New Treatment Options for Pituitary Granulomatosis With Polyangiitis

Background: Granulomatosis with polyangiitis (GPA) rarely involves the pituitary gland and has been reported in 1% of all cases of GPA. Most frequently, it presents with pituitary mass effect and diabetes insipidus (DI). To date, there are no treatment guidelines for this rare condition. Case Presentation: Case 1: A 55 year old female with a history of ANCA-positive pulmonary GPA, previously treated with glucocorticoids and immunosuppressants, presented two years later with cranial DI and bitemporal hemianopia. MRI showed a large sellar mass with suprasellar extension. High dose glucocorticoids resulted in good clinical and radiological response. Further treatment consisted in a combination of Cyclophosphamide and Rituximab (RTX). Further doses of RTX are planned aiming for a period of B-cell depletion. Case 2: A 38 year old female, presented with polyuria, recurrent nosebleeds, headaches and a left visual field defect. Pituitary profile revealed ACTH deficiency and MRI showed a heterogenous cystic lesion with peripheral enhancement and stalk thickening. Steroid replacement led to immediate improvement in her symptoms. Cranial DI was confirmed and raised Proteinase 3 (PR3) antibody suggested GPA. A combination of prednisolone and Methotrexate led to significant improvement of MRI appearances and declining PR3 antibody levels. For remission maintenance, two cycles of RTX were given with further radiological and biochemical improvement, and, following dynamic assessment of her HPA axis, she could be fully weaned off steroids. Case 3 is a 47 year old female with a history of childhood asthma. She was found to have cavitating lung lesions. ANCA positivity confirmed GPA and she was commenced on high-dose steroids. During follow-up, she developed headache, polyuria and polydipsia. MRI pituitary showed a suprasellar lesion and pituitary biopsy revealed inflammatory hypophysitis. Cranial DI was confirmed by water deprivation testing. Previous allergic reactions to both RTX and Ofatumumab precluded anti-CD40 monoclonal antibodies and she was commenced on Azathioprine. A further recurrence of pituitary GPA necessitated escalation of the steroid dose and switch of azathioprine to mycophenolate mofetil. She remains in remission and her steroids reduced to a maintenance dose. Conclusion: GPA pituitary has been observed to occur at variable time after diagnosis often in the absence of any other systemic features. A combination of glucocorticoids and RTX has been approved for severe relapsing pulmonary GPA, however, limited data is available for pituitary GPA. In this case series, the response to high dose steroids and RTX for remission maintenance has been encouraging. Experience with ‘conventional’ immunosuppresants remains limited and therapeutic responses remain variable. Further clinical studies are required to establish effective treatment for pituitary GPA.

MO271PROGNOSIS OF NON-PR3 ANCA-ASSOCIATED VASCULITIDES WITH RENAL INVOLVEMENT

Background and Aims Immunosuppressive treatments have improved the prognosis of anti-neutrophil cytoplasm antibody (ANCA)-associated vasculitides (AAV), transforming these formerly fatal diseases into chronic conditions, with periods of remission and relapse. Relapse prevention is based on remission-maintenance immunosuppressive treatment with a usual duration of 18 to 24 months. Recent studies demonstrated that a prolonged - 48 to 54 months - maintenance treatment reduced the risk of relapse and could reduce end-stage renal disease (Karras A 2017, Charles P 2020). However, prolonged maintenance treatment may not be necessary for all patients. On the one hand, MPO-ANCA (vs PR3-ANCA) and decreased estimated glomerular filtration rate (eGFR) have been associated with a low risk of relapse (Walsh 2012). On the other hand, treatment of AAV is not devoid of risk. Flossman et al showed that mortality after the first year of treatment was mainly related to cardiovascular, infectious and neoplastic complications (Flossman 2011). Thus, it has been well demonstrated that patients with renal AAV without PR3 ANCA have the lowest risk of relapse and the highest mortality rate (Mahr A 2013). This study aimed to determine: first, the risk of late relapse in AAV patients with renal involvement and without PR3-ANCA after end of remission-maintenance treatment, and second, risk factors for relapse in this population. Method Patients with renal involvement without PR3-ANCA recruited to prospective, randomized trials of the European Vasculitis Study group (EUVAS): CYCAZAREM, CYCLOPS, MEPEX, IMPROVE and the French Vasculitis Study Group (FVSG): WEGENT were included in the analysis if their disease was in remission at the end of relapse-prevention therapy. This consisted in azathioprine, methotrexate or mycophenolate mofetil and was stopped after 18-24 months (around 24-27 months after diagnosis). Cumulative incidence of relapse was estimated using the Kalbfleich and Prentice method, considering death as a competing event. Risk factors for relapse were assessed using the Fine and Gray competing risk regression model. Results 108 patients were included, 64 of whom (59.3%) were male, 79 were MPO-ANCA positive (73.1%) and 29 ANCA negative (26.9%). Average age at diagnosis was 59.6 +/- 12.4 years. Relapse rate was 25.5% 60 months after cessation of maintenance treatment (figure 1) of which 46.2% were renal relapses (figure 2). Lower GFR at diagnosis was correlated with a lower risk of relapse. For every 15-point decrease in GFR at diagnosis, the risk of relapse decreased by a factor of 0.72 (HR 95% CI: 0.59 to 0.88). Figure 3 represents the cumulative incidence of relapse by eGFR level. Relapse risk did not appear to be impacted by the presence at diagnosis of systemic/constitutional (HR: 0.70; CI 95%: 0.30-1.65; p: 0.47), lung (HR: 0.87; CI 95%: 0.40-1.86; p: 0.71), skin involvement (HR: 0.84; CI 95%: 0.29-2.39; p: 0.74), ear, nose and throat (HR: 1.53; CI 95%: 0.74-3.27; p: 0.28) or eye disease (HR: 1.58; CI 95%: 0.62-4.10; p: 0.34). Presence of MPO-ANCA at diagnosis did not influence relapse-risk. Conclusion Even in this population of renal AAV without PR3-ANCA, there remains a risk of late relapse, after the end of a two-year conventional maintenance regimen. Using additional criteria (such as eGFR at diagnosis < or > 45 ml/min/1.73m2) could help select a group of patients who are at lower risk of relapse. Factors that potentially increase (ENT or eye disease) risk of relapse need to be explored further. If these data are confirmed, sub-groups could be identified who could receive only a short maintenance treatment, or perhaps none. These findings also need to be to be analysed following rituximab maintenance.

EULAR guidelines on ANCA-associated vasculitis in the real life

Anti-neutrophil cytoplasmic antibodies-associated vasculitides (AAVs) are a heterogenous group of inflammatory diseases which primarily involve small vessels and include granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA) and eosinophilic granulomatosis with polyangiitis (EGPA). They present heterogeneous clinical manifestations, while their diagnosis and management still remain a challenge for clinicians. Nowadays, the treatment is based on two different regimens: the remission-induction treatment and the remission-maintenance treatment. The therapeutic armamentarium has grown over the years, with the aim to lessen adverse effects, improve quality of life of patients and maintain the disease under control. Biological treatments are the future: they act on different pathogenic pathways and may offer in the future a personalized management approach tailored to actual clinical manifestations. The latest guidelines were published in 2015 by the European League Against Rheumatism (EULAR) and still represent the vade mecum for the management of AAVs. In this review, we will focus on the principal strategies to treat AAVs. We discuss the remission-induction therapy and the remission- maintenance therapy; we have also distinguished the management of GPA and MPA from that of EGPA, because of their different clinical pictures.

Clinical outcomes of patients with giant cell arteritis treated with tocilizumab in real-world clinical practice: decreased incidence of new visual manifestations

Background Placebo-controlled clinical trials have demonstrated the efficacy of tocilizumab (TCZ) for remission maintenance and glucocorticoid sparing in patients with giant cell arteritis (GCA). However, limited data exist on the effectiveness and safety of TCZ for GCA in real-world clinical practice. Methods This was a retrospective, single-center analysis of patients with GCA treated with intravenous or subcutaneous TCZ (2010–2018). Outcomes evaluated before and after TCZ initiation included occurrence of flare, time to flare, annualized flare rate, flare characteristics (i.e., polymyalgia rheumatica [PMR] symptoms, cranial manifestations), prednisone use, and safety. Flare was defined as the recurrence of unequivocal GCA manifestations requiring treatment intensification. Subgroup analyses of patients with PMR or visual manifestations at GCA diagnosis were performed. Results Sixty patients with GCA were included. The median (IQR) disease duration before and after the start of TCZ was 0.6 (0.2–1.6) and 0.5 (0.3–1.4) years, respectively. At least 1 flare was observed in 43 patients (71.7%) before and in 18 (30.0%) after TCZ initiation. Median (IQR) time to flare was 0.5 (0.3–0.7) years before TCZ treatment and 2.1 (0.6–2.6) years after TCZ initiation (HR 0.22; 95% CI 0.10–0.50; p = 0.0003). The annualized flare rate significantly decreased following TCZ use (before TCZ 1.4 [95% CI 1.0–2.1]; after TCZ 0.6 [95% CI 0.3–1.0] events/year; p < 0.001). Similar improvements were observed in patients with visual manifestations or PMR symptoms at GCA diagnosis. TCZ reduced the incidence of new visual manifestations, and no flares associated with permanent vision loss occurred while patients were receiving TCZ. Mean (SD) prednisone dose at TCZ onset and at the end of follow-up was 30 (18.3) and 5 (6.9) mg/day, respectively (p < 0.0001). After TCZ initiation, 46.6% of patients successfully discontinued prednisone. The incidence of adverse events, primarily attributed to glucocorticoids, was similar before and after TCZ initiation. Conclusions In this real-world setting, TCZ improved GCA clinical outcomes significantly and demonstrated effectiveness in the subgroups of patients with PMR symptoms and GCA-related visual manifestations at GCA diagnosis. No new cases of blindness occurred after TCZ initiation. Adverse events, many attributable to glucocorticoids, were comparable before and after TCZ treatment.

On Frankincense (Olibanum, Boswellia spp., Burseraceae)

Boswellia species (Burseraceae) are trees or shrubs whose area of distribution covers the wide geographic area between North Africa and India. After incision, their bark produces oleogum resin known as frankincense (Olibanum). In traditional medicine, frankincense is often used for medical treatment of arthritis, asthma, ulcerative colitis, coughs, sores, and wound healing. Various frankincense preparations are marketed almost exclusively as dietary supplements. Indian frankincense, or Olibanum indicum, is official in the European Pharmacopoeia. The major components of frankincense are boswellic acids, among which the most important and abundant is 3-O-acetyl-11-keto-b-boswellic acid (AKBA). AKBA is a 5-lipoxygenase inhibitor with anti-inflammatory and anti-arthritic effects. Besides, frankincense contains essential oil, whose composition greatly depends on the biological source, as well as arabinogalactans and glycoproteins. In small clinical trials, certain benefits of various frankincense preparations have been demonstrated in cases of ulcerative colitis, bronchial asthma, mild symptoms of irritable bowel syndrome, and various disorders of osteo-muscular system. However, for collagenous colitis and Crohn's disease remission maintenance, the evidence is ambiguous or negative. AKBA-containing extract was found advantageous in patients with osteoarthritis, and to some extent with rheumatoid arthritis. Almost all the trials had serious flaws in experimental design, such as insufficient sample size and/or incomplete reporting of data. For any clinical recommendation of frankincense preparations, larger and better-designed studies are needed.

Real-World Long-Term Remission Maintenance for 10 Years With Thiopurines in Ulcerative Colitis

Background To evaluate the therapeutic outcomes and long-term prognosis of patients receiving remission maintenance therapy using thiopurines for ulcerative colitis (UC). Methods Of 193 biologic-naive patients with UC who began thiopurine therapy at our hospital between 2000 and 2019, 161 patients were included after the exclusion of 32 patients who were intolerant to thiopurines and discontinued the drugs within 3 months. Short- and long-term clinical outcomes were retrospectively analyzed. Subsequently, the patients were divided into 2 groups (exacerbation and nonexacerbation groups) and clinical outcomes were analyzed and compared. Multivariate analysis was performed to identify risk factors for UC exacerbation. Finally, adverse events observed in 193 patients were examined. Results Clinical remission rates at 2 months, 6 months, and 1 year after the start of thiopurine therapy were 50.0%, 58.0%, and 63.9%, respectively. At 1, 2, 5, and 10 years, the cumulative event-free rates were 77.6%, 60.8%, 48.5%, and 42.2%, respectively; the cumulative UC exacerbation rates were 17.0%, 32.5%, 42.2%, and 43.7%, respectively; and the cumulative colectomy rates were 0.6%, 1.3%, 8.5%, and 10.7%, respectively. Prior use of steroids (dose ≥40 mg/d) was a significant risk factor for UC exacerbation during remission maintenance therapy with thiopurines (hazard ratio, 2.26; 95% confidence interval, 1.18–4.34; P = 0.014). Adverse reactions occurred in 42 patients (21.8%; 46 events). Concurrent diseases were observed in 18 patients (9.3%). Conclusions Thiopurines were effective for long-term maintenance of remission in steroid-dependent/refractory UC. Their effect weakened in only a few patients continuously treated with them for 4 years or longer.