edwardns-autoimmunes-blog

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Managing rheumatic and musculoskeletal diseases: past, present and future

Progress in rheumatology has been remarkable in the past 70years, favourably affecting quality of life for people with rheumatic and musculoskeletal diseases. Therapeutics have advanced considerably in this period, from early developments such as the introduction of glucocorticoid therapy to the general use of methotrexate and other disease-modifying agents, followed by the advent of biologic DMARDs and, most recently, small-molecule signalling inhibitors. Novel strategies for the use of such agents have also transformed outcomes, as have multidisciplinary nonpharmacological approaches to the management of rheumatic musculoskeletal disease including surgery, physical therapy and occupational therapy. Breakthroughs in our understanding of disease pathogenesis, diagnostics and the use of ‘big data’ continue to drive the field forward. Critically, the patient is now at the centre of management strategies as well as the future research agenda.

Nature Reviews Rheumatology

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Negative anti-neutrophil cytoplasm antibody at switch to maintenance therapy is associated with a reduced risk of relapse

Negative anti-neutrophil cytoplasm antibody at switch to maintenance therapy is associated with a reduced risk of relapse

Relapse of disease is frequent in anti-neutrophil cytoplasm antibody (ANCA)-associated vasculitis (AAV). It is unclear whether persistent ANCA when starting maintenance therapy increases the risk of relapse. We examined the association between ANCA status and relapse in two randomised controlled trials.

Methods: ANCA-positive patients in two trials, CYCLOPS and IMPROVE, were switched from cyclophosphamide to maintenance therapy after achieving clinical remission. We classified patients as being either ANCA-positive or ANCA-negative at the time they started maintenance therapy. We compared the risk of relapse in ANCA-positive and ANCA-negative patients.

Results: Of 252 patients included, 102 (40%) experienced at least one relapse during the follow-up period. At the time of the switch from induction to maintenance therapy, 111 were ANCA-positive, of whom 55 (50%) relapsed, compared to 141 patients who were ANCA-negative, of whom 47 (33%) relapsed. In multivariable time-to-event analysis, a reduced risk of relapse was associated with having become ANCA-negative at the time of switching to maintenance therapy (hazard ratio 0.63, 95% confidence interval 0.42–0.95; p = 0.026). In addition, initial proteinase 3 (PR3)-ANCA, younger age, lower serum creatinine, pulsed cyclophosphamide for remission induction, and mycophenolate mofetil for remission maintenance were all associated with an increased risk of relapse.

Conclusions: Becoming ANCA-negative before the switch to maintenance is associated with a reduced risk of relapse

Arthritis Research & Therapy (2017) 19:129

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Repositioning tolcapone as a potent inhibitor of transthyretin amyloidogenesis and associated cellular toxicity

Transthyretin (TTR) is a plasma homotetrameric protein implicated in fatal systemic amyloidoses. TTR tetramer dissociation precedes pathological TTR aggregation. Native state stabilizers are promising drugs to treat TTR amyloidoses. Here the Spanish team repurpose tolcapone, an FDA-approved molecule for Parkinson’s disease, as a potent TTR aggregation inhibitor. Tolcapone binds specifically to TTR in human plasma, stabilizes the native tetramer in vivo in mice and humans and inhibits TTR cytotoxicity. Crystal structures of tolcapone bound to wild-type TTR and to the V122I cardiomyopathy-associated variant show that it docks better into the TTR T4 pocket than tafamidis, so far the only drug on the market to treat TTR amyloidosis. 

These data indicate that tolcapone, already in clinical trials for familial amyloid polyneuropathy,  has the potential of becoming an efficacious small molecule to prevent the onset of TTR deposition diseases; tolcapone could be in the market in a relatively short time frame as it has already entered into clinical trials. The unique ability of tolcapone to penetrate the blood–brain barrier and to reduce A25T-TTR aggregation indicate that it could become the first pharmacologic treatment available for TTR leptomeningeal amyloidosis.

Nat Commun. 2016 Feb 23;7:10787

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Suppression of DC cholesterol efflux pathways might have a role in the pathogenesis of autoimmune diseases

Plasma high-density lipoproteins (HDL) concentrations are reduced in patients with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). These patients have an increased risk of cardiovascular disease (CVD) that cannot be explained by traditional risk factors. Recent studies have suggested that the capacity of HDL to function as an acceptor for cholesterol efflux is a better predictor of incident CVD than plasma HDL cholesterol concentrations. Interestingly, RA disease activity is inversely correlated with the capacity of HDL to function as an acceptor for cellular cholesterol efflux. Apolipoprotein A1 (ApoA1) and HDL mediate the efflux of cholesterol from immune cells via the ATP binding cassette transporters A1 and G1 (ABCA1 and ABCG1). Whether low HDL and efflux pathways have a causal relationship to autoimmune diseases is unknown.

To investigate this hypothesis, the researchers characterized the phenotype of mice deficient in both Abca1 and Abcg1. After 40 weeks on a chow diet, these mice showed glomerulonephritis and enlarged lymph nodes, consistent with autoimmunity. Further analysis using tissue-specific knockout mice indicated that deficiency of Abca1 and Abcg1 in dendritic cells (DCs), but not in macrophages or T cells, led to this autoimmune phenotype, which was also characterized by increased plasma levels of double-stranded DNA antibodies similar to those seen in patients with SLE.

Inflammatory stimuli, such as interferon-ɣ or TLR3/4 activation, suppress cholesterol efflux pathways. This study suggest that, in autoimmune disorders such as SLE or RA, inflammatory suppression of HDL levels and of cholesterol efflux pathways and cholesterol accumulation in DCs amplifies autoimmune responses.

Cell Metab. 2017 May 4

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Effect of Continuous B Cell Depletion With Rituximab on Pathogenic Autoantibodies and Total IgG Levels in Antineutrophil Cytoplasmic Antibody–Associated Vasculitis

Retrospective analysis of 239 patients with AAV treated with rituximab-induced continuous B cell depletion. Two treatment cohorts were analyzed: an induction group (n = 52) and a maintenance group (n = 237). Changes in ANCA titers and total Ig levels over time were evaluated using mixed-effects models. Risk factors for serious infections during maintenance treatment were evaluated using Poisson regression.

During induction, IgG levels fell at a mean rate of 6% per month (95% confidence interval [95% CI] 4, 8%), while ANCA levels declined at a mean rate of 47% per month (95% CI 42, 52%) and 48% per month (95% CI 42, 54%) for patients with antimyeloperoxidase (anti-MPO) antibodies and those with anti–proteinase 3 (anti-PR3) antibodies, respectively. 

During maintenance treatment, with a median duration of 2.4 years (interquartile range 1.5, 4.0 years), IgG levels declined a mean of 0.6% per year (95% CI −0.2, 1.4%). New significant hypogammaglobulinemia (IgG level of <400 mg/dl) during maintenance treatment occurred in 4.6% of the patients, all of whom were in the lowest baseline IgG quartile. Serious infections during maintenance therapy occurred at a rate of 0.85 per 10 patient-years (95% CI 0.66, 1.1) and were independently associated with an IgG level of <400 mg/dl.

Conclusion >> B cell–targeted therapy causes a preferential decline in ANCA titers relative to total IgG levels. Despite prolonged maintenance therapy with rituximab, IgG levels remain essentially constant. Serious infections were rare

Arthritis & Rheumatology, 69: 1045–1053 Source: onlinelibrary.wiley.com

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Giant Cell Arteritis–related Stroke: A Retrospective Multicenter Case-control Study

Retrospective multicenter cohort of patients with (1) GCA diagnosed according to the American College of Rheumatology criteria between 1995 and 2015, and (2) stroke occurring at the time of GCA diagnosis or occurring within 4 weeks of starting GCA therapy. The control group consisted of GCA patients without stroke.

Results. Forty patients [21 women (53%), median age 78 (60–91) yrs] with GCA-related stroke were included and were compared with 200 control patients. Stroke occurred at GCA diagnosis in 29 patients (73%), whereas it occurred after diagnosis in 11 patients. Vertebrobasilar territory was involved in 29 patients (73%). Seven patients died within a few hours or days following stroke. Compared with the control group, stroke patients had more ophthalmic ischemic symptoms [25 (63%) vs 50 (25%), p < 0.001]. Conversely, they demonstrated lower biological inflammatory variables [C-reactive protein: 61 (28–185) mg/l vs 99 (6–400) mg/l, p = 0.04] and less anemia [22/37 (59%) vs 137/167 (79%), p = 0.03] than patients without stroke. Multivariate logistic regression revealed that the best predictors for the occurrence of stroke were the presence of ophthalmic ischemic symptoms at diagnosis (OR 5, 95% CI 2.14–12.33, p = 0.0002) and the absence of anemia (OR 0.39, 95% CI 0.16–0.99, p = 0.04).

Conclusions. Stroke is a rare and severe ischemic complication that may develop in patients with recently diagnosed GCA. It is more likely to occur in the vertebrobasilar territory and in patients who experience ophthalmic ischemic symptoms with low inflammatory variables. Treatment relies on GC and at least longterm antiplatelet agents, because stroke can occur within a few days or weeks of GC onset. Therefore, further prospective studies are still required to define the involvement of anticoagulants and IV methylprednisolone bolus medication in this setting.

The Journal of Rheumatology March 2017, 44 (3) 297-303

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Trigger for autoimmune disease identified

Mer–/– and Nba2 mice with B cell–specific T-bet deletion exhibit reduced titers of autoantibodies, and reduced frequency of CD11c+ and GC B cells

Researchers at National Jewish Health have identified a trigger for autoimmune diseases such as lupus, Crohn's disease and multiple sclerosis. The findings, published in the April 2017 issue of Journal of Clinical Investigation, help explain why women suffer autoimmune disease more frequently than men, and suggest a therapeutic target to prevent autoimmune disease in humans.

B cells are important players in autoimmune disease. The National Jewish Health research team, led by Chair of Biomedical Science Philippa Marrack, PhD, previously identified a subset of B cells that accumulate in autoimmune patients, autoimmune and elderly female mice. They named the cells Age-associated B cells, or ABCs. Subsequent research showed that the transcription factor T-bet plays a crucial role in the appearance of ABC The findings are important as they are the first evidence that ABCs are drivers of autoimmune disease rather than merely a link to autoimmune disease. ABCs have drawn significant interest since being discovered six years ago. The National Jewish Health research team has expanded its analysis of ABCs outside of autoimmune disease. They are currently studying ABCs involvement in chronic beryllium disease, hypersensitivity pneumonitis and sarcoidosis

J Clin Invest. 2017

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Excess atherosclerosis in systemic lupus erythematosus,—A matter of renal involvement: Case control study of 281 SLE patients and 281 individually matched population controls

Systemic lupus erythematosus (SLE), is a heterogeneous disease which predominantly affects young females (90%). SLE is associated with a shorter life expectancy than in the general population. Standardized mortality ratios (SMR) of 2.4 have been reported, which is comparable to diabetes. In modern societies cardiovascular disease (CVD) is the major cause of premature mortality. Accelerated atherosclerosis is generally assumed to be the underlying cause for SLE related CVD. However, previous studies diverge regarding whether atherosclerosis is more common in SLE than in controls. 

Hypothesis >> accelerated atherosclerosis is not a general feature of SLE, but prevails in SLE subgroups.

PLoS ONE, april 2017

281 SLE patients and 281 individually age and sex matched population controls, were investigated clinically. Fasting blood samples and risk factor data were collected. All participants were subject to B-mode ultrasonography of the carotid arteries. Carotid plaque occurrence and mean intima media thickness (mIMT) were recorded. Two SLE subgroups previously described to be at high CVD risk; 1) patients with nephritis and 2) patients with anti-phospholipid antibodies (aPL), and one subgroup reported to be at comparatively lower CVD risk; patients positive for Sjögren´s syndrome antigens A/B (SSA/SSB) antibodies were analyzed separately in comparison with their respective matched controls.

Results

Median age was 49 (IQR 36–59) years, 93% were females. Manifest CVD; ischemic heart, cerebro- and peripheral vascular disease, prevailed in patients (12% vs. 1%, p<0.0001). Overall plaque prevalence did not differ (20% vs. 16%), but patients had slightly higher mIMT than controls (0.56 vs. 0.53 mm, p<0.0033). After age adjustment plaques, but not mIMT, remained associated with previous CVD events. Therefore we focused further analyses on plaques, a more robust measure of atherosclerosis. Patients with nephritis (40%), but neither aPL (25%) nor SSA/SSB (40%) positive patients, had more plaques than their respective controls (23% vs. 11%, p = 0.008). Notably, patients with nephritis were younger than other SLE patients (45 vs.49 years, p = 0.02). To overcome the confounding effect of age we performed an age-matched nested case-control analysis, which demonstrated that patients with nephritis had twice as often plaques (23%) as both non-nephritis patients (11%, p = 0.038) and controls (12%, p = 0.035).

Conclusions

In SLE excess carotid plaques are essentially confined to the SLE subgroup with nephritis. This subgroup had plaques twice as often as age-matched non-nephritis SLE patients and population controls. Non-nephritis SLE patients, including the aPL positive subgroup, which has a high CVD risk, had similar prevalence of plaques as controls. To prevent later CVD events, this novel observation calls for risk factor screening and initiation of anti-atherosclerotic treatment selectively in SLE nephritis patients. Preferably at nephritis onset, which is often at a young age. In a general perspective this study demonstrates the importance to perform careful clinical subgroup analyses when investigating heterogeneous, hitherto not clearly defined, conditions like SLE.

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Isolated Tricuspid Valve Libman-Sacks Endocarditis in Systemic Lupus Erythematosus with Secondary Antiphospholipid Syndrome

Systemic lupus erythematosus (SLE) is an inflammatory disease with multi- organ involvement. In patients with SLE, Libman-Sacks endocarditis most frequently affects the aortic and mitral valves. The echocardiographic presentation of Libman-Sacks endocarditis includes leaflet thickening, and masses or verrucous vegetations that cause regurgitation. Tricuspid valve (TV) involvement, particularly in isolation, is rarely seen in SLE. Secondary antiphospholipid syndrome (APLS) increases the severity of valvular disease in SLE.

Case of a 47-year-old woman with lupus and antiphospholipid syndrome whose massive tricuspid regurgitation was caused by Libman-Sacks endocarditis isolated to the tricuspid valve

Texas Heart Inst J 2017 Apr 1