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The association between the use of certain medications (including sulfonamides, hydralazine, and procainamide) and the occurrence of drug-induced lupus or hepatitis is well established. More recently, cases of immune-related adverse events ranging from inflammatory polyarthritis to necrotizing myositis in patients taking checkpoint inhibitors have been reported. However, data linking drugs to systemic vasculitis are scarce and at times debatable. Propylthiouracil, hydralazine, and minocycline have been associated with rare cases of ANCA-associated syndromes, including life-threatening pulmonary-renal syndromes and systemic polyarteritis nodosa-like diseases. Eosinophilic granulomatosis with polyangiitis (EGPA) has been reported in patients taking leukotriene inhibitors. Since the link between the use of leukotriene inhibitors and occurrence of EGPA remains highly controversial, we performed a literature review for cases of EGPA in patients taking montelukast without prior history of oral corticosteroid use. We found 24 cases, along with our own two cases described, making 26 cases in total. The mean age was 43 and a majority (18/26) were female. In majority of cases EGPA-like disease never relapsed after they were taken off leukotriene inhibitors suggesting a clear causal relationship between the use of these drugs and occurrence of eosinophil-rich systemic EGPA.

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Discovery of antinuclear antibodies (ANA) enabled earlier diagnosis of systemic lupus erythematosus (SLE) and other ANA+ connective tissue diseases (CTD). Rheumatologists increasingly encounter high referral volume of ANA+ patients. It has been estimated that only a small percentage of these patients will eventually transition to either SLE or other specified CTD. Incomplete lupus erythematosus (ILE) has been defined as a subset of patients who have some SLE-specific clinical manifestations but do not meet currently accepted classification criteria for SLE. Several studies have been performed with the goal of identifying clinical features, serum and tissue biomarkers that can distinguish those patients with ILE at risk of transitioning to SLE from those who will not. Increased autoantibody diversity, presence of anti-double-stranded DNA (dsDNA) antibodies, high expression of type I and type II interferon (IFN)-gene products, increased serum levels of B-cell-activating factor of the TNF family (BAFF), and certain serum cytokines and complement products have been identified as markers with positive predictive value, particularly when combined together. Once this patient population is better characterized biochemically, clinical trials should be considered with the primary objective to completely halt or slow down the transition from ILE to SLE. Hydroxychloroquine (HCQ) appears to be a promising agent due to its good tolerability and low toxicity profile and open-label studies in ILE patients have already shown its ability to delay the onset of SLE. Other therapeutics, like those targeting abnormal type I and type II IFN-signatures, B-cell specific signaling pathways, complement activation pathways and high BAFF levels should also be evaluated, but the risk to benefit ratio must be carefully determined before they can be considered.

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A 46-year-old female with interstitial lung disease presented with proximal muscle weakness, worsening hypertension, microangiopathic hemolysis, thrombocytopenia and deteriorating renal function. She had no sclerodactyly, but had abnormal capillaroscopy. She tested positive for PM-Scl antibodies, and a renal biopsy showed an acute thrombotic microangiopathy consistent with scleroderma renal crisis (SRC). She failed to respond to corticosteroids, plasmapheresis and renin-angiotensin pathway inhibitors. She recovered quickly with the anti-C5 antibody, eculizumab. She had no genetic abnormalities associated with atypical hemolytic uremic syndrome except a DNA variant of unknown significance in C3. This case suggests that eculizumab may be effective for SRC.

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Toll-like receptor 9 (TLR9) is an endosomal DNA sensor that warns us of the presence of infectious danger and triggers a rapid pro-inflammatory response in dendritic cells, macrophages, and B cells. The consequences of uncontrolled TLR9 activation can be detrimental for the host, contributing to the pathogenesis of bacterial septic shock or autoimmune diseases, such as systemic lupus erythematosus. Therefore, we need to develop TLR9 antagonists. We and others have created inhibitory oligonucleotides (INH-ODN) that are capable of sequence-dependent inhibition of TLR9-induced activation in both human and mouse cells. However, it is not clear whether marked differences in INH-ODN activity related to base sequence derived from polymerization of INH-ODNs or their ability to complex with stimulatory CpG-oligonucleotides (ST-ODN). Furthermore, the 5' end of INH-ODNs may assume a particular loop configuration that may be needed for binding to a critical site on TLR9. Here, we show that 1) G-tetrads required for ODN stacking were compatible with INH-ODN activity but were not necessary; 2) there was no relationship between activity and self-association at endosomal pH; 3) there was no evidence for direct binding between ST-ODNs and INH-ODNs; 4) when a 3G sequence was disrupted, despite a preserved stem-loop formation, INH-ODN activity was abolished. These results support the conclusion that certain features of the primary linear sequence are critical for TLR9 inhibition, but changes in secondary structure or in ODN aggregation are irrelevant.

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Our immune defense depends on two specialized armed forces. The innate force acts as an alarm mechanism that senses changes in the microenvironment through the recognition of common microbial patterns by Toll-like receptors (TLR) and NOD proteins. It rapidly generates an inflammatory response aimed at neutralizing the intruder at the mucosal checkpoint. The innate arm also communicates this message with more specialized adaptive forces represented by pathogen-specific B cells and T cells. Interestingly, B cells also express some innate sensors, like TLR7 and TLR9, and may respond to bacterial hypomethylated CpG motifs and single-stranded RNA viruses. Intracellular nucleic acid sensing TLRs play an important role in the pathogenesis of Systemic Lupus Erythematosus (SLE). In this review, we describe recent achievements in the development of oligonucleotide-(ODN)-based inhibitors of TLR9 and/or TLR7 signaling. We categorize these novel therapeutics into Classes G, R, and B based on their cellular and molecular targets. Several short ODNs have already shown promise as pathway-specific therapeutics for animal lupus. We envision their future use in human SLE, microbial DNA-dependent sepsis, and in other autoinflammatory diseases.

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This review focuses on the role of Toll-like receptors (TLRs) in lupus and on possibilities to treat lupus using TLR modulating inhibitory oligodeoxynucleotides (INH-ODNs). TLRs bridge innate and adaptive immune responses and may play an important role in the pathogenesis of systemic lupus erythematosus. Of particular interest are TLR3, -7, -8, and -9, which are localized intracellularly. These TLRs recognize single-stranded or double-stranded RNA or hypomethylated CpG-DNA. Exposure to higher order CpG-DNA ligands or to immune complexed self-RNA triggers activation of autoreactive B cells and plasmacytoid dendritic cells. INH-ODNs were recently developed that block all downstream signaling events in TLR9-responsive cells. Some of these INH-ODNs can also target TLR7 signaling pathways. Based on their preferential cell reactivity, we classify INH-ODNs into class B and class R. Class B ('broadly reactive') INH-ODNs target a broad range of TLR-expressing cells. Class R ('restricted') INH-ODNs easily form DNA duplexes or higher order structures, and are preferentially recognized by autoreactive B cells and plasmacytoid dendritic cells, rather than by non-DNA specific follicular B cells. Both classes of INH-ODNs can block animal lupus. Hence, therapeutic application of these novel INH-ODNs in human lupus, particularly class R INH-ODNs, may result in more selective and disease-specific immunosuppression.

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