Francesca Satolli Miriam Rovesti, and Claudio Feliciani
Dermatology Unit, Deparment of Medicine and Surgery, University of Parma, Parma, Italy
Autoimmune skin disorders are a heterogeneous group of inflammatory disorders in which immunological abnormalities play a crucial role, expressing IgG/IgA autoantibodies or cell‐mediated immune responses against self‐antigens.
These diseases are characterized by a chronic relapsing course, and could have a devastating effect on the patient’s well‐being and quality of life.
Recent investigations  attempting to link autoimmune skin diseases and oxidative stress have had varying degrees of success. Antioxidants, in fact, play the important role in our body of neutralizing free radicals and peroxides that are formed during normal physiologic events. While these reactive oxygen species are necessary for numerous biological processes, when created in excess they can have deleterious effects. The skin as an organ is constantly under attack by reactive oxygen species from both endogenous and exogenous sources. The pathophysiology of many autoimmune diseases is still unknown but recently oxidative stress has come to light as a possible triggering mechanism.
Regarding endocrine factors, there are many possible inflammatory mediators that have been suggested to play a role in insulin resistance pathogenesis (such as tumor necrosis factor‐α (TNF‐α), interleukin‐6, leptin, and adiponectin) and that are also abnormal in autoimmune skin disorders.
For this reason, metabolic syndrome and autoimmune skin diseases are correlated.
In fact, chronic inflammation, shared risk factors (i.e. smoking and alcohol consumption), treatment (i.e. immunosuppressive agents and drugs that alter the lipid profile), and shared genetic risk loci have been proposed to cause metabolic syndrome and cardiovascular morbidity of autoimmune diseases .
Also, the relationship between microbial composition of the skin and autoimmune skin diseases has been studied more and more in recent years.
A 2017 paper  shows how the microbial composition of the skin is important for the functionality of the skin barrier and autoimmune skin diseases.
Autoimmune disorders include autoimmune bullous diseases, collagen vascular diseases, alopecia areata, and vitiligo. There is growing evidence that more common disorders, such as psoriasis, atopic dermatitis (AD), and lichen planus are also linked to the autoimmune processes .
We will herein analyze these autoimmune skin diseases and the different factors involved in their pathogenesis, some of which are still unclear (see Figure 7.1 below).
We will also discuss the main therapeutic options and recent advances.
Lupus erythematosus (LE) is a prototypical autoimmune disorder characterized by the inflammation of the skin, sometimes associated with the involvement of several tissues and the production of autoantibodies directed against nuclear antigens. It includes a spectrum of diseases ranging from purely cutaneous, subacute cutaneous lupus erythematosus (SCLE) with little organ involvement, to systemic ones (systemic lupus erythematosus, SLE) which may involve many organs (causing nephritis, pneumonitis, arthritis, encephalitis, myocarditis).
Evidence is growing that defective clearance of apoptotic products leads to the initial innate immune responses preceding autoimmunity. Many tissues may be implicated, but the frequency of skin disease, even without autoantibodies, and the role of UV light as a trigger, suggest that keratinocytes may be a key site of initiation .
The interactions between apoptotic cells, dendritic cells, and lymphocytes activate the production of pathogenetic antibodies and T lymphocytes .
Clinical features of cutaneous involvement are often observed and include specific and non‐specific skin manifestation in different forms: discoid lupus erythematosus (DLE) is found in up to 80% of the cases and most commonly affects the face and the scalp with erythematous patches, scaling, and follicular plugging, even if any part of the body could be involved.
Lesions may be bilateral or unilateral; alopecia occurs in the scalp lesions in approximately one‐third of the patients, and is usually permanent.
Over time, particularly if treated, lesions flatten and can evolve into white scarred areas with zones of hyperpigmentation.
Laboratory abnormalities in DLE are found in 30% of patients with anemia, leukopenia, and thrombocytopenia. Antinuclear antibodies are detected in about one third of them, with the homogeneous type of antinuclear factor being twice as frequent as the speckled type .
The estimated risk of developing SLE following a diagnosis of cutaneous lupus erythematosus (CLE) varies, with rates up to 25% .
SCLE, which comprises approximately 10% of patients, is characterized by non‐scarring papulo‐squamous (two‐thirds) or annular polycyclic (one third) lesions. Lesions usually occur above the waist and particularly around the neck, on the trunk, and on the outer sides of the arms.
Collagen Vascular Skin Disorders
Collagen vascular skin disorders are rare autoimmune diseases with an incidence of 1 to >10 cases per million that affect women more frequently than man during adulthood.
Photosensitivity occurs in approximately half of patients.
Homogeneous antinuclear factor is found in 60%, and the anticytoplasmic antibodies anti Ro in 80% and anti_La in 40% of patients.
SLE is a systemic disease with multisystem organ inflammation that commonly involves the skin, joints, and vasculature, and is associated with immunological abnormalities.
The characteristic specific skin sign of LE is malar or butterfly rash, described as discrete erythematous macules, papules, and plaques associated with a congestive erythema in the central areas of the face. However, widespread erythematous macular and papular lesions are seen in the generalized form. Lesions predominate on UV‐exposed areas and they usually appear after sun exposure .
SLE is associated with antinuclear autoantibodies (ANA) and the fine specificity of the ANA profile helps to distinguish the different clinical subtypes and may be of prognostic value .
In terms of the psychological aspect of SLE, a recent study  shows SLE individuals with insomnia symptoms have high levels of perceived stress and more frequent use of disengaging and emotionally focused coping strategies. This body of evidence suggests that individuals with SLE and comorbid insomnia symptoms may therefore require additional interventions for insomnia.
Cutaneous manifestations occur in approximately 80% of patients during the course of the disease and are the first sign of SLE in up to 20% of cases.
Their prompt recognition is important for the clinical diagnosis, which must be confirmed by histology, and by a positive lupus band test at direct immunofluorescence.
Given the clinical heterogeneity and unpredictable disease course, the management of CLE is highly variable and is usually guided by predominant manifestations .
In the purely cutaneous form topical corticosteroid therapy can frequently control, and sometimes clear, lesions without systemic treatment. But autoimmune disorders that affect the skin and internal organs with a chronic relapsing course can have a high impact on patients’ general physical conditions, psyche, life span, social life, and also work productivity, and they require a complex, interdisciplinary management due to multiple organ involvement.
Treatment options for CLE have increased with the introduction of new biological therapies. However, the majority of the patients still benefit from antimalarials, which remain the cornerstone of treatment. The evaluation and management of CLE patients depend on the clinical findings and associated symptoms.
New targeted therapies will allow for more specific, highly effective and less harmful treatments.
Recent studies have tried to elucidate the role of cytokines such as interferon‐alpha in SLE to establish targets for treatment; future treatments aimed at correcting the intracellular and intercellular signaling may prove effective in restoring immune tolerance in SLE .
Scleroderma is a disorder of an autoimmune etiology which can be limited to the skin, as in the localized morphea or scleroderma, or be associated with vascular abnormalities, connective tissue sclerosis, and atrophy and autoimmune changes characterizing progressive systemic sclerosis.
In systemic scleroderma, ANA specific to centromers are characteristic to the diffuse form with prominent, mainly acral sclerosis of the skin. In contrast, IgG against topoisomerase (Scl‐70) is characteristic to the diffuse form which is associated with a more severe course (nephrosclerosis, pulmonary sclerosis, and myocardial fibrosis).
Dermatomyositis is a clinical spectrum of cutaneous symptoms on the one hand and myositis on the other hand. The cardinal cutaneous symptoms are heliotrope facial erythema, red to purple papules over the knuckles and sometimes the interphalangeal Joints (Gottron’s sign) and nail fold hyperkeratosis and teleangectasia (Keining sign). Myositis‐specific ANA (anti‐Jo1, anti‐Mi‐2) are less sensitive (<30%) but highly specific.
Two main types of pemphigus are classified: P. vulgaris and P. foliaceous. Some other forms, such as paraneoplastic pemphigus (PNP), pemphigus herpetiformis, and IgA pemphigus have also been recognized.
Pemphigus vulgaris (PV) is a rare blistering skin disorder characterized by the disadhesion of keratinocytes due to autoantibody attack against epidermal targets, including desmoglein (Dsg) 3, Dsg 1, and possibly other adhesion and non‐adhesion molecules. The mechanisms leading to immune‐mediated pathology in PV are multifactorial and not fully understood. Recently, oxidative stress (antioxidant/oxidant disequilibrium) has been proposed as a contributory mechanism of autoimmune skin diseases, including PV. In a recent study , data of the measurement of total antioxidant capacity (TAC) in patients with PV, in healthy controls and in bullous pemphigoid patients were collected. These data indicate that there was a significant reduction in TAC levels in PV patients compared with healthy controls, as well as bullous pemphigoid patients. Furthermore, PV patients with active disease have significantly lower TAC levels than PV patients in remission. We also find that HLA (human leukocyte antigen) allele status has a significant influence on oxidative stress. Therefore these findings provide support for the role of oxidative stress in PV.
Major reported trigger factors are drugs, which are divided into three main groups: thiol drugs, phenol drugs, and non‐thiol, nonphenol drugs . Thiol drugs which contain a sulfhydryl group (–SH) are the most common type of pemphigus‐inducing drugs. Thiol drugs inhibit enzymes that aggregate keratinocytes and activate enzymes that disaggregate keratinocytes. Some of the members of the thiol group may also induce autoantibody formation. Phenol drugs are able in vitro to stimulate keratinocytes to release proinflammatory cytokines such as TNF‐α and IL‐1, which are involved in acantholysis through direct and indirect mechanisms amplifying the acantholytic process [15, 16]. Addiction to heroin (a phenol drug) has been reported to increase the risk of pemphigus foliaceous development. Some non‐thiol, non‐phenol drugs can induce pemphigus or cause a reactivation of the disease by altering target antigens or autoantibodies, or aggravating the immune response. Some drugs that have been reported to induce pemphigus are: ingenol mebutate, cilazapril, dipyrone, imiquimod, penicillin, fosinopril, diazinon, captopril, glibenclamide and cilazapril, bucillamine, carbamazepine, lisinopril, nifedipine, penicillamine, rifampin, ceftazidime, and chloroquine/hydroxychloroquine [17–20].
Even the most effective drug in treating pemphigus, rituximab, has been included in the list of possible inducers of the disease .
The risk of pemphigus induction or exacerbation associated with herpes virus infections is well known and frequently described in the literature .
Vaccinations have been highly recommended (against seasonal influenza, H1N1, tetanus, and pneumococci) by the European guidelines for pemphigus  even if there is some evidence of pemphigus induction or exacerbation as a consequence of different types of vaccines [24–26].
Predicting triggering factors for pemphigus is possible; infections, autoimmune/autoinflammatory diseases, vaccines, immune stimulator treatments, and allergies may be considered as possible triggers since they are able to modulate a Th1 and Th17 response. It is expected that some conditions that cause skewed Th1:Th2 toward Th1 dominance should induce remission of pemphigus or at least prevent pemphigus exacerbation or induction .
An alteration in the Th1:Th2 balance toward more Th2 populations induced by increased estrogen levels during pregnancy leads to increased levels of IgG antibodies. Estrogen can lead to the promotion of Th2 cytokine production that is followed by the promotion of B cell‐mediated autoimmunity .
PNP is an example of how cancer also decreases effector T cell functions and populations. This is due to an overactivation of T cell regulatory responses .
The co‐existence of pemphigus with other autoimmune conditions has also been shown; a large number of PV patients have a family history of autoimmune diseases .
The appearance of new autoimmune conditions could be explained by a decrease in regulatory responses because of primary autoimmune disease activity. Autoimmune thyroiditis is the most common pemphigus‐associated condition, but several reports show associations between different autoimmune conditions, including SLE, pemphigoid, lichen planus, psoriasis, alopecia areata/universalis, and RA [35–37]. This may be due to a high incidence of this disease or because of some common signaling pathways with pemphigus.
Together with a genetic predisposition, pemphigus could be induced by triggers including certain nutrients (e.g. allium vegetables) and low levels of some micronutrients (vitamin D, selenium, copper, and zinc), emotional stress, radiotherapy, pregnancy, ultraviolet radiations (UVRs), etc. Some evidence in vitro shows that tannic acid is able to induce acantholysis by inducing an amplifying system in keratinocytes immune response .
Among the pemphigus trigger factors, dietary factors are rarely discussed. Nevertheless, it is important to consider nutrients and micronutrients as critical factors in the management of pemphigus since there is a close relationship between the diet/micronutrients and skin immune response.
Tannins‐rich foods include grapes, pomegranates, berries, sorghum, barley, nuts, chocolate, rhubarb, squash and legumes (chickpeas and beans), red wine, and tea. Allium vegetables, such as garlic, onion, chive, and leek are well‐known dietary triggers for the induction or provoking of pemphigus. Based on literature, we suggest avoiding a dietary rich in thiols, isothiocyanates, phenols, and tannins .
Vitamin D is also a well‐known element associated with autoimmune diseases . Considering its immunoregulatory role, it may be essential for the initiation of regulatory responses, which seems critical in cases of patients with different autoimmune diseases. Some patients improve after regular vitamin D intake [40, 41]. In addition to vitamin D, several other significant elements show decreased levels in serum selenium, copper, and zinc in pemphigus patients . The evaluation of other micronutrient levels in those patients may reveal other facts that could help improve their management. It is advisable for patients with pemphigus to take multivitamin/multimineral supplements.