O02 Cancer, Covid and control of RA – a toxic combination?

Abstract Case report - Introduction This case highlights the dilemma of keeping rheumatoid arthritis disease under control in active cancer cases and establishing a consistent multidisciplinary dialogue during a pandemic and staffing crises. During chemotherapy and active cancer treatment, disease-modifying therapies (conventional and biologic) are often stopped. In some cases, the potential benefits versus risks of restarting usual therapies have to be balanced against risks of suppressing disease activity with high-dose steroids. Risks of infection (common and atypical) need to be considered. Case report - Case description A is a 67-year-old female non-smoker diagnosed with seropositive rheumatoid arthritis (RF, anti –CCP positive) in 2008. Other conditions include type 2 diabetes, atrial fibrillation (on warfarin), hypothyroidism and obstructive sleep apnoea. Due to active disease, despite triple therapy (methotrexate, sulphasalazine and hydroxychloroquine), anti-TNF therapy (etanercept) commenced in 2009 with primary non-response. However, she responded well to B-cell therapy (rituximab) in conjunction with oral methotrexate (25mg weekly) receiving annual infusions from 2010 to 2016. In 2017, an elective sleeve gastrectomy procedure for high BMI was abandoned after peritoneal deposits of concern were noted. Histology and CT imaging were consistent with a primary peritoneal malignancy (Stage 3c low-grade serous adenocarcinoma). Treatment involved debulking surgery (total abdominal hysterectomy, bilateral salpinoophorectomy, omentectomy) and tamoxifen. Treatment for rheumatoid arthritis stalled during this period but as frequent steroids were required for active joint inflammation, in agreement with the oncologists, she had a rituximab cycle in 2018. Unfortunately, in 2019 she had signs of cancer progression (elevated tumour markers, CT imaging) and has subsequently started carboplatin chemotherapy. She has been unable to continue methotrexate or rituximab pending completion of the chemotherapy cycles (ongoing). However, her arthritis is now uncontrolled without increased steroids. Due to recurrent flares, her maintenance dose has been increased from 5mg to 7.5—10mg prednisolone daily until we can establish if it is safe and appropriate to recommence her usual arthritis regime. Even without disease-modifying therapy like methotrexate and rituximab, risk of infection (including atypical ones) is still significant with the combination of chemotherapy and steroids. Risk of progressive joint damage and adverse quality of life with active arthritis also needs to be considered. Staffing crises, exacerbated by COVID pandemic issues, have added to complexity of decision making and coordination of regular multidisciplinary discussions regarding treatment. Case report - Discussion Cancer is a known association in rheumatoid arthritis patients with a twofold higher risk of lymphoma compared to the general population. Whether condition or treatment affects risk remains unclear as immune dysregulation is relevant in both autoimmunity and cancer. Paraneoplastic, recent onset arthritis, chemotherapy- or immunotherapy-induced arthralgia/arthritis are also well documented. This case had a seropositive rheumatoid arthritis phenotype quite a few years prior to cancer diagnosis. Primary peritoneal cancer is uncommon, often presenting as in this case as an incidental finding. It is usually treated like ovarian cancer Whilst methotrexate has been implicated in lung cancer, melanoma and non-Hodgkin lymphoma, overall safety data suggest any risk is quite low (e.g., EBV-associated lymphoproliferative disorders usually resolve with drug discontinuation). It is also a known chemotherapeutic agent. Anti-TNF treatment algorithms generally exclude patients with recent cancer. Rituximab, originally developed as a cancer drug, is not thought to affect risk of cancer development or progression. Treatment with disease-modifying therapy (conventional and biologics) is often withheld in patients with active malignancy undergoing chemotherapy due to a theoretical risk of potentiated immunosuppression and toxicity, particularly cytopaenias. However, maintaining arthritis control with glucocorticoids also has short- and long-term risks. Combining chemotherapy agents like carboplatin with methotrexate has been used for urothelial carcinoma and can be well tolerated with close monitoring of haematological parameters. Thus, it could be argued this patient is at risk of infections whichever treatment approach is taken and regaining control of arthritis with recommencement of methotrexate and rituximab is much better for her quality of life. Regular multidisciplinary discussions are important to outline risks versus benefits of combined treatment. This may be difficult in practice during staffing crises. Covid risk in patients receiving rituximab and/or chemotherapy, timing and response to COVID vaccination are also important considerations. Case report - Key learning points Primary peritoneal cancer is uncommon and can present as an incidental finding Whilst treatment for progressive cancer is important, withholding rheumatoid arthritis treatment can have a significant adverse impact on quality of life Morbidity and mortality risks of stopping treatment versus combined treatment (cancer therapy and disease-modifying therapy) ideally needs to be fully discussed and agreed with the patient and all care providers – lack of “named” providers, restructuring, redeployment, multi-specialty care and a global pandemic can make coordination of this difficult


apy.
Case report -Case description: A 53-year-old woman with a 15-year history of rheumatoid factor positive, erosive inflammatory arthritis and autoimmune hepatitis, on long term azathioprine and low dose prednisolone, presented with increasing arthralgia, intermittent skin rashes "like spots" and recurrent "throat infections". She had active inflammatory arthritis, CRP of 63 and DAS28 score of 5.58. A decision was made to escalate to biologic therapy. A chest radiograph demonstrated left lower zone opacity and subsequent CT TAP reported saddle PE, multiple bilateral lung nodules with cavitation, liver and renal lesions with extensive pericolic inflammation. She was commenced on anticoagulation and, whilst awaiting further tests, developed a fever with raised acute phase reactants. Listeria monocytogenes was ultimately isolated from blood cultures. Two weeks later, despite commencing appropriate intravenous antibiotics, she experienced a partial seizure. An MRI of her brain revealed a rim-enhancing lesion in the right parietal lobe with extensive oedema and mass effect. There was also persistence of the multi-organ abnormalities on cross sectional imaging including PET CT. Extensive additional immunologic and microbiological testing revealed an atypical ANCA positivity (MPO and PR3 negative) with a low titre rheumatoid factor (16), negative anti CCP, positive ANA but negative ENA and dsDNA with normal complements. Her EBV IgG was positive, IgM negative but she had an EBV viral load of 714 copies/mL. Numerous attempts were made to obtain definitive histology: an initial CT-guided lung biopsy reported non-diagnostic necrotic tissue; a subsequent VATS-guided biopsy of a lung lesion revealed histology suggestive of a rheumatoid nodule. A brain biopsy was deemed too high risk. A liver biopsy ultimately demonstrated features on a spectrum between polymorphic post-transplant lymphoproliferative disorder (P-PTLD) and a monomorphic B-cell PTLD resembling EBVþ diffuse large B-cell lymphoma. She was commenced on high dose methotrexate and R-CHOP chemotherapy as per haematology/oncology MDT. Case report -Discussion: This case posed a number of clinical conundrums. Firstly, a wide differential diagnosis including infection (Listeria cerebritis), extra-articular manifestations of her rheumatoid arthritis (RA), including rheumatoid vasculitis, metastatic malignancy or a lymphoproliferative disorder. It was therefore crucial to continually review and reconsider the diagnosis in light of new information. The second issue is consideration of opportunistic infection in a patient on long-term immunosuppression. We rarely encounter listeriosis and are consequently unfamiliar with the way the disease manifests itself in the context of immunosuppressed patients. This case posed a question of how we can monitor for over-immune suppression; whether leukocyte count is a reliable measure of the patient's immune system or whether the frequency of infection is more a sensitive marker. Thirdly, the role of EBV monitoring in this case is also interesting. We do not routinely measure EBV titres at time of initiation of DMARD therapy and we do not measure viral load. However, EBV DNA measurement withdraw immunosuppressive therapy or treat RA more aggressively. Kaiser et al.'s systematic review of lymphoma incidence in RA patients demonstrated 20 out of 26 studies reporting an increased incidence of lymphoma in RA and eight studies reporting a positive correlation between DMARD use and increased incidence of lymphoma. Furthermore, these studies, although underpowered, suggest that azathioprine and TNF inhibitors were more likely to be associated with lymphomas. Only 3 studies investigated the role of EBV, which was inconclusive. Similarly, there is a paucity of literature on the role of EBV and lymphoproliferative disorders in rheumatology patients on long-term immunomodulatory therapy and further research is needed so that we can mitigate this risk for our patients. In summary, PTLD is a rare, sometimes rapidly progressive and fatal, complication of RA in patients on long-term immunomodulatory therapy. Consequently, it is important to be alert to, and consider, this as a differential diagnosis and obtain appropriate tissue samples for histological confirmation. Furthermore, this case also highlights the real risk of opportunistic infection amongst our patient population in addition to the need to carefully monitor this so called 'stable' cohort of patients to ensure early detection of potential complications of both long-term autoimmune disease and immunomodulatory therapy with de-escalation of the latter where appropriate.

Sharmin Nizam Mid Yorkshire NHS Trust, Wakefield, United Kingdom
Case report -Introduction: This case highlights the dilemma of keeping rheumatoid arthritis disease under control in active cancer cases and establishing a consistent multidisciplinary dialogue during a pandemic and staffing crises. During chemotherapy and active cancer treatment, disease-modifying therapies (conventional and biologic) are often stopped. In some cases, the potential benefits versus risks of restarting usual therapies have to be balanced against risks of suppressing disease activity with highdose steroids. Risks of infection (common and atypical) need to be considered. Case report -Case description: A is a 67-year-old female nonsmoker diagnosed with seropositive rheumatoid arthritis (RF, anti -CCP positive) in 2008. Other conditions include type 2 diabetes, atrial fibrillation (on warfarin), hypothyroidism and obstructive sleep apnoea. Due to active disease, despite triple therapy (methotrexate, sulphasalazine and hydroxychloroquine), anti-TNF therapy (etanercept) commenced in 2009 with primary non-response. However, she responded well to B-cell therapy (rituximab) in conjunction with oral methotrexate (25mg weekly) receiving annual infusions from 2010 to 2016. In 2017, an elective sleeve gastrectomy procedure for high BMI was abandoned after peritoneal deposits of concern were noted. Histology and CT imaging were consistent with a primary peritoneal malignancy (Stage 3c low-grade serous adenocarcinoma). Treatment involved debulking surgery (total abdominal hysterectomy, bilateral salpinoophorectomy, omentectomy) and tamoxifen. Treatment for rheumatoid arthritis stalled during this period but as frequent steroids were required for active joint inflammation, in agreement with the oncologists, she had a rituximab cycle in 2018. Unfortunately, in 2019 she had signs of cancer progression (elevated tumour markers, CT imaging) and has subsequently started carboplatin chemotherapy. She has been unable to continue methotrexate or rituximab pending completion of the chemotherapy cycles (ongoing). However, her arthritis is now uncontrolled without increased steroids. Due to recurrent flares, her maintenance dose has been increased from 5mg to 7.5-10mg prednisolone daily until we can establish if it is safe and appropriate to recommence her usual arthritis regime. Even without disease-modifying therapy like methotrexate and rituximab, risk of infection (including atypical ones) is still significant with the combination of chemotherapy and steroids. Risk of progressive joint damage and adverse quality of life with active arthritis also needs to be considered. Staffing crises, exacerbated by COVID pandemic issues, have added to complexity of decision making and coordination of regular multidisciplinary discussions regarding treatment. Case report -Discussion: Cancer is a known association in rheumatoid arthritis patients with a twofold higher risk of lymphoma compared to the general population. Whether condition or treatment affects risk remains unclear as immune dysregulation is relevant in both autoimmunity and cancer. Paraneoplastic, recent onset arthritis, chemotherapy-or immunotherapy-induced arthralgia/arthritis are also well documented. This case had a seropositive rheumatoid arthritis phenotype quite a few years prior to cancer diagnosis. Primary peritoneal cancer is uncommon, often presenting as in this case as an incidental finding. It is usually treated like ovarian cancer Whilst methotrexate has been implicated in lung cancer, melanoma and non-Hodgkin lymphoma, overall safety data suggest any risk is quite low (e.g., EBV-associated lymphoproliferative disorders usually resolve with drug discontinuation). It is also a known chemotherapeutic agent. Anti-TNF treatment algorithms generally exclude patients with recent cancer. Rituximab, originally developed as a cancer drug, is not thought to affect risk of cancer development or progression. Treatment with disease-modifying therapy (conventional and biologics) is often withheld in patients with active malignancy undergoing chemotherapy due to a theoretical risk of potentiated immunosuppression and toxicity, particularly cytopaenias. However, maintaining arthritis control with glucocorticoids also has short-and long-term risks. Combining chemotherapy agents like carboplatin with methotrexate has been used for urothelial carcinoma and can be well tolerated with close monitoring of haematological parameters. Thus, it could be argued this patient is at risk of infections whichever treatment approach is taken and regaining control of arthritis with recommencement of methotrexate and rituximab is much better for her quality of life. Regular multidisciplinary discussions are important to outline risks versus benefits of combined treatment. This may be difficult in practice during staffing crises. Covid risk in patients receiving rituximab and/or chemotherapy, timing and response to COVID vaccination are also important considerations. Case report -Key learning points: . Primary peritoneal cancer is uncommon and can present as an incidental finding . Whilst treatment for progressive cancer is important, withholding rheumatoid arthritis treatment can have a significant adverse impact on quality of life . Morbidity and mortality risks of stopping treatment versus combined treatment (cancer therapy and disease-modifying therapy) ideally needs to be fully discussed and agreed with the patient and all care providers -lack of "named" providers, restructuring, redeployment, multi-specialty care and a global pandemic can make coordination of this difficult

Amelia Holloway and Catherine Mathews Queen Elizabeth Hospital, London, United Kingdom
Case report -Introduction: Golimumab is an anti-TNF alpha drug used in the treatment of inflammatory arthritis including spondyloarthritis (SpA). The introduction of this drug class has revolutionised the treatment of SpA over the last 20 years with significantly improved patient outcomes. Despite their treatment benefits multiple adverse effects of TNF-alpha inhibition have been reported through clinical trials including a possible increased risk of malignancy. We describe a case of a patient with known ankylosing spondylitis (AS) on golimumab who was diagnosed with low-grade prostate carcinoma and discuss the factors taken into consideration in guiding our decision-making process regarding ongoing treatment.
Case report -Case description: A 57-year-old gentleman with known AS presented to the rheumatology clinic for routine review. His AS was well controlled, and he had been taking golimumab for the past 3 years. Upon review he was in clinical remission with a CRP <1 and ESR 5.
Prior to the initiation of anti-TNF therapy his disease had been poorly controlled. However, following commencement his symptoms had significantly improved and he was able to work as a professional sports coach whilst bringing up a young family. On review he had recently been diagnosed with low-risk cancer of the prostate by his urologist. A prostate biopsy found Gleason 3 þ 3 adenocarcinoma involving 2 out of 22 cores on each side, with a prostate specific antigen (PSA) of 3.95ng/ml. An MRI had shown chronic prostatitis. He was in the lowest risk category of grade group 1 prostate cancer and no treatment for his prostate cancer was indicated. The plan from his urology team was active surveillance with PSA monitoring. Whilst being investigated for possible malignancy his golimumab had been held for six months and during this period he had a significant flare in symptoms. He experienced severe back pain that forced him to stop working. Following his prostate cancer diagnosis, golimumab was restarted by his urologist with a subsequent improvement in his AS symptoms.
To guide ongoing treatment his case was reviewed in the local biologics multi-disciplinary team meeting, alongside close communication with his urologist. The patient was informed of the risks of continuing golimumab in relation to his malignancy. Despite this he was reluctant to stop anti-TNF therapy or switch to another treatment, citing concerns about the impact it might have on his symptoms and ability to work. Case report -Discussion : This case highlights the complexities involved in the management of a patient on anti-TNF therapy, who receives a diagnosis of malignancy, particularly when the diagnosis is classed as low risk. Traditionally anti-TNF therapy was contraindicated for patients with a history of a solid organ tumour within the previous five years. The British Society of Rheumatology (BSR) guidelines recommends that patients should be advised that there is no conclusive evidence for an increased risk of solid organ tumours but that on-going vigilance is required. A holistic patient-centred approach needs to be taken in these contexts, and consideration of cases on an individual basis is needed.
Inter-disciplinary and multi-speciality team input, with the effective use of a biologics MDT, is crucial. The patient was understandably reluctant to stop his treatment due to the significant impact this may have on his quality of life. On liaison with his urologist his prostate cancer was in the lowest risk category with 99% 5-year survival rates with low risk of disease progression or spread. Evidence in this field to date has been conflicting and studies have predominantly focused on the safety of anti-TNFs in rheumatoid arthritis patients. Recent large national registry data has been reassuring. Few studies have looked at the AS and psoriatic arthritis anti-TNF treated population; however, a meta-analysis of RCTs found no evidence of increased incidence of malignancy. Taking into account his low-risk cancer, the patient's wishes and clinical evidence in this field we have made to decision to continue anti-TNF treatment for now but with ongoing surveillance for any tumour progression. The patient will undergo urology follow up alongside regular PSA monitoring, and there will be a low threshold to stop or switch treatment in the future Case report -Key learning points: 1. Treatment with anti-TNF therapy in patients with concomitant inflammatory arthritis and malignancy pose a specific challenge that require close co-ordination of care between rheumatologists,