Steroid-sparing Immunosuppressant Research Articles

A wolf in sheep’s clothing

A 28 year-old Caucasian woman was found to have reduced visual acuity during routine optician checks and was referred to ophthalmology and then neurology. Examination revealed acuities of 6/12 in both eyes, pale optic discs and reduced colour perception. MRI brain did not show any lesions. Routine bloods were normal as were serum ACE, B1, B12, folate, HIV, syphilis, Lyme serology, AQP4-IgG and MOG-IgG. Leber’s and AD optic atrophy screens were negative. CSF protein was 0.41, WBC 7 (100% lymphocytes), elevated IgG Index 1.4 (normal<0.8),OCBs in serum and CSF with a single additional band raising the possibility of inflammatory optic neuritis. There was apparent stabilisation on empiric steroids which was then converted to steroid sparing immunosuppressants. However, as vision declined, whole mitochondrial genome sequencing and the clinical Exome Optic Atrophy Panel revealed compound heterozygous WFS1 mutations (c.605A>G p. (Glu2020Gly); c.874C>T p.(Pro292Ser) leading to diagnosis of‘Wolfram’Syndrome or DIDMOAD (diabetes insipidus, diabetes mellitus, optic atrophy, deafness) with an isolated optic atrophy phenotype. This case is unusual given the late age of presentation, lack of classical associ- ated features, suggestion of CSF inflammation and apparent steroid responsiveness. It also highlights the importance of expanded genetic testing in atypical optic atrophy cases.emily.gibbons@doctors.org.uk

Facial nerve palsy in neurosarcoidosis: clinical course, neuroinflammatory accompaniments, ancillary investigations, and response to treatment

Facial nerve palsy is a cardinal manifestation of neurosarcoidosis, but dedicated studies of this disease feature have not been conducted. We sought to clarify the impact of facial palsy on the diagnosis of neurosarcoidosis, its subsequent clinicoradiographic evolution, and eventual treatment decisions. A single-center retrospective analysis of patients with neurosarcoidosis and facial palsy was conducted over the preceding 10years (01/01/2011-08/12/2021). 23/218 (10.6%) patients with neurosarcoidosis developed facial neuropathy. It was the inaugural manifestation of neurosarcoidosis in 17/23 (73.9%) and presented in isolation of other neurologic deficits or extra-facial MRI abnormalities in 12/23 (52.2%). At onset, facial palsy was unilateral in 20/23 (87.0%), and multiple cranial neuropathies were seen in 8/23 (34.8%). Non-facial inflammatory MRI abnormalities were observed in 6/15 (40.0%) patients at onset with leptomeningitis being most common (5/15, 33.3%). 13/23 (56.5%) experienced a second attack of neurosarcoidosis at a median of 8months, including 3/23 (13.0%) with recurrent facial palsies. In the 12 patients with isolated facial paresis at onset, 4/12 (33.3%) remained free of new deficits or neuroimaging abnormalities by last follow-up. 17/23 (73.9%) eventually required initiation of steroid-sparing immunosuppressants, almost all for development of non-facial disease. The final median House-Brackmann score was 1. Facial neuropathy occurred less commonly than historically reported, and it often acts as a forerunner to systemic sarcoidosis and more widespread neurologic disease. Recurrent attacks of neurosarcoidosis occur early at high frequency following facial palsy. Recovery of facial nerve function is typically excellent.

P043 Challenges in the diagnosis and management of immune-mediated necrotizing myopathy in a patient on long-term statins

Abstract Background/Aims Statins are very common medications prescribed for cardiovascular disease prevention and with their ever-increasing use; we expect a significant increase in even the rarest side-effects. Immune-mediated necrotising myopathy (IMNM) is a rare type of autoimmune myopathy characterised by relatively severe proximal weakness and is most associated with the development of anti-HMGCoAR (3-hydroxy-3-methylglutaryl CoA Reductase) autoantibodies in statin users. The objective of this clinical case report is to highlight this rare condition to avoid incorrect diagnosis, particularly in primary care, to ensure prompt and specific management. Methods A 51-year-old female presented to her GP with gradual onset muscle weakness particularly around her shoulders and legs. She had a history of hypercholesterolemia, for which she had been on atorvastatin 20mg daily for 4 years. Results Following a blood test by her GP, a raised CK of 16,670 iU/L prompted a hospital admission due to suspected skeletal muscle damage. MRI scan of thighs showed features of myositis and muscle biopsy showed necrotic regenerating muscle fibres with lymphohistiocytic inflammation consistent with necrotizing myopathy. Blood tests revealed positive anti-HMGCoAR antibodies (negative ANA, DNA, ENA & other myositis-specific antibodies) confirming a diagnosis of anti-HMGCoAR IMNM. Atorvastatin was stopped and treatment was initiated with high-dose IV methylprednisolone followed by oral prednisolone tapering course. She showed only minor improvement in symptoms over the initial 6 weeks. Methotrexate was then added, with gradual improvement in her symptoms and normalization of CK over the next 6 months. Conclusion IMNM is unique in that it does not improve with statin discontinuation alone, and usually requires a combination of steroid and steroid-sparing immunosuppressant. Early diagnosis is crucial as commencing treatment early leads to better outcomes in patients. Anti-HMGCoAR antibodies are highly specific for this condition and not associated per se with hyperlipidaemia, self-limiting statin side effects or genetic muscle disease. In patients presenting with muscle weakness who are taking statins, it is beneficial to perform anti-HMGCoAR antibody test (especially if persistent symptoms despite statin cessation) to promptly differentiate this rare condition from more common but less severe statin related myotoxicities. Disclosure F. Khan: None. A. Kuttikat: None.

Working Towards a Treat-to-Target Protocol in Juvenile Proliferative Lupus Nephritis - A Survey of Pediatric Rheumatologists and Nephrologists in Germany and Austria.

BackgroundTo describe treatment practices for juvenile proliferative lupus nephritis (LN) class III and IV of pediatric rheumatologists and nephrologists in Germany and Austria in preparation for a treat-to-target treatment protocol in LN.MethodsSurvey study by members of the Society for Pediatric and Adolescent Rheumatology (GKJR) and the German Society for Pediatric Nephrology (GPN) on diagnostics and (concomitant) therapy of LN.ResultsFifty-eight physicians completed the survey. Overall, there was a considerable heterogeneity regarding the suggested diagnostics and management of juvenile proliferative LN. Increased urinary protein excretion, either assessed by 24 h urine collection or spot urine (protein-creatinine ratio), and reduced estimated glomerular filtration rate were specified as important parameters for indication of kidney biopsy to diagnose proliferative LN and monitoring of therapy. Corticosteroids were generally proposed for induction and maintenance therapy, most often in conjunction with either mycophenolate mofetil (MMF) or cyclophosphamide (CP) as steroid-sparing immunosuppressants. MMF was clearly preferred over CP for induction therapy of LN class III, whereas CP and MMF were equally proposed for LN class IV. MMF was most often recommended for maintenance therapy in conjunction with oral corticosteroids and continued for at least 3 years and 1 year, respectively, after remission. Hydroxychloroquine was widely accepted as a concomitant measure followed by renin-angiotensin system inhibitors in cases of arterial hypertension and/or proteinuria.ConclusionThe majority of pediatric rheumatologists and nephrologists in Germany and Austria propose the use of corticosteroids, most often in combination with either MMF or CP, for treatment of proliferative LN in children. The considerable heterogeneity of responses supports the need for a treat-to-target protocol for juvenile proliferative LN between pediatric rheumatologists and nephrologists.

Bullous Pemphigoid: Readability, Quality, and Treatments of Online Health Resources

Bullous Pemphigoid: Readability, Quality, and Treatments of Online Health Resources

Pemphigus Vulgaris: Present and Future Therapeutic Strategies.

Pemphigus vulgaris (PV) belongs to the group of autoimmune blistering diseases. PV can affect not only mucous membranes, but also the skin and it is characterized by serum IgG autoantibodies against desmoglein 1 and 3, two major components of desmosomes. The introduction of glucocorticoids improved dramatically the prognosis of patients affected by PV. However, long-term use of high dose corticosteroids and adjuvant steroid-sparing immunosuppressants can lead to several adverse events. Rituximab, a chimeric anti-CD20 monoclonal antibody, has been recently approved as in-label therapy for PV, leading to an improvement of the prognosis and higher remission rate. Furthermore, other anti B-cell therapies and several anti-CD20 biosimilars have been introduced in the clinical practice. We focused on present and future therapeutic approaches in PV.

Abatacept for IgG4-related disease: therapeutic prospects according to disease immunophenotype.

IgG4-related disease is a chronic, immune-mediated fibroinflammatory disease characterised by disorders of multifunctional immune cells (eg, plasmablasts and T follicular helper [Tfh] cells) in the peripheral blood and involved tissues.1,2 Currently, glucocorticoids are the first-line treatment for IgG4-related disease. Most patients respond well to the initial use of glucocorticoids, but 24–63% relapse and there can be severe adverse events with long-term administration.3 Furthermore, there is no relevant evidence that conventional steroid-sparing immunosuppressants (eg, azathioprine, mycophenolate mofetil, and cyclophosphamide) can replace glucocorticoids in the treatment of IgG4-related disease.

Advancing research in autoimmune neuromuscular disorders

A new Series on autoimmune neuromuscular disorders in The Lancet Neurology comprises three Reviews 1 Huijbers MG Marx A Plomp JJ Le Panse R Phillips WD Advances in the understanding of disease mechanisms of autoimmune neuromuscular junction disorders. Lancet Neurol. 2022; 21: 163-175 Google Scholar , 2 Verschuuren JJGM Palace J Murai H Tannemaat M Kaminski HJ Bril V Advances and ongoing research in the treatment of autoimmune neuromuscular junction disorders. Lancet Neurol. 2022; 21: 189-202 Google Scholar , 3 Punga AR Maddison P Heckmann JM et al. Epidemiology, diagnostics, and biomarkers of autoimmune neuromuscular junction disorders. Lancet Neurol. 2022; 21: 176-188 Google Scholar that altogether provide a broad overview of the current status of, and ongoing research into, the causes and treatment of myasthenia gravis and Lambert-Eaton myasthenic syndrome. The major contribution of this Series is the comprehensive information that they provide about disease mechanisms, 1 Huijbers MG Marx A Plomp JJ Le Panse R Phillips WD Advances in the understanding of disease mechanisms of autoimmune neuromuscular junction disorders. Lancet Neurol. 2022; 21: 163-175 Google Scholar new drugs in development, 2 Verschuuren JJGM Palace J Murai H Tannemaat M Kaminski HJ Bril V Advances and ongoing research in the treatment of autoimmune neuromuscular junction disorders. Lancet Neurol. 2022; 21: 189-202 Google Scholar and known and potential biomarkers. 3 Punga AR Maddison P Heckmann JM et al. Epidemiology, diagnostics, and biomarkers of autoimmune neuromuscular junction disorders. Lancet Neurol. 2022; 21: 176-188 Google Scholar Advances and ongoing research in the treatment of autoimmune neuromuscular junction disordersMyasthenia gravis and Lambert-Eaton myasthenic syndrome are antibody-mediated autoimmune diseases of the neuromuscular junction that usually present with weakness in ocular muscles and in proximal muscles of the limb and trunk. Prognosis regarding muscle strength, functional abilities, quality of life, and survival is generally good. However, some patients do not respond to treatment. Symptomatic drugs, corticosteroids, and steroid-sparing immunosuppressive drugs remain the cornerstone of treatment. Full-Text PDF Advances in the understanding of disease mechanisms of autoimmune neuromuscular junction disordersMuscle weakness and fatigue are the hallmarks of autoimmune neuromuscular junction disorders. Although a plethora of immunosuppressive treatments exist, no cure is available to date and many patients are left with debilitating muscle weakness. Recent advances in the understanding of the structure and function of the neuromuscular junction, and the development of novel in vitro and in vivo models, have been instrumental in unravelling the pathophysiology of these autoimmune diseases. These advances are providing the rationale for the development of new therapeutic strategies. Full-Text PDF Epidemiology, diagnostics, and biomarkers of autoimmune neuromuscular junction disordersAutoimmune neuromuscular junction disorders are rare. However, myasthenia gravis is being increasingly recognised in people older than 50 years. In the past 5–10 years, epidemiological studies worldwide suggest an incidence of acetylcholine receptor antibody-positive myasthenia gravis of up to 29 cases per 1 million people per year. Muscle-specific tyrosine kinase antibody-positive myasthenia gravis and Lambert-Eaton myasthenic syndrome are about 20 times less common. Several diagnostic methods are available for autoimmune neuromuscular junction disorders, including serological antibody, electrophysiological, imaging, and pharmacological tests. Full-Text PDF

Neurosarcoidosis: Pathophysiology, Diagnosis, and Treatment.

Although often regarded as a protean illness with myriad clinical and imaging manifestations, neurosarcoidosis typically presents as recognizable syndromes that can be approached in a rational, systematic fashion. Understanding of neurosarcoidosis has progressed significantly in recent years, including updated diagnostic criteria and advances in treatment. The diagnosis of neurosarcoidosis is established by the clinical syndrome, imaging and histopathological findings, and exclusion of other causes. Mounting evidence supports the use of tumor necrosis factor inhibitors as an important addition to the therapeutic armamentarium, along with glucocorticoids and steroid-sparing cytotoxic immunosuppressants. In this narrative review, we summarize recent advances in the diagnosis and treatment of neurosarcoidosis.

Recurrent bilateral chorioretinitis with positive Lyme serology: a case report

BackgroundIt has been disputed whether Lyme is a true causative agent in posterior uveitis or an incidental finding.Case presentationThis report presents a case of a 33-year-old Caucasian female with a remote history of Lyme disease who presented with blurry vision in the right eye. Exam and imaging revealed a right active chorioretinitis and positive Lyme serology. The patient was systemically treated with prednisone and antibiotics. Symptoms initially improved, but she later developed a localized choriocapillaritis in the left eye. Steroids and antibiotics were restarted many times with fluctuating course of the disease. The patient was then started on chronic steroid-sparing immunosuppression, which has controlled the condition without recurrence.ConclusionsThe current report presents a unique case of recurrent bilateral chorioretinitis with positive Lyme serology and raises the question of the existence of true Lyme-associated uveitis.

Two Cases of Statin Induced Necrotizing Autoimmune Myopathy

Case 1: Six months ago, patient 1 presented with rhabdomyolysis with a CK of 17,622 Units/L. The statin was discontinued at that time, after which the patient noted substantial improvement in muscle symptoms. Two months later the patient was readmitted for complaints related to continued rhabdomyolysis. CK was elevated at 9800 Units/L, raising suspicion for SINAM. Physical exam findings on readmission were pertinent for 4/5 strength in proximal flexion and extension of the upper extremities bilaterally and 4/5 strength in hip flexion. Pertinent lab values on readmission include increased ALT of 122 Units/L, AST of 103 Units/L, TSH of 7.4 mIU/L, HbA1c of 6.6%, and BUN of 14.5 mg/dL. Urinalysis is positive 3+ for glucose, 1+ for ketones, and 2+ for blood. Brain MRI without contrast negative for any brain malignancies or abnormalities. Case 2: Patient 2 presented with gradual proximal muscle weakness while taking a statin for the past six months. Physical exam was notable for 4/5 strength in the biceps and triceps and 3/5 deltoid strength bilaterally. There was 4/5 strength in the knee flexors and extensors with 3/5 strength in the hip flexors bilaterally. Notable lab values include CK of 10,449 Units/L, CK-MB of 492ng/mL, fasting glucose of 160 mg/dL, ALT of 229 Units/L, and HgbA1C of 7.3%. Urinalysis was positive 3+ for glucose, 1+ for ketones, and 2+ for blood. Discussion: Statin induced necrotizing autoimmune myopathy (SINAM) is a rare complication of statin therapy in which subjects develop an immune response to 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR). SINAM’s pathophysiology remains poorly understood. Studies have shown that statins upregulate expression of HMGCR which serve as antibody targets in SINAM (Mohassel & Mammen, 2013). The HMGCR protein is upregulated in regenerating muscle fibers thus preferentially allowing autoantibodies to bind (Mammen et al, 2011). Additionally, complement is implicated in pathogenicity of SINAM with a study showing that C3 deficient mice had less pronounced deficiency in muscle strength (Bergua et al, 2019). This is further reinforced with a muscle biopsy in another SINAM confirmed patient showed C5b-9 sarcolemmal deposits (Sharma et al, 2019). This implicates the formation of antigen-antibody-complement complexes typical of a type III hypersensitivity reaction. Additionally, genetic risk factors for autoimmunity are important to consider. There is an association of SINAM occurrence in individuals with single nucleotide polymorphism in the SLCO1B1 that regulates hepatic uptake of drugs such as statins (SEARCH, 2008). HLA- DRB1*11:01 is associated with the formation of autoantibodies in SINAM (Mammen, 2016). Recent studies show the triple induction therapy of steroids, IVIG, and a steroid sparing immunosuppressant has been very effective (Meyer et al, 2020).

A multi-center case series of sarcoid optic neuropathy

ObjectiveThe diagnosis of sarcoid optic neuropathy is time-sensitive, as delayed treatment risks irreversible vision loss. We sought to analyze its characteristics and outcomes. MethodsWe performed a multi-center retrospective study of sarcoid optic neuropathy among 5 USA medical centers. Inclusion criteria were: 1) clinical optic neuropathy; 2) optic nerve/sheath enhancement on neuroimaging; 3) pathological confirmation of systemic or nervous system sarcoidosis. ResultsFifty-one patients were included. The median onset age of sarcoid optic neuropathy was 50 years (range, 17–70 years) and 71% were female. The median visual acuity at nadir in the most affected eye was 20/80 (range, 20/20 to no-light-perception). Thirty-four of 50 (68%) patients had radiologic evidence of other nervous system involvement and 20 (39%) patients had symptoms/signs of other cranial nerve dysfunction. Cerebrospinal fluid analysis revealed an elevated white blood cell count in 22 of 31 (71%) patients (median: 14/μL; range: 1–643/μL). Pathologic confirmation of sarcoidosis was by biopsy of systemic/pulmonary site, 34 (67%); optic nerve/sheath, 9 (18%); or other nervous system region, 8 (16%). Forty patients improved with treatment (78%), 98% receiving corticosteroids and 65% receiving steroid-sparing immunosuppressants, yet 11/46 patients (24%) had a visual acuity of 20/200 or worse at last follow-up. ConclusionsSarcoid optic neuropathy frequently occurs with other clinical and radiologic abnormalities caused by neurosarcoidosis and diagnostic confirmation occasionally requires optic nerve/sheath biopsy. Improvement with treatment is common but most patients have some residual visual disability. Improved recognition and a more expeditious diagnosis and treatment may spare patients from permanent vision loss.

60P Real-world experience of immunotherapy in elderly cancer patients in a UK cancer centre

Cancer tends to affect the elderly; however, they are less represented in clinical trials. Therefore, real-world data of Immune-related adverse events (irAEs) of patients on immune checkpoint inhibitor (ICIs) can be a useful tool to guide clinical practice. Patients aged ≥65 yrs, with non-small cell lung cancer (NSCLC), malignant melanoma (MM) or renal cell carcinoma (RCC) on ICI ( non- curative intent) either as monotherapy (MT) or in combination (CT), between 2016 – 2018 at Castle Hill Hospital were included in this retrospective analysis to review irAEs and outcome (analyses performed with SPSS v25). Of 90 patients identified; 43 were NSCLC, 30 MM and 17 RCC. 87.8% received αPD-1, 6.7% αCTLA-4, 3.3% αPDL-1 combination αPD-1/αCTLA-4 and 2.2% combination αPD-1/αCTLA-4. Median age was 71 yrs. 92.2% had ECOG performance status of 0-1. Median follow up was 14.5 months. 35/90 (38.8%) had an irAE; 94.2% (33/35) on MT and 5.8% (2/35) on CT. Clinically significant irAE was observed in 30/90 (33.3%) patients with near 1/5th (20/90) suffering from Grade 3 toxicities. 12.2% (11/90) of patients had pre-existing autoimmune disease, 45.4% (5/11) of them experienced irAE. Most common IrAEs witnessed were colitis12 (13.3%), thyroiditis 5 (5.6%), pneumonitis 5 (5.6%) and dermatitis 3 (3.3%). There were 2 cases of grade 5 irAE with αPD-1 MT (1 pneumonitis,1 nephritis). 86.6% (26/30) with clinically significant irAE required corticosteroids with almost half of them needing systemic corticosteroids. Steroid sparing immunosuppression was used in 13.3% (4/30). 63.3% (19/30) had admission, average stay of 12.3 days accounting for 233 bed days. This rate is higher compared to all age group (42%). Colitis 11/19 and pneumonitis 3/19 led to most admissions. Progression free survival (PFS) and overall survival (OS) was higher in patients with irAE Vs no irAE ( PFS 16.3 months [95% CI 7.9, 24.8] Vs 4.6 months [95% CI 1.7, 7.6], p= 0.003; OS 30 months [95% CI 18, 41.9] Vs 7.4 months [95% CI 3.2, 11.6], p=0.01). Incidence of irAE in elderly were comparable to our cohort of patient that includes all age group though more inpatient care observed in this group. There appears to be a toxicity-efficacy relationship with irAEs; however, larger studies are required to validate this.

The role of vitamin D in sarcoidosis.

After the initial description of extrarenal synthesis of 1,25-dihydroxyvitamin D (1,25-(OH)2D) three decades ago, extensive progress has been made in unraveling the immunomodulatory roles of vitamin D in the pathogenesis of granulomatous disorders, including sarcoidosis. It has been shown that 1,25-(OH)2D has dual effects on the immune system, including upregulating innate immunity as well as downregulating the autoimmune response. The latter mechanism plays an important role in the pathogenesis and treatment of sarcoidosis. Vitamin D supplementation in patients with sarcoidosis has been hampered owing to concerns about the development of hypercalcemia and hypercalciuria given that extrarenal 1-α hydroxylase is substrate dependent. Recently, a few studies have cast doubt over the mechanisms underlying the development of hypercalcemia in this population. These studies demonstrated an inverse relationship between the level of vitamin D and severity of sarcoidosis. Consequently, clinical interest has been piqued in the use of vitamin D to attenuate the autoimmune response in this disorder. However, the development of hypercalcemia and the attendant detrimental effects are real possibilities. Although the average serum calcium concentration did not change following vitamin D supplementation, in two recent studies, hypercalciuria occurred in one out of 13 and two out of 16 patients. This review is a concise summary of the literature, outlining past work and newer developments in the use of vitamin D in sarcoidosis. We feel that larger-scale placebo-controlled randomized studies are needed in this population. Since the current first-line treatment of sarcoidosis is glucocorticoids, which confer many systemic adverse effects, and steroid-sparing immunosuppressant treatment options carry additional risks of adverse effects, adjunct management with vitamin D in combination with potent anti-osteoporotic medications could minimize the risk of glucocorticoid-induced osteoporosis and modulate the immune system to attenuate disease activity in sarcoidosis.

IgG4-related disease: a contemporary review

Background/aimImmunoglobulin G4-related disease (IgG4-RD), is an immune-mediated fibroinflammatory condition, which may involve multiple organs and mostly presents with high serum IgG4 levels and specific histopathological characteristics. As IgG4-RD is a relatively new entity the etiology, prevalence and epidemiologic knowledge is quite limited. Although involvement of almost all anatomical regions has been reported, the most commonly affected regions are pancreas, lacrimal glands, salivary glands, retroperitoneum, orbita, lymph nodes, kidney and lungs. Diagnosis is made with combined evaluation of clinical, radiological and histopathological findings. Typical histopathological features include storiform fibrosis, dense lymphoplasmacytic infiltrates and obliterative phlebitis. Its course is typically marked by remission and relapsing attacks and it may lead to fibrosis, destructive lesions in tissues and organ failure unless promptly treated. In the treatment of IgG4-RD, many approaches including surgical resection of tissues, systemic glucocorticoids, steroid-sparing immunosuppressive drugs, and biological agents are employed. Although association is not clear, malignancies are frequently reported in IgG4-RD patients. Therefore, it is prudent to monitor patients for the symptoms of malignant diseases.ConclusionIn this review, recent advances in clinico-pathological characteristics, diagnosis, and treatment of IgG4–RD are discussed.

Steroid-sparing maintenance immunosuppression is safe and effective after simultaneous liver-kidney transplantation.

Optimization of maintenance immunosuppression (mIS) regimens in the transplant recipient requires a balance between sufficient potency to prevent rejection and avoidance of excessive immunosuppression to prevent toxicities and complications. The optimal regimen after simultaneous liver-kidney (SLK) transplantation remains unclear, but small single-center reports have shown success with steroid-sparing regimens. We studied 4184 adult SLK recipients using the Scientific Registry of Transplant Recipients, from March 1, 2002, to February 28, 2017, on tacrolimus-based regimens at 1year post-transplant. We determined the association between mIS regimen and mortality and graft failure using Cox proportional hazard models. The use of steroid-sparing regimens increased post-transplant, from 16.1% at discharge to 88.0% at 5years. Using multi-level logistic regression modeling, we found center-level variation to be the major contributor to choice of mIS regimen (ICC 44.5%; 95% CI: 36.2%-53.0%). In multivariate analysis, use of a steroid-sparing regimen at 1year was associated with a 21% decreased risk of mortality compared to steroid-containing regimens (aHR 0.79, P=.01) and 20% decreased risk of liver graft failure (aHR 0.80, P=.01), without differences in kidney graft loss risk (aHR 0.92, P=.6). Among SLK recipients, the use of a steroid-sparing regimen appears to be safe and effective without adverse effects on patient or graft survival.

Ocular sarcoidosis: clinical experience and recent pathogenetic and therapeutic advancements

PurposeTo describe the ocular manifestations in a cohort of patients with systemic sarcoidosis (SS). Recent advances in the pathophysiology, diagnosis, and therapy of SS are also discussed.MethodsData from 115 Italian patients diagnosed between 2005 and 2016 were retrospectively reviewed. All but the first 17 patients underwent a comprehensive ophthalmologic examination. The diagnosis was based on clinical features, the demonstration of non-caseating granulomas in biopsies from involved organs, and multiple imaging techniques. Data on broncho-alveolar lavage fluid analysis, calcemia, calciuria, serum angiotensin-converting enzyme levels and soluble interleukin-2 receptor levels were retrieved when available.ResultsOcular involvement, detected in 33 patients (28.7%), was bilateral in 29 (87.9%) and the presenting feature in 13 (39.4%). Anterior uveitis was diagnosed in 12 patients (36.4%), Löfgren syndrome and uveoparotid fever in one patient each (3%), intermediate uveitis in 3 patients (9.1%), posterior uveitis in 7 (21.2%), and panuveitis in 9 (27.3%). First-line therapy consisted of corticosteroids, administered as eyedrops (10 patients), sub-Tenon’s injections (1 patient), intravitreal implants (9 patients), or systemically (23 patients). Second-line therapy consisted of steroid-sparing immunosuppressants, including methotrexate (10 patients) and azathioprine (10 patients). Based on pathogenetic indications that tumor necrosis factor (TNF)-α is a central mediator of granuloma formation, adalimumab, targeting TNF-α, was employed in 6 patients as a third-line agent for severe/refractory chronic sarcoidosis.ConclusionUveitis of protean type, onset, duration, and course remains the most frequent ocular manifestation of SS. Diagnostic and therapeutic advancements have remarkably improved the overall visual prognosis. An ophthalmologist should be a constant component in the multidisciplinary approach to the treatment of this often challenging but intriguing disease.

Infiltrative lymphocytic hypophysitis successfully treated with rituximab and mycophenolate mofetil.

SummaryLymphocytic hypophysitis is a rare neuroendocrine disease characterised by an autoimmune inflammatory disorder of the pituitary gland. We report a 50-year-old woman who presented with headaches and bilateral sixth cranial nerve palsies. MRI of the pituitary revealed extensive fibrosis involving the sellar and extending into both cavernous sinuses causing bilateral occlusion of the internal carotid arteries (ICA). Transphenoidal biopsy confirmed the diagnosis of infiltrative fibrotic lymphocytic hypophysitis. Symptoms resolved with high dose of oral steroids but relapsed on tapering, requiring several treatments of i.v. pulse steroids over 8 months. Rituximab combined with mycophenolate mofetil was required to achieve long-term symptom relief. Serial MRI pituitary imaging showed stabilisation of her disease without reduction in sellar mass or regression of ICA occlusion. The patient’s brain remained perfused solely by her posterior circulation. This case demonstrates an unusual presentation of a rare disease and highlights a successful steroid-sparing regimen in a refractory setting.Learning points:Lymphocytic hypophysitis is a rare inflammatory disorder of the pituitary gland. In exceptional cases, there is infiltration of the cavernous sinus with subsequent occlusion of the internal carotid arteries.First-line treatment of lymphocytic hypophysitis is high-dose glucocorticoids. Relapse after tapering or discontinuation is common and its use is limited by long-term adverse effects.There is a paucity of data for treatment of refractory lymphocytic hypophysitis. Goals of treatment should include improvement in symptoms, correction of hormonal insufficiencies, reduction in lesion size and prevention of recurrence.Steroid-sparing immunosuppressive drugs such as rituximab and mycophenolate mofetil have been successful in case reports. This therapeutic combination represents a viable alternative treatment for refractory disease.

Use of leflunomide in patients with chronic hypersensitivity pneumonitis

BackgroundPrednisone has been shown to reverse lung function declines in hypersensitivity pneumonitis patients without established fibrosis. Second line immunosuppressants like azathioprine and mycophenolate mofetil have a steroid sparing effect and improve DLCO. There is no published literature on the use of leflunomide in such patients.MethodsWe reviewed our experience with leflunomide for treatment of chronic hypersensitivity pneumonitis in 40 patients. We stratified patients according to the presence or absence of significant (> 20%) fibrosis. We studied the effect of leflunomide on FVC and DLCO trajectory and reported the changes at 12 months.ResultsTreatment with leflunomide tended to improve the estimated FVC slope from 0.18 ± 1.90% (SEM) of predicted per year to 4.62 ± 1.65% of predicted (NS, p = 0.118). It significantly improved the FVC at 12 months of treatment by 4.4% of predicted (p = 0.02). DLCO continued to increase at 1.45 ± 1.44% (SEM) of predicted per year. Non-fibrotic cHP patients had the largest gain in pulmonary function. Their FVC increased by 8.3% (p = 0.001) and DLCO by 4.8% (p = 0.011). Patients with fibrotic cHP did not improve. Leflunomide treatment was associated with significant gastrointestinal and other adverse effects leading 40% of patients to discontinue therapy. It had a significant steroid sparing effect with half the patients weaned off prednisone entirely.ConclusionsLeflunomide appears to be a fairly well tolerated steroid sparing immunosuppressant that improves pulmonary function in cHP patients. It is most effective in patients without significant fibrosis.

Assessing the effect of immunosuppressive agents for immune-related adverse event management on tumor response.

3066 Background: High grade immune-related adverse events (irAEs) to cancer immune checkpoint inhibitors (ICI) require considerable immunosuppression (IS) with high-dose steroids and steroid-sparing IS (SSIS) for steroid-dependent cases. T lymphocyte-specific IS has generally been avoided or used with significant caution due to the fear that these agents may negatively impact ICI efficacy. We sought to determine whether T cell-specific IS agents, such as calcineurin inhibitors (CNIs), have an adverse effect on tumor control when compared to other immunomodulatory drugs (IMDs). Methods: We retrospectively analyzed clinical annotations of adult patients treated with ICIs for malignancy from 1/1/2000-12/31/2019, highlighting patients who were managed with SSIS, specifically those most commonly used for autoimmune disease therapy. Topical IS use was excluded. Patients were categorized as tumor responders or non-responders, and irAEs were graded according to National Cancer Institute’s Common Terminology Criteria for Adverse Events (CTCAE). Progression-free survival (PFS) was assessed via Kaplan-Meier curve. Results: 1331 unique individuals were prescribed ≥1 ICIs, with 526 prescribed systemic steroids (39.5%) and 90 (6.8%) patients prescribed SSIS agents, 25 patients with >1 SSIS: mycophenolate (39), methotrexate (26), leflunomide (5), azathioprine (3), rituximab (24), tocilizumab (3), infliximab (8), etanercept (1), adalimumab (1), golimumab (1) and CNIs (18): cyclosporine, tacrolimus. IMDs hydroxychloroquine (6) and sulfasalazine (5) were also prescribed. The objective response rate was 50.0% in the CNI group compared to 45.5% in the IMD cohort and 45.4% in the irAE group (CTCAE grade matched) with steroids alone without any SSIS. Median PFS were compared between CNI cohort (5.4 months, range 1.3-34 months) to IMD (1.1 months, range 0.4-6.4, p=0.02) and steroid alone (2.4 months, range 0.69-17.7, p=0.48). Multiple regression analysis identified irAE presence as an independent correlates to tumor response (p=0.02). Conclusions: T cell-specific IS should not be excluded from irAE treatment algorithm as we observed that PFS was comparable to immunomodulators and similar efficacy was observed compared to steroids alone. Rapid identification and management of irAEs can help mitigate morbidity but there are virtually no reliable clinical trials to guide irAE management with SSIS. These findings support the need for larger, prospective evaluation of immunosuppression use for high grade irAE therapy.