Autoinflammation behind the curtain
Tumor, rubor, calor, dolor, functio laesa are translated from Latin as swelling, redness, heat, pain and impaired function these have been the hallmarks of inflammation since the beginning of clinical medicine. Even though nothing has changed over the years in the actual clinical phenotype of our patients, each clinician's perception of inflammatory diseases is constantly evolving prompted by improved understanding of the pathophysiology. However, medicine changes slowly and it can take many years for new findings to be integrated into clinical thinking. The four scholarly reviews in this issue of the BJD address this slow pivot that is currently taking place in dermatology. Two decades ago, a whole new class of inflammatory diseases was identified that had been previously classified incorrectly as autoimmune conditions. These diseases produce sterile inflammation without concomitant detectable autoimmune primed B or T cells. As genetic risk factors were found that lead to production of innate immune cytokines and often fever, they were called autoinflammatory diseases. Interestingly, even though this class of diseases was founded based on evidence primarily from rare genetic conditions, in recent years several much more frequent conditions were identified to be autoinflammatory, such as gout. Rather than producing swarms of B and T cells as in autoimmune conditions, these autoinflammatory diseases feature masses of neutrophils, granulocytes and macrophages. Often also associated is the typical signature cytokine pattern of interleukin (IL) 1, with the subtype IL 1b being the most heavily investigated so far. Dermatology is a traditional clinical specialty in the process of being transformed by the increasing rate of in depth exploration of molecular pathophysiology. At the moment, disease classification is heavily dependent on clinical features. This explains why many conditions have lengthy Latin names that are purely descriptive rather than indicating true understanding of the diseases' inner workings. Indeed, dermatology has whole classes of diseases that are based merely on the excessive cutaneous presence of certain inflammatory cell types. Neutrophilic dermatoses, such as the ulcer forming pyoderma gangrenosum, as well as fever and succulent plaqueforming Sweet syndrome, were originally defined by their histological pattern of cellular infiltration of the skin by polymorphonuclear leucocytes. These conditions arise spontaneously or are triggered by trauma, drugs or other stimuli such as infections and certain types of systemic disease. Subsequently, they produce intense and destructive inflammatory infiltrates without any discernible B cell derived autoantibody titres or even primed T cells. With the newly identified sterile, neutrophil rich autoinflammatory diseases, the neutrophilic dermatoses have now become likely candidates for being reclassified as autoinflammatory conditions. Increasing evidence suggests that autoinflammation underlies these conditions. Indeed, IL 1b is found in both conditions, and in pyoderma gangrenosum IL 1b has even been shown to be a successful biological treatment target. Whether a genetic risk factor is at play, like in the classic autoinflammatory diseases CAPS (cryopyrin associated periodic syndrome) TRAPS (tumour necrosis factor receptorassociated periodic syndrome) and others, remains to be demonstrated and is the focus of intense investigation in several laboratories. In their scholarly review in the current issue of the BJD, Satoh et al. explain these considerations in detail. Another class of diseases that may be ripe for reclassification is the realm of acne. Acne vulgaris and its intertriginous counterpart hidradenitis suppurativa (HS) are traditionally understood as multifactorial diseases with involvement of genetic risk factors, bacterial overgrowth of Propionibacterium acnes, keratinocyte hyperproliferation, seborrhoeic hyperactivity and hormonal triggers. However, bacterial presence has been found to be a minor or even irrelevant factor, as microbiome studies in HS have shown. In addition, the few bacteria that are regularly involved in acne are mostly innocuous and are present in the great majority of human oily skin surfaces. However, the inflammatory machinery in acne that is activated by bacterial products was recently identified as the inflammasome. This protein complex is one core mechanism of autoinflammatory diseases and leads to marked production of IL 1b. Therefore, acne and HS may also be considered in this light to be autoinflammatory dermatoses, although perhaps not in the purest sense, as the triggers are not sterile but are derived molecular patterns from bacteria. Lastly, a small group of orphan diseases could benefit from a second look with the magnification glass of modern molecular pathophysiology: generalized and localized pustular psoriasis. These diseases encompass generalized pustular psoriasis, acrodermatitis continua of Hallopeau and palmoplantar pustulosis. The former produces thousands of primary pustules all over the body, while the latter two affect the hands and feet with sterile pustules. Recently, genetic studies have identified
The British journal of dermatology