B Lymphocytes in Rheumatoid Arthritis and the Effects of Anti-TNF-α Agents on B Lymphocytes: A Review of the Literature.

PURPOSE: The aim of this article was to review published research related to B lymphocytes in rheumatoid arthritis, their role in the pathogenesis of the disease, the effects of tumor necrosis factor (TNF)-α inhibitors on B lymphocytes, the risk for infection, and responses to vaccines. METHODS: A PubMed search was conducted to review recent advances related to B lymphocytes and the effects of anti-TNF-α on B lymphocytes in rheumatoid arthritis. FINDINGS: B lymphocytes play an important role in the pathogenesis of rheumatoid arthritis. In this review, we summarize the major mechanisms by which B lymphocytes play a pathologic role in the development and propagation of the disease, as B lymphocytes are recruited to the synovial fluid, where they contribute to local inflammation through the secretion of pro-inflammatory mediators (cytokines, chemokines, micro-RNAs) and present antigens to T cells. We discuss the effects of TNF-α, either direct or indirect, on B lymphocytes expressing receptors for this cytokine. We also show that total B-cell numbers have been reported to be reduced in the blood of patients with rheumatoid arthritis versus healthy controls, but are significantly increased up to normal levels in patients undergoing anti-TNF-α therapy. As for B-cell subsets, controversial results have been reported, with studies showing decreased frequencies of total memory B cells (and memory subsets) and others showing no differences in patients versus healthy controls. Studies investigating the effects of anti-TNF-α therapy have also given controversial results, with therapy found to increase (or not) the frequency of memory B lymphocytes, in patients with rheumatoid arthritis versus healthy controls. Those highly variable results could have been due to differences in patient characteristics and limited numbers of subjects. Finally, we summarize the effects of blocking TNF-α with anti-TNF-α agents on possible infections that patients with rheumatoid arthritis may contract, as well as on responses to vaccination. IMPLICATIONS: B lymphocytes play a significant role in the pathogenesis of rheumatoid arthritis, and B cell-depletion therapy has a major effect on the course of the disease. The advances in treatment of rheumatoid arthritis include the development of targeted therapies. Anti-TNF-α therapies are widely used despite potentially serious adverse events. The data on the effects of anti-TNF-α therapies on B lymphocytes are limited and conflicting. There is a need for larger studies to better understand the effects of newly discovered therapies on the different cells of the immune system.

Opioid associated intravenous and cutaneous microvascular drug abuse (skin-popping) masquerading as Degos disease (malignant atrophic papulosis) with multiorgan involvement.

BACKGROUND: In 2012, a nephrologist reported the development of a multiorgan thrombotic syndromic complex resembling thrombotic thrombocytopenic purpura (TTP) in patients who were abusing long acting oxymorphone hydrochloride; all patients had hemolytic anemia and thrombocytopenia. OBJECTIVE: Herein, we report another case involving a 31-year-old woman who self intravenously administered dissolved oral oxymorphone resulting in thrombotic sequelae resembling Degos disease. METHODS: Formalin-fixed and paraffin embedded skin biopsies were prepared according to standard protocols for H&E and immunohistochemistry. RESULTS: The clinical presentation and biopsy findings were held to be indicative of Degos disease/malignant atrophic papulosis (MAP) but with unusual clinical features including renal failure and severe respiratory insufficiency. Given the efficacy of eculizumab in the treatment of the acute thrombotic phase of Degos disease/MAP, the patient received this drug, resulting in rapid resolution of signs and symptoms associated with her multiorgan failure. Although she developed recurrent cutaneous ulcers despite complete complement inhibition with eculizumab., her other extracutaneous manifestations did not recur. The patient's pre and post eculizumab skin biopsies showed a striking pauci-inflammatory thrombogenic vasculopathy associated with marked endothelial cell injury along with deposits of C3d and C4d within the cutaneous vasculature; the C5b-9 deposits were limited to the pre-eculizumab biopsy. We discovered that her syndromic complex was a self-inflicted one related to the localized administration of dissolved oxymorphone. CONCLUSION: Our patient's biopsy along with the rapid response to eculizumab indicates that this distinct thrombotic microangiopathy is another complement mediated thrombotic microangiopathy syndrome. Opioid thrombotic microangiopathy has a varied clinical presentation and can mimic other catastrophic microangiopathy syndromes, all of which have in common a responsiveness to complement inhibition.

Subcutaneous nodules are associated with cardiovascular events in patients with rheumatoid arthritis: results from a large US registry.

Subcutaneous nodules are the most common conspicuous extra-articular manifestation of rheumatoid arthritis (RA). Cardiovascular disease (CVD) is the leading cause of death in patients with RA. The objective of this study is to examine the possibility of a relationship between subcutaneous nodules and "first ever" cardiovascular disease event, i.e., myocardial infarction (MI), stroke, or cardiovascular death in a large registry-cohort of patients with RA. Patient information was collected from the CORRONA registry from October 2001 to September 2011. A total of 26,042 patients with RA were studied for the presence or absence of subcutaneous nodules. Cox proportional hazards regression models were constructed to estimate the hazard ratios (HR) for CVD events in relation to subcutaneous nodules at baseline. Three statistical models were used to examine the association between subcutaneous nodules and CVD: Model A adjusted for age and sex associated risk, model B adjusted for traditional CV risk factors, and model C adjusted for factors in models A and B plus underlying RA-specific measures. The definition of primary exposure was "subcutaneous nodules at baseline." A total of 3908 patients had subcutaneous nodules at baseline. Of the 566 total composite CVD events, 138 occurred in the group that had SCN at baseline. Incidence rate-ratio values (patients with subcutaneous nodules at baseline vs. no subcutaneous nodules at baseline) for composite CVD events, MI, stroke, and cardiovascular death were 1.55, 1.65, 1.37, and 1.68, respectively. Adjusted HR values (95 % CI) for composite CVD events based on "subcutaneous nodules-status at baseline" (primary exposure) were as follows: 1.35 (1.11-1.63) for model A, 1.25 (1.03-1.52) for model B, and 1.03 (0.831-1.277) for model C. Subcutaneous nodules were associated with increased CVD events in RA. This association persisted after adjusting for age, sex, and traditional CV risk factors.