Review of the role of the endogenous opioid and melanocortin systems in the restless legs syndrome.

Restless legs syndrome (RLS) is responsive to opioid, dopaminergic and iron-based treatments. Receptor blocker studies in RLS patients suggest that the therapeutic efficacy of opioids is specific to the opioid receptor and mediated indirectly through the dopaminergic system. An RLS autopsy study reveals decreases in endogenous opioids, ß-endorphin and perhaps Met-enkephalin in the thalamus of RLS patients. A total opioid receptor knock-out (mu, delta and kappa) and a mu-opioid receptor knock-out mouse model of RLS show circadian motor changes akin to RLS and, although both models show sensory changes, the mu-opioid receptor knock mouse shows circadian sensory changes closest to those seen in idiopathic RLS. Both models show changes in striatal dopamine, anaemia and low serum iron. However, only in the total receptor knock-out mouse do we see the decreases in serum ferritin that are normally found in RLS. There are also decreases in serum iron when wild-type mice are administered a mu-opioid receptor blocker. In addition, the mu-opioid receptor knock-out mouse also shows increases in striatal zinc paralleling similar changes in RLS. Adrenocorticotropic hormone and α-melanocyte stimulating hormone are derived from pro-opiomelanocortin as is ß-endorphin. However, they cause RLS-like symptoms and periodic limb movements when injected intraventricularly into rats. These results collectively suggest that an endogenous opioid deficiency is pathogenetic to RLS and that an altered melanocortin system may be causal to RLS as well.

Evaluation of a tryptase depletion index for better pathologic identification of mast cell activation syndrome.

BACKGROUND: Laboratory evidence supporting diagnosis of the prevalent condition of mast cell activation syndrome (MCAS) currently includes elevated levels in blood or urine of mediators relatively specific to mast cells (MCs) and/or increased numbers of MCs in luminal gastrointestinal (GI) tract tissues. However, identification of elevated mediators is technically challenging and expensive, and controversy persists regarding the normal ranges of numbers/counts of MCs in various GI tract segments, let alone challenges in determining how many of the visualized MCs are activated. To aid diagnosis of MCAS, we developed a potential new approach for the pathologist to identify the extent of GI tract MC activation easily and inexpensively. PARTICIPANTS AND METHODS: Visualization of MCs in gastrointestinal biopsies from 251 patients vs. 95 controls using antibodies against CD117 and tryptase; MC counting per mm2; calculation of the difference between the CD117-positive MCs (identifying all MCs) vs. tryptase-positive MCs (identifying non-activated tryptase-containing MCs), which we define as the tryptase depletion index (TDI). RESULTS: Mean total MC counts did not differ significantly between patients and controls, but mean TDIs differed significantly. Non-overlapping confidence intervals at the 99.9% level identified cut-offs of TDIs between patients vs. controls of 26, 45 and 32 MCs/mm2 in gastric antrum, duodenum, and colon, respectively. CONCLUSIONS: The TDI may discriminate between MCAS patients vs. controls. If this preliminary work can be independently confirmed, the TDI may become a useful additional minor diagnostic criterion for MCAS.

Some cases of hypermobile Ehlers-Danlos syndrome may be rooted in mast cell activation syndrome.

Hypermobile Ehlers-Danlos syndrome (hEDS) is the most common type of EDS, yet has remained steadfastly inscrutable vis-à-vis efforts to identify its cellular, molecular, and pathophysiologic roots. Once thought to principally affect just connective tissues, hEDS is now appreciated to be a multisystem disease of great heterogeneity with many symptoms and findings difficult to attribute solely to disordered connective tissue development. In the last decade, there has been growth in the appreciation of the existence of a wide range of disorders of chronic inappropriate mast cell (MC) activation (a large heterogeneous pool of MC activation syndromes [MCAS]) distinguishable from other MC disorders such as rare neoplastic mastocytosis. Via chronic aberrant release of the MC's vast repertoire of potent mediators, MCAS can drive extraordinary arrays of pathologies, most commonly of inflammatory, allergic, and dystrophic natures. Although hEDS is seen in only a minority of MCAS cases, limited studies have identified an association between hEDS and MCAS, fueling speculation that certain variants of MCAS may drive hEDS. No laboratory studies probing cellular or molecular linkages between hEDS and MCAS have been conducted yet, and research efforts to identify the genetic roots of hEDS should also consider those of MCAS.

Mast Cell Activation Syndrome: A Primer for the Gastroenterologist.

Mast cell activation syndrome is thought to be a common, yet under-recognized, chronic multi-system disorder caused by inappropriate mast cell activation. Gastrointestinal symptoms are frequently reported by these patients and are often mistaken by physicians as functional gastrointestinal disorders. This syndrome can be diagnosed by the medical history and measurable biomarkers. Gastroenterologists manage diseases associated with active inflammatory cells including neutrophils, lymphocytes, macrophages, and eosinophils. The mast cell has only recently been recognized as a major player in our specialty. Gastrointestinal disorders from mast cell mediators often present with apparent irritable bowel syndrome, dyspepsia, chronic or cyclical nausea, and heartburn. Individuals with mast cell activation syndrome experience significant delays in diagnosis. The gastrointestinal symptoms are often refractory to symptom-targeted prescription medications. Beyond avoiding triggers, the best therapy is directed at modulating mast cell activation and the effects of the mediators. Many of these therapies are simple over-the-counter medications. In this article, we review mast cell function and dysfunction and the gastrointestinal symptoms, comorbid conditions, diagnosis, and management of mast cell activation syndrome. Gastroenterologists who become aware of this syndrome can dramatically improve the quality of life for their patients who previously have been labeled with a functional gastrointestinal disorder.

Effects of Primary Mast Cell Disease on Hemostasis and Erythropoiesis.

Mast cell disease is an epigenetically and genetically determined disease entity with very diverse clinical manifestations in potentially every system and tissue due to inap pro priate release of variable subsets of mast cell mediators together with accumulation of either morphologically normal or altered mast cells. Easy bruising, excessive bleeding, and aberrancies of erythropoiesis can frequently be observed in patients with mast cell disease. A thorough history, including a family history, will guide the appropriate work-up, and laboratory evaluations may provide clues to diagnosis. In recent years, our understanding of the involvement of coagulation and anticoagulant pathways, the fibrinolytic system, and erythropoiesis in the pathophysiology of mast cell disease has increased considerably. This review summarizes current knowledge of the impact of the disturbed hemostatic and erythropoietic balance in patients with mast cell disease and describes options of treatment.

Mast cell activation syndrome in pregnancy, delivery, postpartum and lactation: a narrative review.

Mast cell activation syndrome (MCAS) is a chronic multisystem disease of aberrant constitutive and reactive mast cell mediator release causing generally inflammatory, allergic, and dystrophic issues. The pathobiology of MCAS drives extraordinary clinical complexity and heterogeneity, which led to only recent recognition despite increasingly apparent substantial prevalence, perhaps as high as 17%. It also has a strong female predilection. Thus, MCAS inescapably impacts pregnancy and the post-partum period in many women. No specific research in the pregnant or post-partum MCAS population has been performed yet. However, its prevalence and potential for driving substantial morbidity merit obstetric providers' acquaintance with this illness and its potential impacts on their patients during pregnancy, delivery, the post-partum period, and lactation. Extensive literature review across all medical specialities, plus direct experience in the authors' practices, provides guidance in recognising MCAS in pregnancy and diagnosing and effectively managing it. Described herein are manners in which MCAS, a protean multisystem disease, adversely affects all stages of pregnancy and post-partum. In order to reduce risks of MCAS causing complications before, during and after pregnancy, identifying and controlling the syndrome prior to pregnancy is best, but, even if the disease is not recognised until late, there may still be opportunities to mitigate its effects. There is precedent for improved outcomes if comorbid MCAS is recognised and controlled. This review provides the first comprehensive guide for obstetric providers regarding this emerging major comorbidity.

Successful mast-cell-targeted treatment of chronic dyspareunia, vaginitis, and dysfunctional uterine bleeding.

Dyspareunia, vaginitis and dysfunctional uterine bleeding (DUB) are common problems which, despite their polygenicity, commonly appear idiopathic and treatment-refractory. Mast cell (MC) activation syndrome (MCAS) is a newly-recognised, prevalent, chronic multisystem polymorbidity of general themes of inflammation ± allergic-type phenomena ± aberrant growth/development in assorted tissues. MCs produce significant quantities of heparin, too. As such, MCAS may underlie some cases of chronic dyspareunia, vaginitis or DUB. We report five such patients; all who responded well to MC-targeted treatment. We review aspects of MC biology and pathobiology of potential relevance to otherwise idiopathic persistent inflammatory or coagulopathic genital tract problems. Diagnostic testing for MCAS may be warranted in some patients with chronic dyspareunia, vaginitis or DUB (especially patients whose histories well fit the general profile of MCAS), and prospective therapeutic trials of MC-directed topical and/or systemic therapies may be warranted in such populations. Impact statement What is already known on this subject? Chronic, idiopathic, treatment-refractory female genital tract inflammation or bleeding are common problems for which mast cell (MC) disease, previously generally thought to consist of just rare cases of mastocytosis, and is seldom considered in the differential diagnosis. What do the results of this study add? The substantial prevalence of the newly recognised 'mast cell activation syndrome' (MCAS), featuring chronic inappropriate MC activation with little-to-no MC neoplasia, and its clinical presentation with chronic multisystem inflammation ± allergic-type phenomena ± aberrant growth/development in assorted tissues, raises the possibility that MCAS might underlie the aforementioned genital tract problems, especially in patients whose larger clinical presentations fit the MCAS profile. We report five example patients (among many more we have similarly treated) who enjoyed excellent responses to safe, inexpensive MC-targeted treatments, often given just intravaginally. What are the implications of these findings for clinical practice and/or further research? Our report identifies a potentially significant new MC-focused direction, of relevance to millions of affected women worldwide, for clinical treatment as well as for basic and clinical research, which historically has yielded major advancements disappointingly disproportionate to the scope of the affected population.

Masitinib for treatment of severely symptomatic indolent systemic mastocytosis: a randomised, placebo-controlled, phase 3 study.

BACKGROUND: Indolent systemic mastocytosis, including the subvariant of smouldering systemic mastocytosis, is a lifelong condition associated with reduced quality of life. Masitinib inhibits KIT and LYN kinases that are involved in indolent systemic mastocytosis pathogenesis. We aimed to assess safety and efficacy of masitinib versus placebo in severely symptomatic patients who were unresponsive to optimal symptomatic treatments. METHODS: In this randomised, double-blind, placebo-controlled, phase 3 study, we enrolled adults (aged 18-75 years) with indolent or smouldering systemic mastocytosis, according to WHO classification or documented mastocytosis based on histological criteria, at 50 centres in 15 countries. We excluded patients with cutaneous or non-severe systemic mastocytosis after a protocol amendment. Patients were centrally randomised (1:1) to receive either oral masitinib (6 mg/kg per day over 24 weeks with possible extension) or matched placebo with minimisation according to severe symptoms. The primary endpoint was cumulative response (≥75% improvement from baseline within weeks 8-24) in at least one severe baseline symptom from the following: pruritus score of 9 or more, eight or more flushes per week, Hamilton Rating Scale for Depression of 19 or more, or Fatigue Impact Scale of 75 or more. We assessed treatment effect using repeated measures methodology for rare diseases via the generalised estimating equation model in a modified intention-to-treat population, including all participants assigned to treatment minus those who withdrew due to a non-treatment-related cause. We assessed safety in all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, number NCT00814073. FINDINGS: Between Feb 19, 2009, and July 15, 2015, 135 patients were randomly assigned to masitinib (n=71) or placebo (n=64). By 24 weeks, masitinib was associated with a cumulative response of 18·7% in the primary endpoint (122·6 responses of 656·5 possible responses [weighted generalised estimating equation]) compared with 7·4% for placebo (48·9 of 656·5; difference 11·3%; odds ratio 3·6; 95% CI 1·2-10·8; p=0·0076). Frequent severe adverse events (>4% difference from placebo) were diarrhoea (eight [11%] of 70 in the masitinib group vs one [2%] of 63 in the placebo group), rash (four [6%] vs none), and asthenia (four [6%] vs one [2%]). The most frequent serious adverse events were diarrhoea (three patients [4%] vs one [2%]) and urticaria (two [3%] vs none), and no life-threatening toxicities occurred. One patient in the placebo group died (unrelated to study treatment). INTERPRETATION: These study findings indicate that masitinib is an effective and well tolerated agent for the treatment of severely symptomatic indolent or smouldering systemic mastocytosis. FUNDING: AB Science (Paris, France).

Successful targeted treatment of mast cell activation syndrome with tofacitinib.

Mast cell (MC) activation syndrome (MCAS) is a collection of illnesses of inappropriate MC activation with little to no neoplastic MC proliferation, distinguishing it from mastocytosis. MCAS presents as chronic, generally inflammatory multisystem polymorbidity likely driven in most by heterogeneous patterns of constitutively activating mutations in MC regulatory elements, posing challenges for identifying optimal mutation-targeted treatment in individual patients. Targeting commonly affected downstream effectors may yield clinical benefit independent of upstream mutational profile. For example, both activated KIT and numerous cytokine receptors activate the Janus kinases (JAKs). Thus, JAK-inhibiting therapies may be useful against the downstream inflammatory effects of MCAS. The oral JAK1/JAK3 inhibitor, tofacitinib, is currently approved for rheumatoid arthritis and is in clinical trials for other chronic inflammatory disorders. Herein, we report two patients with MCAS who rapidly gained substantial symptomatic response to tofacitinib. Their improvement suggests need for further evaluation of this class of drugs in MCAS treatment.

Mast cell activation disease: An underappreciated cause of neurologic and psychiatric symptoms and diseases.

Neurologists and psychiatrists frequently encounter patients whose central and/or peripheral neurologic and/or psychiatric symptoms (NPS) are accompanied by other symptoms for which investigation finds no unifying cause and for which empiric therapy often provides little to no benefit. Systemic mast cell activation disease (MCAD) has rarely been considered in the differential diagnosis in such situations. Traditionally, MCAD has been considered as just one rare (neoplastic) disease, mastocytosis, generally focusing on the mast cell (MC) mediators tryptase and histamine and the suggestive, blatant symptoms of flushing and anaphylaxis. Recently another form of MCAD, MC activation syndrome (MC), has been recognized, featuring inappropriate MC activation with little to no neoplasia and likely much more heterogeneously clonal and far more prevalent than mastocytosis. There also has developed greater appreciation for the truly very large menagerie of MC mediators and their complex patterns of release, engendering complex, nebulous presentations of chronic and acute illness best characterized as multisystem polymorbidity of generally inflammatory ± allergic themes--including very wide arrays of central and peripheral NPS. Significantly helpful treatment--including for neuropsychiatric issues--usually can be identified once MCAD is accurately diagnosed. We describe MCAD's pathogenesis, presentation (focusing on NPS), and therapy, especially vis-à-vis neuropsychotropes. Since MCAD patients often present NPS, neurologists and psychiatrists have the opportunity, in recognizing the diagnostic possibility of MCAD, to short-circuit the often decades-long delay in establishing the correct diagnosis required to identify optimal therapy.

Successful treatment of mast cell activation syndrome with sunitinib.

Mast cell (MC) activation syndrome (MCAS) is a recently recognized, likely prevalent collection of heterogeneous illnesses of inappropriate MC activation with little to no MC neoplasia likely driven by heterogeneous patterns of constitutively activating mutations in MC regulatory elements including various tyrosine kinases (TKs, dominantly KIT). MCAS typically presents as chronic multisystem polymorbidity of generally inflammatory ± allergic theme. As with indolent systemic mastocytosis (SM), treatment of MCAS focuses more against MC mediators than MC neoplasia, but some cases prove refractory even to the TK inhibitor (TKI) imatinib reported useful both in uncommon SM cases not bearing SM's usual imatinib-resistant KIT-D816V mutation and in some cases of MCAS (which rarely bears KIT-D816V). Most allergy is principally a MC activation phenomenon and sunitinib is a multitargeted TKI shown helpful in controlling a murine model of oral allergy syndrome. We present the first report of use of sunitinib in life-threatening MCAS refractory to multiple agents including imatinib achieving immediate, complete, sustained, non-toxic remission suggesting a new option for treatment of aggressive MC disease.

Mast Cell-Mediated Mechanisms of Nociception.

Mast cells are tissue-resident immune cells that release immuno-modulators, chemo-attractants, vasoactive compounds, neuropeptides and growth factors in response to allergens and pathogens constituting a first line of host defense. The neuroimmune interface of immune cells modulating synaptic responses has been of increasing interest, and mast cells have been proposed as key players in orchestrating inflammation-associated pain pathobiology due to their proximity to both vasculature and nerve fibers. Molecular underpinnings of mast cell-mediated pain can be disease-specific. Understanding such mechanisms is critical for developing disease-specific targeted therapeutics to improve analgesic outcomes. We review molecular mechanisms that may contribute to nociception in a disease-specific manner.

Imatinib and Trigger Avoidance for Mast Cell Activation Syndrome Presenting With Attacks of Abdominal Pain, Nausea, Vomiting, and Diarrhea.

The etiology for concurrent attacks of abdominal pain, nausea, vomiting, and diarrhea can be obscure. Mast cell activation syndrome is not usually considered in this differential diagnosis. A 53-year-old paint salesman suffered severe attacks of these symptoms for the 3 decades of his career. Nortriptyline, loperamide, hyoscyamine, and ondansetron failed to address his symptoms. Mast cell activation syndrome was ultimately diagnosed. Intravenous mast cell-targeted therapy reduced severity of attacks. Multiple oral mast cell-targeted treatments were ineffective, but addition of low-dose imatinib resulted in dramatic improvement. Recognition that paint-fume exposure-triggered attacks led to behavioral modifications which further reduced symptoms.

Breast Implant Illness May Be Rooted in Mast Cell Activation: A Case-Controlled Retrospective Analysis.

Objective: To investigate the possible association between breast implant illness (BII) and mast cell activation syndrome (MCAS), which often manifests increased mast cells (MCs) in assorted tissues and may explain BII symptoms. Background: Mechanisms by which implants cause BII symptoms remain unclear, but BII and MCAS symptom profiles heavily overlap, warranting investigation of potential linkage. Methods: We retrospectively analyzed 20 implant patients who underwent explantation and total capsulectomy; 15 self-reported preoperatively they had BII (subject group); 5 felt they did not [control group 1 (CG1)]. Five prophylactic mastectomy patients constituted control group 2 (CG2). Subjects and CG1 patients completed BII symptom questionnaires preoperatively and multiple points postoperatively. With CD117 staining, average and maximum mast cell counts (MCCs) in resected tissues were determined. Results: Mean BII symptom score 2 weeks postexplantation was reduced by 77% (P < 0.0001), and 85% by 9 months. Analysis suggested BII in CG1 patients, too, who improved similarly. Among CG2 patients, healthy breast tissue showed mean and maximum MCCs of 5.0/hpf and 6.9/hpf. Mean and maximum MCCs in capsules in BII patients were 11.7/hpf and 16.3/hpf, and 7.6/hpf and 13.3/hpf in CG1 patients. All intergroup comparisons were significantly different (P < 0.0001). Conclusions: MCCs in peri-implant capsules in BII patients are increased; some implanted patients appear to have unrecognized BII. Given that neoantigenic/xenobiotic exposures commonly trigger dysfunctional MCs in MCAS to heighten aberrant mediator expression driving inflammatory and other issues, further investigation of whether BII represents an implant-driven escalation of preexisting MCAS and whether an MCAS diagnosis flags risk for BII seems warranted.

A survey of the currently known mast cell mediators with potential relevance for therapy of mast cell-induced symptoms.

Mast cells (MCs) occupy a central role in immunological as well as non-immunological processes as reflected in the variety of the mediators by which MCs influence other cells. Published lists of MC mediators have all shown only subsets-usually quite small-of the full repertoire. The full repertoire of MC mediators released by exocytosis is comprehensively compiled here for the first time. The compilation of the data is essentially based on the largely cytokine-focused database COPE®, supplemented with data on the expression of substances in human MCs published in several articles, plus extensive research in the PubMed database. Three hundred and ninety substances could be identified as mediators of human MCs which can be secreted into the extracellular space by activation of the MC. This number might still be an underestimate of the actual number of MC mediators since, in principle, all substances produced by MCs can become mediators because of the possibility of their release by diffusion into the extracellular space, mast cell extracellular traps, and intercellular exchange via nanotubules. When human MCs release mediators in inappropriate manners, this may lead to symptoms in any or all organs/tissues. Thus, such MC activation disorders may clinically present with a myriad of potential combinations of symptoms ranging from trivial to disabling or even life-threatening. The present compilation can be consulted by physicians when trying to gain clarity about MC mediators which may be involved in patients with MC disease symptoms refractory to most therapies.

Learned cautions regarding antibody testing in mast cell activation syndrome.

OBJECTIVES: To describe patterns observed in antibody titer trendlines in patients with mast cell activation syndrome (MCAS, a prevalent but underrecognized chronic multisystem inflammatory disorder of great clinical heterogeneity) and offer clinical lessons learned from such pattern recognition. METHODS: The available records of 104 MCAS patients drawn from the authors' practices were reviewed, including all antibody tests therein. RESULTS: All patients had positive/elevated antibodies of various sorts at various points, but for most of the antibodies which were found to be positive at least some points, the diseases classically associated with those antibodies were not present, marking such antibodies as clinically insignificant mimickers (likely consequent to inflammatory effects of MCAS on the immune system itself driving spurious/random antibody production) rather than "on-target" and pathogenic antibodies reflecting true disease warranting treatment. We also observed two distinct patterns in trendlines of the titers of the mimickers vs. the trendline pattern expected in a true case of an antibody-associated disease (AAD). CONCLUSIONS: Our observations suggest most positive antibody tests in MCAS patients represent detection of clinically insignificant mimicking antibodies. As such, to reduce incorrect diagnoses of AADs and inappropriate treatment in MCAS patients, caution is warranted in interpreting positive antibody tests in these patients. Except in clinically urgent/emergent situations, patience in determining the trendline of a positive antibody in an MCAS patient, and more carefully assessing whether the AAD is truly present, is to be preferred.

Chemical Intolerance and Mast Cell Activation: A Suspicious Synchronicity.

Background: Chemical Intolerance (CI) is characterized by intolerances for chemicals, foods, and drugs with multi-system symptoms. As yet, the biomechanism remains unclear. One study reported converging lines of evidence supporting a substantive association between mast cell activation syndrome (MCAS) and CI. The purpose of this study is to (1) confirm a previous report demonstrating that 60% of MCAS patients report CI and (2) examine the parallels between symptoms and intolerances in CI and MCAS. Methods: Five hundred forty-four MCAS patients were assigned a clinical MCAS score using a validated assessment instrument and were assessed for CI using the validated Quick Environmental Exposure Sensitivity Index. Results: Our outcomes confirm the previously published study where the majority of MCAS patients also have CI. There was a clear overlap between various ICD-10 diagnostic categories and CI symptoms, providing further support for a potential shared mechanism. Conclusions: Exposures to pesticides, volatile organic compounds, combustion products, and mold have previously been reported as initiators of CI. However, until recently, little was known about the biological mechanism involved that could explain the multisystem symptoms associated with CI. This paper addresses a newly identified biomechanism for disease, which may underlie a host of "medically unexplained symptoms" triggered by xenobiotics.

Mast cell activation syndrome masquerading as agranulocytosis.

Acquired agranulocytosis is a rare, life-threatening disorder. The few known causes/associations usually are readily identifiable (e.g., drug reaction, Felty syndrome, megaloblastosis, large granular lymphocytic leukemia, etc.). We report a novel association with mast cell disease. A 61-year-old morbidly obese man developed rheumatoid arthritis unresponsive to several medications. Agranulocytosis developed shortly after sulfasalazine was started but did not improve when the drug was soon stopped. Other symptoms across many systems developed including hives and presyncope. Marrow aspiration and biopsy showed only neutropenia. Serum tryptase was mildly elevated; urinary prostaglandin D2 was markedly elevated. Other causes were not found. Mast cell activation syndrome (MCAS) was diagnosed. Oral antihistamines, montelukast, and cromolyn were unhelpful; aspirin was initially felt contraindicated. Imatinib immediately increased neutrophils from 0% to 25% but did not help symptoms; subsequent addition of aspirin increased neutrophils further and abated symptoms. Different presentations of different MCAS patients reflect elaboration of different mediators likely consequent to different Kit mutations. Mast cells (MCs) help regulate adipocytes, and adipocytes can inhibit granulopoiesis; thus, a Kit-mutated MC clone may have directly and/or indirectly driven agranulocytosis. MCAS should be considered in otherwise idiopathic agranulocytosis presenting with comorbidities best explained by MC mediator release.