Was 2014 the annus mirabilis of autoimmunity?

Over the past few years [1], this manuscript has become a regular appointment in the literature to provide a quick overview of the publications dedicated to autoimmunity in the previous solar year. Indeed, each year, we witnessed a steady growth in the absolute number of articles retrieved from PubMed and calculated the ratio among publications in the significantly wider field of immunology. The case of 2014 stands out compared to previous editions as this year was associated with the steepest increase in the absolute number of publications (+28 %) (Fig. 1a) with a stable ratio with the immunology publications around 5 % (Fig. 1b). Our PubMed search performed in July 2015 retrieved 2713 articles published in English between January 1st and December 31st 2014 with ‘autoimmunity’ as keyword. The absolute increase is somehow surprising compared to the previous stability over the previous years (Fig. 1a). Among publications from 2014, we performed a preliminary search using the ‘autoimmunity’ keyword within the major journals in the areas of immunology (Nature Immunology, Nature Medicine, Clinical and Experimental Immunology, and Clinical Reviews in Allergy and Immunology) and autoimmunity (Autoimmunity, Autoimmunity Reviews, and Journal of Autoimmunity) and arrayed the identified articles according to major topics. We arbitrarily selected some articles for further discussion. Among the numerous possibilities, this year, we evaluated new developments in specific clinical settings, i.e., autoimmune and chronic inflammatory diseases, along with common mechanisms which are gathering significant scientific support and point to a therapeutic use. We are well-aware that this choice implies that data on rare and orphan conditions are overlooked [2], as in the case of Behcet disease [3–8], relapsing polychondritis [9, 10], vasculitidies [11–16], myasthenia gravis [17–20], primary immunodeficiencies [21, 22], and others [3, 23–35]. Furthermore, we chose not to address the intriguing field of autoimmunity and cancer which is 2014 has been the subject of numerous studies [36–40].

Fig. 1
figure 1

Full articles in English published during 2013 and previous years were retrieved from PubMed using the search word ‘autoimmunity’. The yearly trends in absolute numbers (a) and as ratio within publications retrieved using ‘immunology’ (b) are represented

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Systemic lupus erythematosus (SLE)

The literature on systemic lupus erythematosus (SLE) during 2014 covered numerous aspects of this complex disease which remain the paradigm for the overlap between internal medicine and rheumatology [41] with variable clinical manifestations [42, 43] and epidemiology which was analyzed in France [44], while clinical patterns may be variable across countries, as illustrated by data from an international European registry [45] and by data on the genetic susceptibility in the Chinese [46, 47] and other populations [48]. Despite recent progress with effective biologics and classical treatments [49], there is a significant unmet need for new therapeutic targets in SLE [50]. Importantly, reports illustrate that the major remaining outcome which most significantly affects survival of patients with SLE is the cardiovascular risk [51] while in a subgroup of patients the risk of specific cancers could be elevated [52]. In the case of thrombotic events, one should rule out the presence of anti-phospholipid syndrome [53] which, while straightforward in cases with typical serological profiles, may be challenging during the acute phases and warrant a specific treatment with recent encouraging data on the protective effects of aspirin [54]. In this group of patients, recent international meetings provided an update on the treatment guidelines [55–57] while more attention should be provided to the most severe forms such as pediatric [58] and neurological cases [59] as well as the classical obstetric manifestations [60]. Recent data also continue to support the direct pathogenetic role of anti-phospholipid antibodies [61], particularly those directed at beta-2 glycoprotein I [62] which may be targeted with elegant treatments [63]. Further, reports suggest new non-invasive tools such as fetal DNA to screen for potential complications [64], that different serum autoantibodies may be associated with the thrombotic risk [65, 66], while the syndrome could be mediated by T regulatory cells [67]. Remaining on clinical grounds, we welcome a comprehensive evaluation of the challenging differential diagnosis with drug-induced autoimmune manifestations [68], mixed connective tissue disease [69], or other conditions including infections and malignancies [70] and the viewpoints provided on the safety and effectiveness of vaccinations in patients with SLE [71]. Translational evidence in the broad field of SLE includes the identification of serum anti-ribosomal-P autoantibodies influencing the renal manifestations [72] similar to the classical anti-double stranded DNA autoantibodies for which a pathogenetic role is strongly supported [73], the role of B cell DNA methylation of specific genes [74] within the broad area of the epigenetics [75–77] and signaling [78] in SLE and the possible links with cytokine alterations [79, 80], possibly through genetic polymorphisms of the oncostatin M receptor (OSMR) activating JAK/STAT and MAPK pathways, and the central role of B cells in disease perpetuation [81]. Among new candidates for SLE initiation and modulation, we should mention the hypotheses related to parasitic [82, 83] or other infections [84] while the study of microRNA and epigenetics [85–87], or IL17 contribution to disease pathogenesis [88–90], remains a hot topic in SLE. Of relevance to SLE, the study of Sjogren syndrome [91–93] provides important clinical observations related to common reproductive factors [94] and diagnostic imaging methods [95]. From an experimental standpoint, data in this related connective tissue disease support the role of autoreactive T cells [96, 97], double negative T cells [98], autoantigen expression in target tissues [99], Th17 cells [100], or candidate biomarkers of disease [101].

Rheumatoid arthritis (RA)

Rheumatoid arthritis (RA) continues to drive a significant amount of research from both basic and clinical groups, and the novel reevaluation of patient classification should be considered when comparing past and future results in patients arrayed according to different criteria [102] or the possible overlapping with other conditions with different clinical manifestations [103, 104] or age of onset [105, 106] with possible diagnostic challenges with seronegative arthritides [107–109]. We may also expect that laboratory data connection with the disease phenotype will continue to gain importance, as demonstrated for genetics [110] and serum autoantibodies against citrullinated peptides [111, 112]. Furthermore, we also read with great interest the newest literature on less common and potentially threatening manifestations such as the cervical vertebral involvement [113] and the cardiac arrhythmias linked to chronic inflammation [114]. Laboratory research pointed at specific features of RA with the identification of new IL17-dependent mechanisms of bone resorption [115], B cell activation profiles in the presence of B cell depleting treatments such as rituximab [116], unexpected links between innate immunity via toll like receptors [117] and synoviocytes [118], and the role of posttranslational modification in autoantigen establishment [119]. Possibly more than in any other rheumatic disease, our therapeutic armamentarium to treat RA has grown significantly over the past decade [120, 121] with numerous biologics now targeting pro-inflammatory molecules such as TNFalpha or IL6 [122], or cell costimulation which may result in a more prominent effect in early stages [123]. A better definition of the safety and efficacy profiles of these treatments is now established [124, 125], and data on biosimilars are awaited to define the clear positioning of these less expensive treatments in the therapeutic flowchart [126], and a fine immunological typing of patients to chose the best treatment remains the ultimate goal [127]. We should underline that methotrexate remains the backbone of any biologic treatment for RA with acceptable safety [128], and data on drug retention confirm the synergy between classical and biological treatments [129] with possible new mechanisms [130]. Finally, it is intriguing that less obvious factors involved in RA onset and perpetuation include obesity [131] and the socioeconomic status [132], although a direct cause-effect relationship is difficult to establish, and we may submit that new evidence in the next months will point to new cytokines [133–136] and chemokines [137] or new genetic functional testing [138, 139] for autoimmunity and RA.

Seronegative arthritides

Despite the jury being still out on the autoimmune features of seronegative spondyloarthropathies, we are convinced that the skin, articular, metabolic, and systemic manifestations of this condition represent a continuum [107, 108, 140] in which similarities with autoimmune diseases (especially rheumatoid arthritis) significantly outnumber differences, similar to inflammatory bowel disease [109, 141–147]. Indeed, the recent progress in the understanding of the pathogenesis of psoriatic disease represents a significant breakthrough which is rapidly opening new therapeutic avenues, as in the case of treatments targeting the IL12/IL23 axis [148], IL17 [149, 150], or other molecular mechanisms [151]. We are particularly intrigued by the recent statements from a joint multispecialist effort to target these conditions which, as in the case of skin or gut manifestations, represent the ideal arena for a multidisciplinary management [152].

Conclusions and hopes for the current year

During the year 2014, we were particularly intrigued by the new scenarios appearing in the field and by the capacity of researchers and physicians worldwide to provide comprehensive reviews and recommendations in the most popular areas of clinical and research activity. As mentioned, this was mirrored by a surprising increase in the number of published articles which may, however, not constitute the ideal marker for the activity and success in this research area. As we have done in the previous years, we herein attempted to provide a bird’s eye view of arbitrarily selected articles that were published in 2014. Nonetheless, we feel that other overlooked reports from our literature search may prove key to future discoveries. Among these, new developments are expected to stem from the interaction between T regulatory cells and B cell anergy in lupus models [81], the role of IL4 in B cell maturation [153], the network connecting innate immunity with autoimmunity via TLRs [36, 117, 154–159], the growing role of the PTPN22 kinase [17, 138, 139, 160, 161], or the new data on T regulatory cells [162] or T cell receptors [163, 164]. While we cannot foresee the number of publications related to autoimmunity in 2015, it is to be expected that new data will be possibly more intriguing compared to 2014.