P20 Treatment resistant psoriatic arthritis: a case report

Abstract Introduction/Background Although the era of targeted drugs has transformed the treatment of psoriatic arthritis (PsA), treatment resistant PsA still occurs. We present a rare case of a patient (renamed Ms Smith) with severe treatment resistant PsA. Ms Smith, a previously healthy 25-year-old, was diagnosed with arthritis in July 2018. She presented at that time with severe monoarthritis of right ankle starting in September 2017. It was initially thought to be possible sarcoma, but biopsy confirmed inflammation. She had no psoriasis and was HLA-B27 positive. She was diagnosed seronegative peripheral spondyloarthritis (psoriatic type). Description/Method She was treated with sulfasalazine and methotrexate in September 2018 but had side effects and no response. Her arthritis spread to multiple joints (tender joint count (TJC) 8, swollen joint count (SJC) 5, patient/physician global 4) and treatment was escalated to adalimumab biosimilar, but with minimal improvement (6 TJC, 5 SJC, patient/physican global 4). Despite additional prednisolone and subcutaneous methotrexate, she did not make a significant response. Given her poor response, she was switched to secukinumab in March 2019 along with short course prednisolone. At 12 weeks she had partial response from physician assessment, but she did not feel much better. To maximise response, she was also given leflunomide but experienced side effects and no benefit. She also developed bloody diarrhoea, raising concern about inflammatory bowel disease (a recognised complication of IL-17), but investigations were negative. Given the side-effects and non-response, secukinumab and leflunomide were stopped after 6 months. In January 2020, she presented with TJC 24, SJC 6 and patient/physician global of 5. She was switched to tofacitinib and restarted on leflunomide with subcutaneous methotrexate. Again, she stopped leflunomide but continued tofacitinib plus methotrexate until August 2020. At that time, she had presented with left hip pain; MRI confirmed sacroiliitis and left hip synovitis. She also had multiple swollen joints. Given worsening disease and spinal involvement, she was switched to etanercept as fourth biologic but did not respond to this either. Discussion/Results She saw a second rheumatologist who agreed with diagnosis/treatments. Bloods tests, illustrated in Table 1, showed increase in her CRP. X-rays reviewed by radiology specialist interestingly showed significant erosive disease as well as unexpectedly some subluxation that appeared more like RA than PsA. Following an IFR, she was started on tocilizumab (subcutaneously initially and then one intravenously) but developed a non-allergic reaction to it (so only given half the infusion) and unusually her CRP increased to 325.P20 Table 1: Blood test results Blood tests Results C-reactive protein 127 (previously consistently around 80-90) Rheumatoid factor Negative Anti-cyclic citrullinated peptides (anti-CCP) Negative Anti-nuclear antibodies Negative Proteinase 3 (PR3) Normal (2.5) Myeloperoxidase (MPO) Borderline positive (4.3) IgG4 Very raised (no antibodies identified) Triglycerides Normal Ferritin 300 A PET-CT scan showed FDG avid nodes in the axillae, abdominal retroperitoneum, pelvis, and inguinal regions. A lymph node biopsy found IgG4 cells and reactive changes to a tattoo. Discussion in regional IgG4 meeting felt IgG4 disease was unlikely. Echocardiogram and blood cultures were negative. She was recently started on rituximab, alongside methotrexate. If no response to this - what next? Cyclophosphamide? She has recently been diagnosed with Human Papillomavirus and had Cervical Intraepithelial Neoplasia 1 on colposcopy. Key learning points/Conclusion Ms Smith has one of the most resistant forms of arthritis that did not respond to any treatment to date.

of undifferentiated connective tissues disease (uCTD), treated with methotrexate and ixekizumab. She developed systemic symptoms of fever, photosensitive rash, recurrent renal impairment, and was found to have pancytopenia with rapidly rising ferritin. During the course of her disease, her dsDNA antibodies became positive by Crithidia. Bone marrow biopsy showed prominent haemophagocytosis. Coupled with raised soluble CD25 receptor and triglycerides levels, this established the diagnosis of macrophage activation syndrome secondary to either uCTD progression or ixekizumab. Description/Method: A 43-year-old female nurse with PsA and uCTD (strongly positive ANA, anti-Ro and Anti-La), but no clinical features of CTD, has been treated with methotrexate with good response since 2011. In 2019 she was started on ustekinumab for psoriasis with excellent response. In April 2020 her biologic therapy was changed to ixekizumab due to secondary failure. In July 2020 she presented with a thigh abscess, upper airway swelling and acute kidney injury. Investigations demonstrated leucopenia, CRP 18mmol/l, and ferritin 764mmol/l. She was treated with oral prednisolone, antibiotics, fluids and underwent incision and drainage of thigh abscess. Repeat tests showed lymphopenia, ESR of 98mm/hr and polyclonal gammaglobulinaemia. MRI thigh ruled out osteomyelitis. In August 2020 she was readmitted with high fever, florid photosensitive rash and productive cough. Thorough infection screen was negative. Antibiotics were not effective. dsDNA antibodies were now positive by Crithidia. Differential was either natural progression of CTD or secondary to ixekizumab. A bone marrow biopsy showed no evidence of malignancy. Symptoms settled with high dose oral steroids. She was readmitted two weeks later with recurrence of symptoms, renal impairment, pancytopenia, ferritin >8000mmol/l, raised lactate dehydrogenase and triglycerides. A CT chest, abdomen and pelvis was largely unremarkable. Repeat bone marrow biopsy demonstrated prominent haemophagocytosis. A diagnosis of macrophage activation syndrome (MAS) secondary to CTD was made. Genetic HLH testing (perforin) was normal, soluble CD25R (sCD25R) was markedly raised. She was treated with IV methylprednisolone, followed by dexamethasone and cyclosporine. Her symptoms settled, cytopenia resolved and ferritin improved. Due to new renal impairment, cyclosporine was discontinued. Renal biopsy demonstrated immunologically mediated glomerulonephritis, likely secondary to CTD. There was mild glomerular damage. Mycophenolate mofetil was added with good response; prednisolone dose was reduced successfully. There was no recurrence of fever or other systemic symptoms, renal function remains stable. Discussion/Results: MAS is part of a diverse group of inflammatory hyperferritinaemic syndromes. It is considered a secondary form of haemophagocytic lymphohistiocytosis (HLH) developing in patients with autoimmune conditions. Typically MAS is triggered by systemic lupus erythematosus (SLE). To our knowledge, there are no case reports in the literature describing the onset of MAS on the background of PsA. The diagnosis of MAS is invariably challenging due to lack of early biomarkers and non-specific presenting features. This case illustrates a rare presentation of MAS in a patient with overlapping CTD, psoriasis, and PsA. This patient developed features of lupus as well as a change in her immune profile with positive dsDNA and renal histology in keeping with lupus. This was further complicated by the development of MAS. Renal function decline was noted prior to starting cyclosporine, and kidney biopsy was not typical for acute interstitial nephritis, making cyclosporine an unlikely culprit. Mild glomerular damage did not warrant immunosuppression beyond steroids. Fortunately, the patient responded well to IV methylprednisolone and later mycophenolate mofetil. Therefore, anakinra, cyclophosphamide and rituximab were not considered necessary. There is paucity of data on the treatment choices in MAS, with the commonly used HLH 2004 protocol (etoposide, dexamethasone and cyclosporine) showing disappointing results. With her overlapping immune conditions, the choice of immunosuppressive therapies might also be challenging in future should her symptoms of psoriasis and PsA reoccur after further steroid reduction. Key learning points/Conclusion: HLS and MAS are poorly understood conditions, thought to be caused by exaggerated inflammatory response to defective granule-mediated cytotoxicity and uncontrolled T-cell activation. This response, in turn, leads to cytokine storm, consequent tissue damage and multi-organ failure. Hystiocytosis Society has developed diagnostic criteria for HLH, which include a molecular diagnosis consistent with HLH (pathological mutations of PRF1, UNC13D, or STX11), or at least five of eight criteria: fever, splenomegaly, cytopenia, hypertriglyceridaemia/hypofibrinogenaemia, haemophagocytosis on biopsy, low/absent natural killer (NK) cell activity, hyperferritinaemia, elevated sCD25R. Our patient fulfilled six out of eight criteria, making the diagnosis certain.
It should however be noted that these criteria were developed based on paediatric population and their specificity and sensitivity is not tested in adults. Furthermore, haemophagocytosis may not be present in the initial stages of HLH, as in our case, and is not essential for diagnosis. To complicate matters further, haemophagocytosis can be found in bone marrow in other conditions, such as infections and bone marrow disorders. Extreme hyperferritinaemia is a characteristic feature of HLH, and can be found in only a handful of other conditions, which aids the diagnostic process. These include SLE, hepatocellular injury, adult onset Still's disease (AOSD), and haematological malignancies. Interestingly, the patient also meets Yamaguchi criteria for diagnosis of AOSD due to having fever, rash, abnormal liver function tests, minor lymphadenopathy, and arthralgia. This fact illustrates that clinicians should avoid using diagnostic criteria as a tick-box exercise in the search for diagnosis. By presenting this case at the Case-Based Conference we are aiming to raise awareness about MAS in the context of PsA and learn how other teams approach patients with known autoimmune conditions and fever of unknown origin. The authors received no financial support for the research, authorship, and publication of this article. Introduction/Background: Although the era of targeted drugs has transformed the treatment of psoriatic arthritis (PsA), treatment resistant PsA still occurs. We present a rare case of a patient (renamed Ms Smith) with severe treatment resistant PsA. Ms Smith, a previously healthy 25-year-old, was diagnosed with arthritis in July 2018. She presented at that time with severe monoarthritis of right ankle starting in September 2017. It was initially thought to be possible sarcoma, but biopsy confirmed inflammation. She had no psoriasis and was HLA-B27 positive. She was diagnosed seronegative peripheral spondyloarthritis (psoriatic type). Description/Method: She was treated with sulfasalazine and methotrexate in September 2018 but had side effects and no response. Her arthritis spread to multiple joints (tender joint count (TJC) 8, swollen joint count (SJC) 5, patient/physician global 4) and treatment was escalated to adalimumab biosimilar, but with minimal improvement (6 TJC, 5 SJC, patient/physican global 4). Despite additional prednisolone and subcutaneous methotrexate, she did not make a significant response. Given her poor response, she was switched to secukinumab in March 2019 along with short course prednisolone. At 12 weeks she had partial response from physician assessment, but she did not feel much better. To maximise response, she was also given leflunomide but experienced side effects and no benefit. She also developed bloody diarrhoea, raising concern about inflammatory bowel disease (a recognised complication of IL-17), but investigations were negative. Given the side-effects and non-response, secukinumab and leflunomide were stopped after 6 months. In January 2020, she presented with TJC 24, SJC 6 and patient/physician global of 5. She was switched to tofacitinib and restarted on leflunomide with subcutaneous methotrexate. Again, she stopped leflunomide but continued tofacitinib plus methotrexate until August 2020. At that time, she had presented with left hip pain; MRI confirmed sacroiliitis and left hip synovitis. She also had multiple swollen joints. Given worsening disease and spinal involvement, she was switched to etanercept as fourth biologic but did not respond to this either. Discussion/Results: She saw a second rheumatologist who agreed with diagnosis/treatments. Bloods tests, illustrated in Table 1, showed increase in her CRP. X-rays reviewed by radiology specialist interestingly showed significant erosive disease as well as unexpectedly some subluxation that appeared more like RA than PsA. Following an IFR, she was started on tocilizumab (subcutaneously initially and then one intravenously) but developed a non-allergic reaction to it (so only given half the infusion) and unusually her CRP increased to 325. A PET-CT scan showed FDG avid nodes in the axillae, abdominal retroperitoneum, pelvis, and inguinal regions. A lymph node biopsy found IgG4 cells and reactive changes to a tattoo. Discussion in regional IgG4 i32 https://academic.oup.com/rheumap POSTERS meeting felt IgG4 disease was unlikely. Echocardiogram and blood cultures were negative. She was recently started on rituximab, alongside methotrexate. If no response to this -what next? Cyclophosphamide? She has recently been diagnosed with Human Papillomavirus and had Cervical Intraepithelial Neoplasia 1 on colposcopy. Key learning points/Conclusion: Ms Smith has one of the most resistant forms of arthritis that did not respond to any treatment to date.

Abstract citation ID: rkac067.021 P21 THE FLY IN THE OINTMENT: A RARE CAUSE OF CYTOPAENIA
and Norwich University Introduction/Background: Those working in Rheumatology frequently encounter cytopaenia both as adverse effects of many conventional and biological disease modifying drugs and as manifestations of autoimmune diseases. In cases where cytopaenia progresses, other explanations should be sought. Here we present an unusual cause of cytopaenia, seen in a patient with psoriatic arthritis on immunosuppression. Description/Method: An 81-year-old woman with a diagnosis of psoriatic arthritis had been maintained on Infliximab (3mg/kg 8 weekly) and Methotrexate (7.5mg PO weekly) for 12 years. She then developed mild neutropaenia (1.52 x 109/L). Methotrexate was stopped and she continued on Infliximab monotherapy for several months, until ongoing neutropenia resulted in Infliximab being withheld. Sustained mild neutropenia and the development of thrombocytopenia (platelets 95 x 109/ L) prompted a referral to Haematology, who suspected autoimmune neutropenia and advised checking haematinics and monitoring the FBC monthly. The neutropenia improved and Infliximab was restarted. Over 6 months she developed gradually worsening and persistent pancytopenia (neutrophils 1.36 x 109/L, platelets 134 x 109/L, Hb 91 g/L). There was no history of fevers, night sweats, bone pain, headaches, recurrent infections, lumps or bumps, chest symptoms, change in bowel habit or urinary symptoms. Examination revealed no pallor, jaundice, clubbing, peripheral lymphadenopathy or sternal tenderness. The chest was clear and the abdomen soft with no organomegaly. Repeat bloods showed microcytic hypochromic anaemia (Hb 86 g/L, MCV 73 fL, MCH 24.6 pg) with target cells on blood film. Iron was low (iron 5.1 umol/L, transferrin 1.52 g/L). Serum protein electrophoresis showed paraprotein bands with abnormal serum free light chain assay possibly consistent with myeloma, lymphoma or MGUS. Haematology suspected myelodysplasia, potentially secondary to previous long term Methotrexate therapy. A bone marrow biopsy was performed; the unexpected result was Leishmaniasis. Our patient was admitted to hospital and, following microbiology review, was treated with liposomal amphotericin (IV) for Visceral Leishmaniasis as an inpatient. Her Infliximab was suspended and her joints have remained quiescent. Discussion/Results: Leishmania is an intracellular parasitic protozoan that is transmitted to humans by sandfly bites. It is endemic in Africa, America, Central Asia and the Mediterranean. It usually has an incubation period of 3-8 months. Those who are immunosuppressed, for example due to immunotherapy or HIV, are at increased risk of infection. The patient had only ever travelled to Portugal and Gibraltar. One trip to Gibraltar occurred whilst on dual immunosuppression with Infliximab and Methotrexate and prior to the development of neutropenia. She has no recollection of any insect bites.
Visceral leishmaniasis is variable in the severity of symptoms experienced ranging from asymptomatic to a febrile illness with lymphadenopathy, hepatospenomegaly, night sweats, cutaneous pigmentation, appetite loss and weight loss, which can be drastic. Our patient indeed described significant weight loss in the preceding year. This case demonstrated the laboratory abnormalities which are typical of Visceral Leishmaniasis: pancytopenia and hypergammaglobulinaemia. Treatment for visceral Leishmaniasis has classically been with pentavalent antimonials (based on the heavy metal antimony) such as Sodium stibogluconate. Their toxicity profile and growing resistance however has meant amphotericin B is often used first line. This is given intravenously, with the liposomal form preferred as it has lower toxicity. Our patient received 4 mg per kg daily on days 1-5, 10, 17, 24, 31, and 38, following the FDA-approved regimen for immunosuppressed patients. Without treatment Leishmaniasis is usually fatal, with haemmorrhage, infection, cachexia and multiorgan failure as causes of death. Key learning points/Conclusion: Whilst patients with Rheumatological conditions may have cytopaenia due to their disease or its treatment, persistent, progressive or unexplained results should be investigated further.
In patients with cytopaenia of unclear aetiology, thorough investigation with Haematology involvement is mandatory. You may find an unexpected diagnosis . . . we did! l, Belfast, United Kingdom Introduction/Background: Rheumatic diseases can manifest as a paraneoplastic phenomenon. They can be seen during the course of neoplastic disease, precede the diagnosis, appear simultaneously or occur after the diagnosis of malignancy. Overall, paraneoplastic rheumatic syndromes are rare. It is however important to be aware of this phenomenon as the signs and symptoms of the rheumatic syndrome will usually subside with treatment of the underlying malignant disease. Furthermore, reappearance of symptoms may suggest cancer relapse. Description/Method: 51 year old woman with no significant past medical history was referred by her General Practicioner with 6-week history of pain and stiffness in hands, arms and legs. There was also associated 4-week history of change in bowel habit (diarrhoea and faecal incontinence). Clinical examination revealed skin thickening proximal to elbows and knees, sclerodactyly, facial telangiectasia as well as tendon friction rubs in lower limbs. There was also a mass palpable on digital rectal examination. Investigations revealed that the patient had new iron deficiency anaemia and mildly raised carcinoembryonic antigen. Anti-RNA polymerase III antibody returned positive. CT of chest, abdomen and pelvis suggested tumour involving the anus and lower rectum with metastatic lymphadenopathy. Those findings were also confirmed on subsequent MRI pelvis and PET CT. She underwent anal biopsy, examination under anaesthesia and formation of loop colostomy. Histopathology results confirmed poorly differentiated squamous carcinoma. Patient was then reviewed by oncology and discussed at multidisciplinary meeting. She was commenced on palliative chemotherapy (paclitaxel and carboplatin). After the first session she became severely anaemic and developed acute renal failure. She passed away approximately three months after initial referral to rheumatology. Discussion/Results: This patient was diagnosed with paraneoplastic diffuse systemic sclerosis in association with ano-rectal tumour. Unfortunately at the time of diagnosis the disease was metastatic therefore the only treatment option available was palliative rather than curative. Paraneoplastic rheumatic syndromes are rare. The signs and symptoms are secondary to the presence of malignancy. They may be induced by the substances that are secreted by the tumour or the immune system's response to the malignant cells. Usually once patient recovers from the neoplastic disease the rheumatic disease signs/symptoms subside. In our patient's history there were a number of features which raised the possibility of paraneoplastic aetiology. These included: sudden onset and rapid progression of clinical symptoms, late onset of disease (after 50 years of age), family history of cancer (dad had prostate cancer), new iron deficiency anaemia as well as the presence of anti-RNA polymerase P20 Very raised (no antibodies identified) Triglycerides Normal Ferritin 300