trix components (ECM) such as collagen and proteoglycans.46,47 Abundant release of MMPs may act alone or in conjunction with increased tryptase to alter the ECM architecture in the CT of patients with iMCAS directly, thereby contributing to an HT EDS-like phenotype. Evidence has shown that increased activity of MMPs has been associated with a HT EDS-like phenotype in the absence of collagen gene mutations.48,49 Lyons et al suggest that activation of protease-activated receptor 2 (PAR2)-dependent pathways may also be responsible for tryptase-mediated CT changes.44 PAR2 is a G protein-coupled protease-activated receptor involved in pathways relevant to both acute and chronic inflammation, inflammatory pain, and allergy.50–53 Proteases, such as tryptase and matrix metalloproteinase (MMP)-1, cleave a portion of this receptor, initiating events leading to transmembrane signaling.54–57 PAR2 is up-regulated by mediators of inflammation, including TNF-α and interleukin (IL)-1α, and overstimulation of PAR2 can lead to increased tissue permeability, granulocyte infiltration, tissue damage, and edema.51,58,59
Although there are no large scale trials to support treatments in iMCAS patients, conventional pharmacologic therapy involvesH1 and H2 histamine receptor antagonists, leukotriene-altering agents, glucocorticoids, cromolyn sodium, and omalizumab.5,60In the author’s experience with MCAD patients, off-label treatment with low dose doxycycline 40mg daily along with topical stabilized hypochlorous acid as needed has demonstrated benefit in improving pruritus and controlling cutaneous rash whenused in conjunction with topical super-potent steroids and oral anti-histamine therapy. Hypochlorous acid has been shown tocontribute to reduced histamine levels in skin, and in addition to doxycycline, has previously been shown to inhibit MMPs.61–64Within a few weeks of initiating treatment, a 23 year old female patient with a three year history of MCAD symptoms experiencedimprovement of her erythematous, excoriated, and papular rash.As the differentiation of iMCAS from secondary MCAD may not be obvious at the time of presentation, avoidance of possible triggers is paramount in management.29 Medications are triggers of particular interest, and may hold the key for furthering understanding of the underlying genetic basis for MCAD, possibly found in mutations in drug-metabolizing enzymes of thecytochrome P450 (CYP450) system.65 Although there is a lack of literature attributing CYP450 mutations with MCAD, further investigation is needed in order to both enhance patient ability to avoid triggers and provide the basis for more targeted therapy.
The iMCAS subtype of MCAD is a disorder characterized by chronic multisystem inflammation triggered by non-neoplasticMC over-activity and is a diagnosis of exclusion after ruling out primary or secondary causes of MC activation.5,6,29 Although proposed to be on the same spectrum of disease as other MCAD, such as SM and MMAS, iMCAS has been previouslydifferentiated from other members of the MCAD family on the basis of having no underlying cause (including a lack of clonalproliferation of MCs) and often being associated with lower tryptase elevations.6–8,10,19 A paucity of literature has sought tocharacterize the dermatologic clinical presentation of iMCAS, which is classically described as having similar symptomatologyto other MCADs. Current literature suggests that the most common cutaneous findings include flushing, pruritus, clottingor bleeding disorders, dermatographism, and urticaria. The most robust characterization of iMCAS clinical presentationconfirms the highly sensitive finding of dermatographism, while providing evidence that flushing may be a finding oflower sensitivity than pruritus or urticaria, unspecified rashes, diaphoresis, and easy bleeding and bruising.14 This review alsohighlights the prominence of bleeding disorders in iMCAS, which is an underappreciated characteristic of the disease also shared with SM but without a direct neoplastic cause.66 An emerging association between patients with MCAD, iMCAS, and familial hypertryptasemia having CT abnormalities also implicates tryptase and/or MMPs as potential mediators of CTD and joint hypermobility.Limitations of the current review include the heterogeneity of studies featuring iMCAS clinical descriptions, inconsistency of diagnostic criteria implemented in the literature, and small volume of studies available. The adapted diagnostic criteria utilized for inclusion into the present review also presents a limitation, in that the criteria used did not account for response to therapy targeting MC activation. Nonetheless, the chosen inclusion criteria for the present review afforded specificity for iMCAS while allowing for reasonable sensitivity by including various aspects of previously proposed diagnostic criteria, justified by advances in iMCAS understanding gained in recent years. This observation underscores the need for more appropriate implementation of diagnostic criteria for iMCAS in the literature. Furthermore, this review highlights the importance of recognizing this highly prevalent syndrome in patients by possibly more subtle dermatologic findings, as increases in plasma tryptase are less extreme and less common in this disorder in comparison to other MCAD.6,10,19 Reports suggest that iMCAS is largely treatment-responsive, and there has been evidence suggesting that treatment can even result in improvement of other co-morbidities, such as metastatic uterine cancer and sickle cell disease.25,26 Due to a lack of testing for iMCAS markers in routine labs, serum tryptase levels not always being helpful, and iMCAS patients tending to have good response to treatment, it is imperative for clinicians to have a suspicion for iMCAS when the clinical presentation is relevant.6,8,19
Knowledge of the cutaneous manifestations of iMCAS is vital