is still scarce and is an interesting point of discussion. There have been co-existent reports of testicular tumours in sarcoid, and as most of these patients are seen by surgical specialties, further work must heighten awareness of sarcoid in this cohort of patients. Case report -Key learning points: We feel this is an unusual presentation of sarcoidosis; a patient who presented with primary testicular involvement and is pertinent to the topic of extrapulmonary disease manifestation. Despite appropriate treatment, he developed recurrence within the other testis two years later. Testicular involvement as a manifestation of extra-pulmonary sarcoidosis is rare and difficult to treat. There are limitations in treatment beyond corticosteroid, although DMARD therapy with methotrexate being favoured in case reports listed elsewhere. It is difficult to differentiate from malignancy andinfection,andasaresultoftenrequirescomplete removal of the testis forhistological interpretation. This can lead to hypogonadism and may affect long-term fertility which has significant psychosocial impacts for patients. There is an association between sarcoidosis and the development of co-morbidities which carries significant long-term complications. The relationship between longterm corticosteroid use and ethnicity in the development of co-morbidities in patients with sarcoidosis is poorly understood. Medical and surgical specialties that manage most cases involving testicular masses may not be aware of the differentials such as sarcoid; clinicians may therefore be exposed to a degree of cognitive bias in these cases. We propose this as an example to improve framing of similar cases for clinicians in the future. From a patient's perspective, similar cases require careful discussion to explore potential management options and their outcomes as the impact maybe life changing. Case report -Introduction: Sarcoidosis is a systemic granulomatous disease without a known aetiology. Patients can be asymptomatic and do not require treatment. However, for the severe cases of sarcoidosis, anti-tumour necrosis factor-a (TNF-a) agents have been used in addition to corticosteroids and disease modifying anti-rheumatic drugs (DMARDs). Paradoxically, anti-TNF-a treatment has also been shown to induce sarcoidosis in patients with autoimmune diseases, though what is known about the pathogenesis of this phenomenon is limited. We present a case of renal sarcoidosis occurring following Certolizumab Pegol (CZP) treatment in apatient with psoriatic arthritis. Case report -Case description: A 55-year-old Caucasian man presented to the emergency department in Jan 2020 with a seizure and was found to have astage 3acute kidney injury. He was diagnosed with psoriatic arthritis (PsA) at age 47 and plaque psoriasis at 20. He has no other past medical history. For PsA, he was initially treated with Methotrexate, but this was stopped due to nausea. After failing on sulfasalazine, he was started on Humira (Adalimumab) and low dose Methotrexate, 10mg weekly. Due to lack of efficacy, he switched to Benepali (Etanercept) monotherapy. One year later, he was switched to Cimzia (Certolizumab Pegol) due to worsening disease activity. He was on the treatment for 7 months before presenting with seizures and renal failure. His seizure was caused by uraemia and hypertension secondary to renal failure. He has severe renal dysfunction (eGFR of 8ml/min/1.73m2), but low-level proteinuria (uPCR of 47mg/mmol). A renal biopsy was performed which showed features of non-necrotising interstitial nephritis, with well-formed granulomas & multiple giant cells, consistent with renal sarcoidosis.Infectionswere excludedincludingTB. He was started onhighdoseprednisolone 80mg daily,amodest improvement in creatinine was observed from 636mmol/L (eGFR 8ml/min/ 1.73m 2 ) on admission to 526mmol/L (eGFR 10ml/min/1.73m 2 ) on discharge a week later. He did not require renal replacement therapy during admission. The dose of prednisolone was tapered over time, he is now on 10mg per day and his creatinine in April 2020 was 344 mmol/L, (eGFR 16 ml/min/1.73m 2 ). Currently, his psoriatic arthritis is under control, and his latest creatinine in July was 293 mmol/L (eGFR 20ml/min/1.73m 2 ), his prednisolone was reduced further to 5mg daily. In this case report, we reviewed the evidence on anti-TNF-a induced sarcoidosis and options for future biologic agent therapy if there were to be deterioration of psoriatic arthritis orflare of psoriasis. Case report -Discussion: Certolizumab-induced sarcoidosis is still a rare, but emerging phenomenon, with an unclear pathogenesis. Of the 87 published case reports of anti-TNF-a agent-induced sarcoidosis, 85 were in patients receiving Etanercept, Adalimumab, and infliximab. In terms of Certolizumab-induced sarcoidosis, a PubMed search using the terms "sarcoidosis, and Certolizumab", found only two previously reported cases. In the first case, a 45-year-old Caucasian woman with HLA-B27-positive non-radiographic axial spondyloarthritis developed severe renal insufficiency and mediastinal lymphadenopathy following 6 months of Certolizumab therapy. Renal biopsy showed granulomatous interstitial nephritis consistent with renal sarcoidosis, and bronchial biopsies showed non-caseating granulomas. The patient was treated with prednisolone 60mg daily, which was weaned over 6 months along with the initiation of Methotrexate and Secukinumab. This combination led to a minor improvement in her axial symptoms and stabilisation of her renal disease. In the second case, a 69-year-old woman with rheumatoid arthritis developed fatigue, appetite loss and low-grade fever after 6 years of Certolizumab Pegol therapy. She was found to have granulomatous uveitis, bilateral hilar and mediastinal lymphadenopathy, a subcutaneous nodule on her right knee, and micronodules in the upper lobes of both lungs. A video-assisted thoracoscopic biopsy showed noncaseous epithelioid cell granulomas consistent with sarcoidosis. Furthermore, a biopsy of the nodule on her knee showed noncaseous epithelioid cell granulomas. She received 20mg of prednisolone daily to advantageous effect, which was then tapered to 10mg daily without recurrence of sarcoidosis. She was then started on abatacept treatment while further tapering her prednisolone. Case report -Key learning points: In these two cases plus this current case, discontinuation of anti-TNF-a agents with systemic corticosteroid treatment resulted in the regression of sarcoidosis. One proposed mechanism of Certolizumab-induced sarcoidosis involves neutralising antibodies, though data on the impact and frequency of anti-drug antibodies in Certolizumab therapy is still unclear. Even the frequency of anti-drug antibodies in Certolizumab therapy is still unclear, with reported percentages ranging from 3.3% to 25.3%. Antidrug antibodies with Adalimumab is thought to be more common with reported frequency as high as 38.0%, with 21 case reports published about Adalimumab-induced sarcoidosis. There are also case reports on Secukinumab (anti-IL17) associated with onset of sarcoidosis, this is one of the treatment options for psoriatic arthritis and psoriasis as per NICE guidance (TA445). Tofacitinib has been approved by NICE recently (TA543) for PsA, so far, there are no case reports associated with the onset of sarcoidosis, rather, it has been used to treat sarcoidosis successfully. Therefore, Tofacitinib seems to be a potential treatment option for this patient.

Tanya Chopra and Gordon MacDonald
Royal Berkshire Hospital, Reading, United Kingdom Case report -Introduction: Sarcoidosis often classically presents as Lofgren's syndrome in up to 30% of cases, a triad of erythema nodosum, bilateral hilar lymphadenopathy and polyarthritis. However, the lack of identificationandawarenessofextrapulmonarymanifestationsofsarcoidosis can often lead to delayed diagnosis and treatment. In sarcoidosis, hypercalcaemia is a feature in only 10-20% of all cases. However, the manifestation of hypercalcaemia may be the first presentation of sarcoidosis in patients who do not show the classical features of acute sarcoidosis. Case report -Case description: A 38-year-old man presented with a 5month history of profound fatigue, poor concentration, and non-specific joint pains. He reportedearlierswelling of his ankles and feet. He had lost 1 stone in weight over the last month. There was no history of fever or night sweats. He smoked 10 cigarettes per daybut was otherwise fit and well. On examination urine dipstick testing was negative. There was no evidence of lymphadenopathy. Cardio-respiratory and abdominal examinations were unremarkable. Examination of his skin and joints was also unremarkable. There was mild non-tenderankle oedema. His first blood tests showed a raised adjusted calcium of 3.25 and a raised white cell count of 11.8, with an eosinophilia of 0.75. Other preliminary blood results were unremarkable (normal Hb, UþEs, LFTs, CRP, ESR, RF, anti-CCP,ANA and TFTS). His chest X-ray was reported as clear. His PTH was appropriately suppressed and vitamin D level was adequate with normal urinary calcium and normal serum protein electrophoresis. Serum ACE level was raised at 114 (normal 8-52). PTH related peptide test was not available. A CT chest abdomen and pelvis scan carried out to rule out malignancy was normal with no notable lymphadenopathy. A subsequent PET CT scan was normal. Acutely, his hypercalcaemia was treated with IV fluids and IV pamidronate. Although his calcium rapidly normalised, he reported feeling only 10% better. He complained of ongoing ankle pain. An MRI scan of both ankles with contrast showed mild synovitis of ankle, subtalar and talonavicular joints. There was also evidence of tenosynovitis. 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.