Cutaneous manifestations in patients with mastocytosis: Consensus report of the European Competence Network on Mastocytosis; the American Academy of Allergy, Asthma & Immunology; and the European Academy of Allergology and Clinical Immunology

Mastocytosis is a condition characterized by expansion of clonal mast cells in various organ systems, often in association with activating KIT mutations. The organs most frequently affected are the skin and bone marrow. Traditionally, the disease is divided in cutaneous mastocytosis (CM) and systemic mastocytosis (SM). CM is further divided into maculopapular cutaneous mastocytosis (MPCM), also known as urticaria pigmentosa, diffuse cutaneous mastocytosis (DCM), and mastocytoma of skin. Children with mastocytosis usually have CM, whereas the majority of adults are diagnosed with SM. Both children and adults usually present with typical cutaneous (red or brown) lesions.

These cutaneous lesions are highly heterogeneous, encompassing local and disseminated forms. Overall there is a need for a better definition and a clinically meaningful classification of cutaneous lesions detectable in CM and SM. To address this need, an international task force of experts from the European Competence Network on Mastocytosis, the American Academy of Allergy, Asthma, and Immunology, and the European Academy of Allergology and Clinical Immunology met several times between 2010 and 2014. The resulting task force report published by Hartmann et al. in the current issue includes updated criteria for CM, a revised classification of cutaneous lesions, and related recommendations for daily practice (J Allergy Clin Immunol 2016; 137(1): 35-45).

Among other recommendations, the authors indicate that maculopapular cutaneous mastocytosis (urticaria pigmentosa) lesions should be subdivided into two distinct variants: a monomorphic variant characterized by small monomorphic maculopapular lesions that are typically found in adult patients, and a polymorphic variant with larger lesions of varying shape and size that are almost only detectable in children. Clinical experience suggests that the lesions of the monomorphic variant, when detected in children, always persist into adulthood, whereas the polymorphic lesions – when seen – usually fade away and disappear until puberty.

These observations highlight the prognostic value of a detailed inspection and subsequent classification of skin lesions in UP, and the related clinical implication for the management of patients in daily practice. Another recommendation of the task force group is that the Darier’s sign should be regarded as standard method for the evaluation and diagnosis of adult patients with mastocytosis with skin involvement.

Autoimmunity of the lung and oral mucosa in a multisystem inflammatory disease: the spark that lights the fire in rheumatoid arthritis?

Rheumatoid arthritis (RA) is a systemic autoimmune disease that primarily manifests in synovial joints, such as those in the hands and feet. It can appear at any age in life and affects up to 1% of the population. While it is classified based on the presence of articular inflammation, a growing body of evidence indicates that RA autoimmunity begins outside of the joint. Circulating rheumatoid factor (RF), anti-citrullinated protein antibody (ACPA), anti-peptidylarginine deiminases (anti-PAD4), and anti-carbamylated proteins (anti-CarP) have been detected in many people years prior to the development of joint symptoms and an RA diagnosis. Several lines of investigation have implicated mucosal tissues of the lung and oral cavity as possible sites of initial autoantibody generation and inflammation. Mikuls et al. review the recent reports of this line of investigation (J Allergy Clin Immunol 2016; 137(1): 28-34).

In addition to harboring host inflammatory cells, mucosal tissues support a rich and diverse microbiome, which is increasingly understood to contribute to host immunity and autoimmunity. Mucosal tissues provide the first line of defense against environmental challenges such as invading pathogens and cigarette smoke. Both of these have been shown to be RA risk factors. Approximately one in six new cases of RA are attributable to smoking, with the risk highest among those who carry the HLA-DRB1 shared epitope. Disease-related autoantibodies in RA include IgA isotypes; the mucosal immune system and the ectopic lymphoid tissues that can develop at mucosal surfaces show dense infiltration by IgA-producing plasma cells.

Patients with RA often have extra-articular, pulmonary complications, and a number of reports of pulmonary involvement preceding joint symptoms in seropositive patients underscore the possibility that RA may be initiated in the lung. Disease-related antibodies have been detected in sputum, and in higher levels than in sera. Those with RA are also prone to disorders characterized by chronic oral inflammation, and the authors have recently found such patients showed a 50% greater prevalence of chronic periodontitis (PD) than those with osteoarthritis. The association was strongest among patients with ACPA-positive disease. 

The evolving evidence presented here suggests the lung and periodontium can be producers or reservoirs of RA-related auto-antigens. Much remains to be elucidated. Such questions include: a) What are the mechanisms through which this autoimmunity leads to the development of an articular disease? b) Does the same occur in other mucosal surfaces? c) Might the initiating site vary across individuals? 

The crossroads of autoimmunity and immunodeficiency: Lessons from polygenic traits and monogenic defects

Autoimmunity and immunodeficiency represent two sides of the same coin. Whether the human body’s defenses attack its own healthy cells or its ability to fight off disease is compromised, both result in a dysfunctional immune system. In their review article, Grimbacher et al. discuss the contribution of various immune system genes to common polygenic autoimmune disorders, as well as the pathophysiological pathways and clinical features of monogenic defects that result in autoimmune disease (J Allergy Clin Immunol 2016; 137(1): 3-17).

Multiple single gene defects have been shown to result in rare diseases that show features of both autoimmunity and immunodeficiency. Nearly 300 monogenic traits have been associated with various forms of primary immunodeficiency diseases and auto-inflammatory syndromes. It is likely that more common autoimmune diseases, such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) result from a polygenic inheritance. Genes implicated in single gene disorders have also been linked to polygenetic disorders thus confirming the intricate connections and overlays between autoimmunity and immune deficiency,

In the case of SLE, genome-wide association studies and their follow-up studies have identified more than 50 robust loci associated with susceptibility, suggesting polygenic disease development. There are also emerging monogenic SLE disease models, as factors such as early disease onset, familial SLE, and syndromal lupus likely involve monogenic defects. The authors outline nine pathophysiological pathways, which, if impaired, inevitably lead to serious disease and ultimately to autoimmunity.

Different pathways can lead to the development of a given disease.. Autoimmunity is one of these etiopathologies, and recent and continued advancement in detection methods, in particular next generation sequencing, has led to the identification of genetic defects associated with autoimmune phenotypes. The monogenic defects explored here all interrupt the equilibrium of the immune system, and they have already begun to influence and change our patients’ management. 

This review thus emphasizes of looking at immune dysfunction as a whole rather than breaking it down into silos of immunodeficiency and autoimmunity