Lupus Nephritis Outcomes after Stopping Immunosuppression.

Background/Objectives: Immunosuppression (IS) is a standard therapy for lupus nephritis (LN). Data on the outcomes of patients with LN after the discontinuation of immunosuppression remain uncertain. This study aimed to evaluate the outcomes and results of patients with lupus nephritis (LN) who ceased immunosuppressive (IS) therapy. Methods: Records were obtained on the clinical and laboratory features of LN patients who were treated at our Lupus Unit. They included median values and ranges for various numerical variables such as patient age, disease duration, and treatment duration. Categorical variables such as gender, LN class, IS treatment type, and patient outcomes, which were categorized as either "stable" or "flare experienced", were presented as percentages and frequencies. A flare in LN was characterized by a two-fold increase in serum creatinine levels and a rise in proteinuria following the cessation of IS medication. Results: Outcomes were assessed for 45 patients with LN who ceased IS therapy after achieving remission. The patients' median age was 55 years (29-78). The median duration of treatment was 4 years (0.5-14). The LN histology distribution was class V = 24.4%, class IV = 17.8 %, class III = 17.8%, class III + IV = 15.6%, class III + V = 6.7%, class IV + V = 2.2%, and class II + IV and II = 2.2%. At the discontinuation of IS treatment, creatinine levels were elevated in 9/45 (20%) patients. Furthermore, 28.9% of patients relapsed after IS treatment discontinuation. Patients with anti-Smith antibodies (anti-Sm) were observed to have a higher occurrence of relapses, with six patients experiencing flare compared to four patients who remained stable (p = 0.03). Five (38.5%) of the patients with flares had high creatinine levels after IS discontinuation. Conclusions: Most of our patients maintained clinical remission and stable levels of LN parameters after IS treatment discontinuation. Those with a high serum creatinine level, ongoing proteinuria, depleted complement levels, and the presence of anti-Sm antibodies were more likely to experience flares after the discontinuation of IS therapy.

Lupus enteritis: a narrative review.

Lupus enteritis (LE) is a rare manifestation of systemic lupus erythematosus. The pathophysiology of LE has not been fully elucidated, although inflammatory and thrombotic processes are likely important factors. The underlying pathophysiological mechanisms may depend on which portion of the intestine is affected. Over half of the patients with LE also present with renal or haematological complications. The diagnosis of LE is based on clinical, histopathological and imaging findings; abdominal computed tomography (CT) is the gold standard in diagnosis. Abdominal CT can also identify factors that predict complications and could potentially guide pharmacological and nutritional management. Timely identification and prompt treatment initiation are paramount to avoid life and organ threatening complications. Glucocorticoids are often the first-line treatment. Additional therapy including immunosuppressive therapy is utilised on a case-by-case basis as there are no clinical trials to define the optimal therapeutic approach. Surgical intervention may be needed especially if there is bowel perforation or peritonitis. In general, the prognosis of LE is good.

Transverse myelitis associated with systemic lupus erythematosus (SLE-TM): A review article.

Systemic lupus erythematosus-related transverse myelitis (SLE-TM) is a rare but serious complication of SLE, which may result in significant morbidity. Its incidence is estimated between 0.5% and 1% of all SLE patients but may be the presenting feature in 30%-60% of these patients. Unfortunately, due to lack of high-quality studies, data regarding this condition remains limited. Its pathogenesis remains largely unknown and clinical presentation is variable. There are still no set guidelines regarding diagnosis, management, or monitoring and the role of autoantibodies remains controversial. In this review, we aim to summarize the available data regarding the epidemiology, pathogenesis, clinical features, management, and prognosis of this rare disease.

Relapsing polychondritis - A single Centre study in the United Kingdom.

INTRODUCTION AND OBJECTIVES: Relapsing Polychondritis (RP) is a rare immune mediated inflammatory disorder that may result in damage and destruction of cartilaginous tissues. PATIENTS AND METHODS: We retrospectively analysed patients with a clinical diagnosis of RP. Patients were investigated using pulmonary function tests, dynamic high-resolution CT scans, bronchoscopy, laryngoscopy and/or PET-CT scans along with autoimmune serology. Patients had other specialist reviews when indicated. RESULTS: We identified 68 patients with a diagnosis of RP, 55 (81%) were Caucasian, 8 (12%) Afro Caribbean, 4 (6%) Asian and 1 patient had Mixed Ethnicity. Twenty-nine (43%) had pulmonary involvement and in 16, pulmonary involvement was the initial presentation. The mean age at onset was 44 years (range 17-74). There was a mean diagnostic delay of 55 weeks. Sixty-six (97%) patients received a combination of oral Prednisolone and disease modifying anti-rheumatic drugs. Twelve of 19 (63%) received biologics, with an initial good response, and 10 remain on treatment. Eleven patients with respiratory collapse required CPAP to maintain airway patency. Twelve (18%) patients died due to RP and 9 had respiratory complications. Two patients developed myelodysplasia and one had lung carcinoma. In a multivariate regression analysis, the prognostic variables were ethnicity, nasal chondritis, laryngotracheal stricture and elevated serum creatinine. CONCLUSION: RP is a rare autoimmune condition often associated with significant delays in diagnosis and initiation of treatment. Pulmonary involvement in RP may cause significant morbidity and mortality due to organ damage. Disease modifying anti rheumatic drugs and biologics should be considered early in the disease course to minimise adverse effects of long-term corticosteroid therapy and organ damage.

The HAVEN study-hydroxychloroquine in ANCA vasculitis evaluation-a multicentre, randomised, double-blind, placebo-controlled trial: study protocol and statistical analysis plan.

BACKGROUND: Patients with non-severe ANCA-associated vasculitis (AAV) are often prescribed immunosuppressive medications that are associated with severe side effects and a reduced quality of life. There is an unmet need for safer effective treatments for these patients. Hydroxychloroquine is being explored due to its effect in similar autoimmune conditions such as systemic lupus erythematosus. METHODS: Double-blind, placebo-controlled multicentre trial recruiting 76 patients across 20 sites. Participants will be randomised 1:1 to hydroxychloroquine or placebo in addition to standard of care immunosuppressive therapies over the course of 52 weeks. A phase II selection design will be used to determine hdroxychloroquine's efficacy, using prednisolone dosage and Birmingham Vasculitis Activity Score as a measure of disease activity. Secondary outcomes will explore other elements of AAV progression, including disease flares and time to remission. DISCUSSION: This trial aims to explore Hydroxychloroquine as a treatment for patients with AAV. If effective, the need for immunosuppressive treatments such as prednisolone could be reduced. Hydroxychloroquine is safer, cheaper and has fewer adverse effects than conventional immunosuppressive treatments. This could improve patient outcomes while saving money for the NHS. TRIAL REGISTRATION: ISRCTN: ISRCTN79334891. Registered 07 June 2021. EudraCT: 2018-001268-40. Registered 13 September 2019. CLINICALTRIALS: gov: NCT04316494. Registered 20 March 2020.

Proton pump inhibitor induced subacute cutaneous lupus erythematosus: Clinical characteristics and outcomes.

BACKGROUND: There is a growing literature reporting the association between proton pump inhibitor (PPI) use and subacute cutaneous lupus erythematosus (SCLE). AIMS: To compare the clinical characteristics of a cohort of patients with PPI-induced SCLE, their clinical course and treatment with a control group of primary SCLE patients not exposed to PPI. METHODS: We conducted a matched case-control study in a tertiary referral setting at the Louise Coote Lupus Unit. There were 64 SCLE patients: 36 with PPI-induced SCLE and 28 patients with primary SCLE. RESULTS: Twenty-six patients (72%) had pre-existing SLE in the PPI-induced SCLE group. Lower limb skin lesions were significantly more prevalent in the PPI group (p < 0.0001). The prevalence of anti-Ro and anti-Ro-52 antibodies was numerically higher in the PPI group (64% and 60%), respectively, compared with 46% and 42% in the primary SCLE group. Peripheral blood eosinophils were normal in all patients in the PPI group. Thirteen patients underwent skin biopsy in the PPI group and 12 had histology in keeping with SCLE. The median time to presentation was 8 months with a median resolution period of 6 weeks. PPIs were stopped in 34 patients, while 2 patients continued treatment for other clinical indications. Twelve patients received concurrent oral corticosteroids. Two patients had severe SCLE in the form of Toxic Epidermal Necrolysis requiring critical care admission and were managed with corticosteroids, IV immunoglobulin and/or belimumab. CONCLUSION: Lower limb involvement is a pointer to PPI-induced SCLE which is likely a class effect with all PPI.

Use of Glomerular CD68+ Cells as a Surrogate Marker for Endocapillary Hypercellularity in Lupus Nephritis.

Introduction: Lupus nephritis (LN) class III or IV is strongly related to patient mortality and morbidity. The interobserver agreement of endocapillary hypercellularity by routine light microscopy, one of the most important lesions determining whether class III or IV is present, is moderate. In IgA nephropathy (IgAN), the presence of glomerular CD68+ cells was found to be a good surrogate marker for endocapillary hypercellularity. We investigated whether the presence of glomerular CD68+ cells could serve as a surrogate marker for endocapillary hypercellularity as well in LN. Methods: A total of 92 LN biopsies were scored for the number of glomerular CD68+ cells using CD68 staining, including endocapillary hypercellularity and the activity index (AI). A new AI was calculated in which CD68+ cells replaced endocapillary hypercellularity. Clinical parameters were obtained from time of biopsy, 1 year after, and 2 years after. Results: The number of glomerular CD68+ cells significantly correlated with endocapillary hypercellularity. A cutoff value of 7 for the maximum number of CD68+ cells within 1 glomerulus in a biopsy yielded a sensitivity of 88% and a specificity of 67% for the presence of endocapillary hypercellularity. Both endocapillary hypercellularity and CD68+ cells correlated with renal function during follow-up. The current and the new AI correlated equally well with the clinical outcome. Conclusion: In LN, CD68+ cells can be used as a surrogate marker for endocapillary hypercellularity.

Defective STAT5 Activation and Aberrant Expression of BCL6 in Naive CD4 T Cells Enhances Follicular Th Cell-like Differentiation in Patients with Granulomatosis with Polyangiitis.

Granulomatosis with polyangiitis (GPA) is a potentially fatal small vessel vasculitis of unknown etiology, characterized by anti-neutrophil cytoplasmic autoantibodies, chronic inflammation, and granulomatous tissue damage. T cell dysregulation, comprising decreased regulatory T cell function and increased circulating effector memory follicular Th cells (TFH), is strongly associated with disease pathogenesis, but the mechanisms driving these observations are unknown. We undertook transcriptomic and functional analysis of naive CD4 T cells from patients with GPA to identify underlying functional defects that could manifest in the pathogenic profiles observed in GPA. Gene expression studies revealed a dysregulation of the IL-2 receptor ß/JAK-STAT signaling pathway and higher expression of BCL6 and BCL6-regulated genes in GPA naive CD4 T cells. IL-2-induced STAT5 activation in GPA naive CD4 T cells was decreased, whereas STAT3 activation by IL-6 and IL-2 was unperturbed. Consistently, BCL6 expression was sustained following T cell activation of GPA naive CD4 T cells and in vitro TFH differentiation of these cells resulted in significant increases in the production TFH-related cytokines IL-21 and IL-6. Thus, naive CD4 T cells are dysregulated in patients with GPA, resulting from an imbalance in signaling equilibrium and transcriptional changes that drives the skewed pathogenic CD4 effector immune response in GPA.

Abdominal arterial lesions associated with antiphospholipid antibodies: a comparative cross-sectional magnetic resonance angiography study.

OBJECTIVE: Case reports and small case series suggest that stenotic lesions of the renal, coeliac and mesenteric arteries may occur in the antiphospholipid syndrome (APS) resulting in clinical consequences such as hypertension and abdominal angina. The objective was to determine the prevalence of stenotic lesions in arteries arising from the middle aorta in patients with antiphospholipid antibodies (aPL) compared with healthy, hypertensive and atherosclerotic controls. METHODS: In a cross-sectional comparative radiological study using magnetic resonance angiography (MRA), we assessed five groups of subjects for the prevalence of stenotic lesions in arteries arising from the middle aorta: APS/aPL positive, healthy renal donors, patients with hypertension, patients with atherosclerosis defined radiologically and patients with systemic lupus erythematosus and vasculitis who were negative for aPL. All subjects underwent MRA in suspended respiration and images were assessed by two senior radiologists blinded to the clinical details. RESULTS: In the atherosclerosis group, vascular stenotic lesions were more prevalent (71%) than in any other group (P ≤0.000002). The prevalence of all stenotic lesions in aPL positive patients (33%) was significantly higher than in the renal donors (18%) and hypertensive patients (19%) (P ≤0.009). Renal artery stenosis was significantly more prevalent in aPL positive patients than in renal donors (P ≤0.0006) but similar to the prevalence in hypertensive patients. Coeliac and/or mesenteric lesions were significantly more common in aPL positive patients vs hypertensive patients (P ≤0.001). Stenoses did not correlate with traditional risk factors. CONCLUSION: Arterial stenotic lesions in arteries arising from the middle aorta were highly prevalent in atherosclerotic subjects and were more common in aPL-positive patients than in hypertensive patients and healthy renal donors.

Physician-patient interaction and medication adherence in lupus nephritis.

OBJECTIVE: The quality of physician-patient interaction can have a significant impact on medication adherence. Little is known about this relationship in patients with lupus nephritis. METHODS: A cross-sectional, quantitative study. Data collected included demographics, current medication, systemic lupus erythematosus disease activity index, medication adherence, beliefs about medicines, shared decision-making, patient-doctor depth of relationship, patient-doctor quality of relationship, interpersonal trust in a physician and illness perceptions. RESULTS: Ninety-eight patients with lupus nephritis completed the questionnaires. Logistic regression indicated that medication adherence was significantly predicted by (a) interpersonal trust in a physician (B = 0.85, Wald 3.94, 95% confidence interval (CI) 1.01, 5.44; P = 0.05); (b) timeline cyclical (B = -0.89, Wald 4.95, 95% CI 0.19, 0.90; P < 0.05) and beliefs about the necessity of medicines (B = 0.75, Wald 4.14, 95% CI 1.03, 4.38; P < 0.05). Mediation analysis showed that beliefs about the necessity of medicines significantly mediated the relationship between trust and medication adherence when adjusted for age (B = 0.48, 95% CI 0.06, 1.08; P < 0.01). A further mediation analysis showed that patient-doctor depth of relationship (B = 0.05, 95% CI 0.01, 0.09; P < 0.001), shared decision-making (B = 0.07, 95% CI 0.01, 0.13; P < 0.001) and patient-doctor quality of relationship (B = 0.08, 95% CI 0.01, 0.16; P < 0.001) significantly mediated the relationship between illness coherence and interpersonal trust in a physician. CONCLUSION: The findings highlighted two key elements: (a) the importance of trust in relation to medication adherence; and (b) a good understanding of patients' illness is linked to a better relationship with their doctor and greater participation in shared decision-making which is associated with increased trust. Tailored psycho-educational interventions could contribute to improving the patient-doctor relationship quality, trust and increased shared decision-making, which, in turn, might improve medication adherence in patients with lupus nephritis.

High-sensitive troponin is associated with subclinical imaging biosignature of inflammatory cardiovascular involvement in systemic lupus erythematosus.

BACKGROUND: Cardiovascular (CV) involvement in patients with systemic lupus erythematosus (SLE) is presumably subclinical for the major part of its evolution. We evaluated the associations between high-sensitive troponin T (hs-TropT), a sensitive marker of myocardial injury, and CV involvement using cardiac magnetic resonance (CMR). METHODS AND RESULTS: This is a two-centre (London and Frankfurt) CMR imaging study at 3.0 Tesla of consecutive 92 patients with SLE free of cardiac symptoms, undergoing screening for cardiac involvement. Venous samples were drawn and analysed post-hoc for cardiac biomarkers, including hs-TropT, high-sensitive C reactive protein and N-terminal pro brain natriuretic peptide. Compared with age-matched/gender-matched non-SLE controls (n=78), patients had significantly raised cardiac biomarker levels, native T1 and T2, aortic and ventricular stiffness, and reduced global longitudinal strain (p<0.01). In SLE, hs-TropT was significantly and independently associated with native T2, followed by the models including native T1 and aortic stiffness (Χ2 0.462, p<0.01). There were no relationships between hs-TropT and age, gender, CV risk factors, duration of systemic disease, cardiac structure or function, or late gadolinium enhancement. CONCLUSIONS: Patients with SLE have a high prevalence of subclinical myocardial injury as demonstrated by raised high-sensitive troponin levels. CMR with T2 mapping reveals myocardial oedema as the strongest predictor of hs-TropT release, underscoring the inflammatory interstitial remodelling as the main mechanism of injury. Patients without active myocardial inflammation demonstrate diffuse interstitial remodelling and increased vascular stiffness. These findings substantiate the role of CMR in screening of subclinical cardiac involvement. TRIAL REGISTRATION NUMER: NCT02407197; Results.

New use for an old treatment: Hydroxychloroquine as a potential treatment for systemic vasculitis.

Antimalarials have been an effective and safe treatment for autoimmune rheumatic diseases such as systemic lupus erythematosus for more than a hundred years. There are surprisingly few reports of hydroxychloroquine use in the systemic vasculitides. Hydroxychloroquine has antithrombotic, cardiovascular, antimicrobial and antineoplastic effects, making it a potentially valuable treatment for patients with systemic vasculitis who are at risk of infections, malignancy and thrombotic events. We report the successful use of hydroxychloroquine in patients with ANCA vasculitis, Henoch Schonlein purpura/IgA vasculitis, Takayasu's arteritis and polyarteritis nodosa. We review the immunomodulatory mechanisms of action of hydroxychloroquine and the existing evidence for its use in the treatment of vasculitis, with a particular focus on ANCA subtypes.

Relapsing polychondritis: a clinical review for rheumatologists.

Relapsing polychondritis (RPC) is a rare autoimmune rheumatic disorder that is traditionally classified as a systemic vasculitis. It is characterized by inflammation of cartilage, and typical presenting features include chondritis of the nasal bridge, auricular chondritis, ocular inflammation and involvement of the bronchial tree. Its rarity often leads to considerable delay in establishing a diagnosis and poses a significant management challenge to clinicians, as no conventional guidelines exist. This review summarizes the clinical features of RPC and provides guidance for rheumatologists on making the diagnosis and assessing organ involvement. The current state of RPC management is reviewed, with a focus on the use of the anti-TNF-α agents in patients with pulmonary involvement, the leading cause of mortality and morbidity in RPC.

Cocaine and ANCA associated vasculitis-like syndromes - A case series.

OBJECTIVES: We analysed the spectrum of clinical manifestations of cocaine associated pseudovasculitis. METHODS: Clinical, serological, radiological and histological features of 14 patients with cocaine pseudovasculitis syndromes were included. RESULTS: Twelve patients had significant sinus thickening or erosive disease. Other multi-system manifestations included vasculitic rashes, pulmonary lesions and peripheral neuropathy. All patients had positive ANCA titres at presentation. All patients were managed with corticosteroids +/- methotrexate and co-trimoxazole, 2 patients received cyclophosphamide. CONCLUSIONS: Advanced erosive nasal septal defects and atypical ANCA patterns are suggestive of cocaine induced pseudovasculitis. Complete drug cessation may negate the need for exposure to potent immunosuppressive agents.

Native T1 and T2 mapping by CMR in lupus myocarditis: Disease recognition and response to treatment.

BACKGROUND: Lupus myocarditis is likely more common than recognized clinically due to non-specific symptoms and lack of reliable non-invasive diagnostic tests. We investigated the role of native T1 and T2 in recognition of active myocardial inflammatory involvement in patients with systemic lupus erythematous (SLE). METHODS: 76 patients with clinically suspected lupus myocarditis (14 males, age: 44±16years) underwent quantitative tissue characterization with native T1 and T2 mapping. Normotensive healthy subjects taking no medication served as controls (n=46). Follow-up CMR studies were performed in a total of 35 subjects of which 14 patients received intensified anti-inflammatory treatment, as guided by SLE disease activity. RESULTS: Compared to controls SLE patients had higher inflammatory markers, LV mass, native T1 and T2 values, and reduced longitudinal strain (p<0.01). In patients with a positive troponin test (n=36; 46%), native T1 and T2 were significantly higher (p<0.01) with otherwise similar proportions of diffuse perimyocardial LGE (33%) and pericardial effusion (32%). Sixty-nine patients (83%) had an abnormal native T1, whereas 51 (71%) met diagnostic criteria for acute myocarditis. Follow-up CMRs revealed significantly greater reduction in native T1 and T2 values in patients with intensified anti-inflammatory treatment (p<0.001) with the greatest change observed within the first follow-up period and plateauing thereafter. Native T1 and T2 were significant predictors of treatment response. CONCLUSIONS: Native T1 and T2 mapping support recognition of lupus myocarditis and reflect the response to anti-inflammatory treatment. Native T1 and T2 mapping may support an effective, noninvasive, radiation- and gadolinium contrast-free screening method for lupus myocarditis.

Pulmonary artery aneurysms in Behçet's disease treated with anti-TNFα: A case series and review of the literature.

Behçet's disease (BD) is a systemic inflammatory disorder of unknown aetiology. Pulmonary haemorrhage from ruptured pulmonary artery aneurysms (PAA) in this condition carries a high mortality but treatment has largely been empiric with use of glucocorticoids and cyclophosphamide. Tumour necrosis factor α (TNF-α) was recently recognised as a mediator in the pathogenesis of BD inflammatory lesions. TNFα inhibitors have been shown in various case reports/series to have beneficial effects in uveoretinitis, entero-Behçet's, neuro-Behçet's and BD arthritis. We describe the efficacy and tolerability of infliximab in 2 patients with Behçet's disease complicated by pulmonary vasculitis admitted to our unit during the years 2004-2015, and discuss the previously published data in this area.

Long-term follow-up of the MAINTAIN Nephritis Trial, comparing azathioprine and mycophenolate mofetil as maintenance therapy of lupus nephritis.

OBJECTIVE: To report the 10-year follow-up of the MAINTAIN Nephritis Trial comparing azathioprine (AZA) and mycophenolate mofetil (MMF) as maintenance therapy of proliferative lupus nephritis, and to test different definitions of early response as predictors of long-term renal outcome. METHODS: In 2014, data on survival, kidney function, 24 h proteinuria, renal flares and other outcomes were collected for the 105 patients randomised between 2002 and 2006, except in 13 lost to follow-up. RESULTS: Death (2 and 3 in the AZA and MMF groups, respectively) and end-stage renal disease (1 and 3, respectively) were rare events. Time to renal flare (22 and 19 flares in AZA and MMF groups, respectively) did not differ between AZA and MMF patients. Patients with good long-term renal outcome had a much more stringent early decrease of 24 h proteinuria compared with patients with poor outcome. The positive predictive value of a 24 h proteinuria <0.5 g/day at 3 months, 6 months and 12 months for a good long-term renal outcome was excellent (between 89% and 92%). Inclusion of renal function and urinalysis in the early response criteria did not impact the value of early proteinuria decrease as long-term prognostic marker. CONCLUSIONS: The long-term follow-up data of the MAINTAIN Nephritis Trial do not indicate that MMF is superior to AZA as maintenance therapy in a Caucasian population suffering from proliferative lupus nephritis. Moreover, we confirm the excellent positive predictive value of an early proteinuria decrease for long-term renal outcome. TRIAL REGISTRATION NUMBER: NCT00204022.

Autoimmune rheumatic disease and sleep: a review.

PURPOSE OF REVIEW: Sleep has an important role to play in the human immune system and it is critical in the restoration and maintenance of homeostasis. Sleep deprivation and disorders may have a profound impact on health, well being and the ability to resist infection. Autoimmune rheumatic diseases are multisystem disorders that involve complicated hormonal and immunological pathophysiology. Previous studies have suggested that sleep deprivation may lead to immunological disturbance in experimental mouse models. RECENT FINDINGS: Sleep disorders may trigger immune system abnormalities inducing autoantibody production, possibly leading to the development of autoimmune disease such as systemic lupus erythematosus, scleroderma or rheumatoid arthritis. Indeed, in experimental models, it has been suggested that sleep deprivation may induce the onset of autoimmune disease. SUMMARY: Chronic deprivation of sleep is common in modern society and has been seen in various autoimmune inflammatory rheumatic diseases. We have reviewed various aspects of sleep deprivation and sleep apnoea syndrome, and their effects on the immune system and their relevance to autoimmune diseases. We hope that these data will encourage greater awareness of the role that improved sleep hygiene may play in the management of these rheumatic diseases.