Current and Emerging Treatment Options for ANCA-Associated Vasculitis: Potential Role of Belimumab and Other BAFF/APRIL Targeting Agents

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) comprises several clinical entities with diverse clinical presentations, outcomes, and nonunifying pathogenesis. AAV has a clear potential for relapses, and shows unpredictable response to treatment. Cyclophosphamide-based therapies have remained the hallmark of induction therapy protocols for more than four decades. Recently, B-cell depleting therapy with the anti-CD20 antibody rituximab has proved beneficial in AAV, leading to Food and Drug Administration approval of rituximab in combination with corticosteroids for the treatment of AAV in adults. Rituximab for ANCA-associated vasculitis and other clinical trials provided clear evidence that rituximab was not inferior to cyclophosphamide for remission induction, and rituximab appeared even more beneficial in patients with relapsing disease. This raised hopes that other B-cell-targeted therapies directed either against CD19, CD20, CD22, or B-cell survival factors, B-cell activating factor of the tumor necrosis factor family (BAFF) and a proliferation-inducing ligand could also be beneficial for the management of AAV. BAFF neutralization with the fully humanized monoclonal antibody belimumab has already shown success in human systemic lupus erythematosus and, along with another anti-BAFF reagent blisibimod, is currently undergoing Phase II and III clinical trials in AAV. Local production of BAFF in granulomatous lesions and elevated levels of serum BAFF in AAV provide a rationale for BAFF-targeted therapies not only in AAV but also in other forms of vasculitis such as Behcet\u27s disease, large-vessel vasculitis, or cryoglobulinemic vasculitis secondary to chronic hepatitis C infection. BAFF-targeted therapies have a very solid safety profile, and may have an additional benefit of preferentially targeting newly arising autoreactive B cells over non-self-reactive B cells

Spotlight on Blisibimod and Its Potential in the Treatment of Systemic Lupus Erythematosus: Evidence to Date

B cells in general and BAFF (B cell activating factor of the tumor necrosis factor [TNF] family) in particular have been primary targets of recent clinical trials in systemic lupus erythematosus (SLE). In 2011, belimumab, a monoclonal antibody against BAFF, became the first biologic agent approved for the treatment of SLE. Follow-up studies have shown excellent long-term safety and tolerability of belimumab. In this review, we critically analyze blisibimod, a novel BAFF-neutralizing agent. In contrast to belimumab that only blocks soluble BAFF trimer but not soluble 60-mer or membrane BAFF, blisibimod blocks with high affinity all three forms of BAFF. Furthermore, blisibimod has a unique structure built on four high-affinity BAFF-binding peptides fused to the IgG1-Fc carrier. It was tested in phase I and II trials in SLE where it showed safety and tolerability. While it failed to reach the primary endpoint in a recent phase II trial, post hoc analysis demonstrated its efficacy in SLE patients with higher disease activity. Based on these results, blisibimod is currently undergoing phase III trials targeting this responder subpopulation of SLE patients. The advantage of blisibimod, compared to its competitors, lies in its higher avidity for BAFF, but a possible drawback may come from its immunogenic potential and the anticipated loss of efficacy over time

2020 American College of Rheumatology Guideline for the Management of Gout

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/155484/1/art41247.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/155484/2/art41247_am.pd

Association of Combined Autoreactivity to Sm/RNP Common Motif and U1 RNP With Mixed Connective Tissue Disease and Systemic Lupus Erythematosus

Objective This study aimed to evaluate the clinical features in patients with suspected connective tissue disease who tested positive for anti‐Sm/RNP common motif antibody with or without associated anti‐RNP antibody. Methods The titers of anti‐Sm/RNP and anti‐RNP antibodies were measured by the multiplex solid‐phase bioassays (Bio‐Rad). Clinical manifestations were compared among the three subgroups (RNP only, Sm/RNP only, and double positive for RNP and Sm/RNP). Patients were further evaluated for the diagnosis of mixed connective tissue disease (MCTD) and/or systemic lupus erythematosus (SLE) using accepted classification criteria. Results A total of 133 patients were included in this study. The rates of inflammatory arthritis and Raynaud phenomenon were significantly higher in patients testing positive for both anti‐RNP and anti‐Sm/RNP antibodies compared to anti‐RNP only or anti‐Sm/RNP only (69.1% vs 28.8% vs 25.0%, P < 0.0001 for arthritis and 59.5% vs 23.3% vs 37.5%, P = 0.0005 for Raynaud phenomenon). Area under the curve (AUC) values were 0.68 (95% confidence interval [CI] 0.59–0.77, P < 0.0001) for anti‐Sm/RNP titers and 0.65 (95% CI 0.55–0.74, P = 0.0039) for anti‐RNP titers with inflammatory arthritis. AUC values were 0.67 (95% CI 0.58–0.77, P = 0.0002) for anti‐Sm/RNP titers and 0.59 (95% CI 0.49–0.69, P = 0.0352) for anti‐RNP titers with Raynaud phenomenon. The odds ratios for the diagnosis of MCTD and SLE were significantly higher in patients with double positivity compared to those testing solely positive for anti‐RNP antibody. Conclusion Anti‐Sm/RNP common motif autoreactivity when combined with anti‐RNP antibody positivity identifies those patients who are closely related with certain clinical manifestations and who are associated with well‐defined connective tissue disease such as MCTD or SLE

Diagnostic Dilemma of Disseminated Histoplasmosis Mimicking Hemophagocytosis Lymphohistiocytosis in Patient with Rheumatoid Arthritis on Anti-TNF Therapy: Case Report and Review of the Literature

Tumor necrosis factor inhibitors (TNFi) have become the cornerstone for the treatment of rheumatoid arthritis and other systemic autoimmune conditions. However, these biologic DMARDs can lead to various opportunistic infections such as viral infection, tuberculosis, and histoplasmosis. Furthermore, these biologics can also cause severe systemic inflammatory reactions known as hemophagocytosis lymphohistiocytosis (HLH) that can lead to multiorgan failure and high mortality. Due to overlapping clinical features and time-intensive microbiological culture methods, distinguishing between HLH and opportunistic infections can be challenging early in the disease course. We present a similar situation with our patient where the patient met the diagnostic criteria for HLH however was found to have disseminated histoplasmosis. This case uniquely evaluates the utility of the HLH diagnostic criteria and hemophagocytosis for accurate diagnosis of HLH