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Q:

1/27/2017
I am taking care of a 30 y/o lady with Telangiectasia Macularis Eruptiva Perstans (biopsy proven). She has had negative BM biopsy with negative mast cell markers. Normal tryptase on several occasions. Increased urinary PGD2. She does have multiple drug allergies (antibiotics, morphine). She had a reaction to a wasp sting. S/p negative venom testing and confirmatory Immunocap. She is on H1 and H2 blockers and prn hydroxyzine. She does not tolerate montelukast. Due to recurrent anaphylactic event she started xolair in August and has been doing well apart from one reaction in December. She has noticed increased TMEP lesions and as it is merely a cosmetic issue, she feels that it is affecting her life adversely.

My questions are: 1) Is there a treatment available to decrease her lesions?
2) Do you have any other treatment suggestions for her apart from what she is already on?

A:

I have included a copy of a question from the Archives of Ask the Expert which deals with increased Prostaglandin D2 and normal tryptase. The point made very well in the discussion is that there can be inconsistency in the measurement of mast cell mediators with Prostaglandin D2 increased without tryptase. I also draw your attention to the observation that other cells, including eosinophils, produce Prostaglandin D2.

The clinical history of multiple systemic reactions is consistent with a mast cell disorder. The improvement with omalizumab is of interest and likely reflects the modification of IgE receptor density and susceptibility to degranulation.

The appearance of the skin lesions may respond to additional therapies but the unanswered question is whether the risk of treatment is justified. There are several reports of using psoralen therapy with ultraviolet light exposure (PUVA) as well as narrow band UBV light exposure in cutaneous mastocytosis, including TMEP (1-4). These reports describe improvement in the skin lesions but there is a risk of photoaging and an increase in skin cancer associated with this therapy. The other issue is that this treatment may be logistically challenging and is often, in my experience, not covered by insurance for these indications. However, the decrease in visible skin lesions may be very appealing in the management of your patient. Finally, there are reports of reduction in mast cell burden using an oral, multikinase inhibitor, midostaurin (FMS-like tyrosine kinase inhibitor or FLT) [Gotlib, Jason, et al. "Efficacy and safety of midostaurin in advanced systemic mastocytosis." New England Journal of Medicine 374.26 (2016): 2530-2541.]. Although cutaneous lesions are reduced, the side effects of tyrosine kinase inhibitor directed cytoreductive therapy is generally not justifiable for cutaneous disease. I could not find any studies investigating this therapy for cutaneous disease. It is also important to remember not to use imatinib if the cKIT mutation D816V is present, although midostaurin may be effective in such patients (Growney JD, Clark JJ, Adelsperger J, et al. Activation mutations of human c-KIT resistant to imatinib mesylate are sensitive to the tyrosine kinase inhibitor PKC412. Blood 2005;106:721-724).

In summary, you might consider referring your patient for narrow band UVB or PUVA light therapy after discussion the potential long term effects on the skin. I would not favor consideration of the tyrosine kinase inhibitors with a negative bone marrow and limited concerns about systemic disease.

I hope this information is of help to you and your patient.

All my best.
Dennis K. Ledford, MD, FAAAAI

1.Short- and long-term effectiveness of oral and bath PUVA therapy in urticaria pigmentosa and systemic mastocytosis. Godt O, Proksch E, Streit V, Christophers E. Dermatology. 1997;195(1):35.
BACKGROUND: Previous studies have shown that oral PUVA is effective in urticaria pigmentosa. Long-term results, however, are unknown.
OBJECTIVE: We studied the long-term effectiveness of oral PUVA treatment in urticaria pigmentosa as well as in systemic mastocytosis. In addition, the success of bath PUVA was examined in these diseases.
METHODS: Twenty patients with urticaria pigmentosa and systemic mastocytosis treated by oral PUVA were examined retrospectively for a time period of up to 18 years. We studied the duration of improvement and correlated these results with the total PUVA dose, the skin type and the age of onset. Four patients were treated by bath PUVA therapy.
RESULTS: In oral PUVA therapy an improvement was seen in 14 out of 20 patients (70%). There was no difference in the response rate between urticaria pigmentosa and systemic mastocytosis and there was no correlation with the total PUVA dosage. The duration of the treatment's success ranged from a few weeks to more than 10 years. 25% of the patients showed an improvement for more than 5 years. Patients with onset during childhood and early adolescence and patients with skin types I and II responded favourably to the treatment. Bath PUVA therapy was without effect in our 4 patients.
CONCLUSION: Oral PUVA is very effective for the long-term treatment of urticaria pigmentosa as well as systemic mastocytosis.

2. Telangiectasia macularis eruptive perstans successfully treated with PUVA therapy. Sotiriou E, Apalla Z, Ioannides D. Photodermatol Photoimmunol Photomed. 2010;26(1):46.
We present the case of a 58-year-old woman who was diagnosed as having telangiectasia macularis eruptiva perstans (TMEP) and was successfully treated with PUVA photochemotherapy. During the 6-month follow-up, no recurrence of pruritus or skin lesions was observed. TMEP represents a rare form of cutaneous mastocytosis, which is clinically characterized by reddish-brown telangiectatic macules symmetrically distributed over the trunk and extremities. Although in the majority of cases the disease is limited to the skin, systemic involvement may occur. The treatment of TMEP is challenging and several therapeutic modalities have been proposed in the past.

3. Telangiectasia macularis eruptiva perstans: unusual presentation and treatment. Rishpon A, Matz H, Gat A, Brenner S Skinmed. 2006;5(6):300.
A 41-year-old woman presented with a 2-month history of pruritus and a generalized dermatitis that developed initially on the head and spread to the trunk, legs, and buttocks. The pruritus caused extreme discomfort and was not relieved by antihistamines or topical steroid treatment. The patient denied flushing, syncope, and vomiting. Her medical history included asthma treated with salmeterol/fluticasone propionate inhaler, and status post silicone breast augmentation. Physical examination revealed a papular dermatitis on the trunk and extremities composed of lesions up to 0.5 cm in diameter, surrounded by excoriation marks (Figure 1). There was no hepatosplenomegaly or lymphadenopathy. Darier's sign was negative. Results of complete blood count, peripheral blood film examination, and liver function tests were all with normal limits. A biopsy specimen taken from a lesion and stained with hematoxylin-eosin showed telangiectasias, with an increased number of mast cells around blood vessels (Figure 2). Positive Giemsa (Figure 3) and c-kit stain (Figure 4) indicated an increased number of mast cells. Bone marrow aspiration and total body CT performed to rule out systemic involvement showed no pathology. Protein electrophoresis was normal. Serum tryptase and histamine were within normal limits, and 24-hour urine collection for histamine was normal. Narrow-band UV-B treatment was begun 3 times weekly, reduced to twice weekly after 2 months, and then stopped. The first few treatments resulted in significant relief of the pruritus and regression of lesions. After 3 months without treatment, the patient remained free of pruritus and lesions.

4. Indolent systemic mastocytosis treated with narrow-band UVB phototherapy: study of five cases. Brazzelli V, Grasso V, Manna G, Barbaccia V, Merante S, Boveri E, Borroni G . J Eur Acad Dermatol Venereol. 2012 Apr;26(4):465-9. Epub 2011 May 13.
BACKGROUND: Mastocytoses represent a heterogeneous group of stem cell disorders marked by an abnormal hyperplasia and accumulation of mast cells in one or more tissues, including bone marrow, gastrointestinal tract, liver, spleen, lymph nodes and skin. Indolent systemic mastocytosis (ISM) is characterized by red-brownish and pruriginous maculopapular lesions, a bone marrow infiltration without functional impairment and an indolent clinical course with a good prognosis. In particular, the most common cutaneous symptoms are urticarial rash and mild-to-high pruritus.
OBJECTIVES: This study analyses the clinical outcome of patients affected by ISM with prevalent pruriginous cutaneous symptoms and a scarce response to anti-histamines treated using narrowband ultraviolet B (NB-UVB) phototherapy.
METHODS: Narrowband ultraviolet B phototherapy was administered in a UV-irradiation cabin equipped with fluorescent UVB lamps with a peak emission at 311-313 nm. The perception of pruritus severity was assessed using the Visual Analogue Scale (VAS) before starting the treatment and at each control.
RESULTS: A complete remission of the cutaneous lesions and pruritus was documented in all patients after a median of 40.3 UV treatments and a median cumulative dose of 51.4 J/cm(2), with a lasting remission over a 6-month follow-up. The median VAS score at the beginning of the treatment was 86.6 (SD=6.64), whereas it decreased to 6.66 (SD=3.75) after 3 months of therapy.
CONCLUSIONS: Our work provides evidence that NB-UVB phototherapy is useful for the treatment of the cutaneous symptoms and pruritus in ISM.

Ask the Expert Archived Question
Repeated episodes of anaphylaxis with normal serum tryptase but elevated levels of urinary prostaglandin D2
1/16/2013
For three years, my 54 year old male patient has had 4 week episodes of urticaria at night asleep in bed, separated by 4 to 6 week asymptomatic periods. Urticaria responds to diphenhydramine. Between March and August, 2012 there were three very different episodes. Each happened when he was asleep at night. He awakens with a "stomach ache" and rectal urgency, His palms itch, then his scalp groin and buttocks itch. He feels hot but does not sweat. Urticaria +/- angioedema of the lips and face follow. He has a bowel movement, then becomes orthostatic and loses consciousness. By the time paramedics arrive he is already improving. If he takes diphenhydramine early in the process and lies flat he is spared the syncope. He is a creature of habit. There have no changes in his home or at his workplace. He doesn't have a snack before bed. He has never been atopic. His only medications are amlodipine, benazepril and metoprolol for hypertension, pravachol for dyslipidemia and a baby aspirin. These have been the same for years. He occasionally takes ibuprofen for low back pain, but never has done so on a day he has one of these episodes. He feels very well overall and has no constitutional symptoms of illness.

Vital signs: heart rate 88, BP 134/90, Resp. 22, temp 98.8, height 70", wt. 215#

Darier's sign was negative. There is no redness of his bulbar or palpebral conjunctivae. His nasal mucosa is slightly pale pink, but there is no turbinate edema or abnormal mucus. There is no lymphadenopathy, hepatosplenomegaly, or thyroidomegaly. The heart and lung exams are unremarkable. There are no cutaneous stigmata of atopy or urticaria pigmentosa. The rest of the physical exam is normal.

Laboratory: Baseline studies are all normal, namely serum serotonin, catecholamines, substance P, vasointestinal polypeptide, pancreastatin, plus 24 hr urine for 5HIAA. The plasminogen activator inhibitor antigen and the T cell subsets by flow cytometry were drawn but are not available.

I asked the patient to talk to his cardiologist about getting off his beta blocker and to take no other NSAID than his baby aspirin. In the subsequent four months he had only one episode which was very mild. He had flushing and felt hot, but had none of the other symptoms. He took hydroxyzine and ranitidine and went to the ER as I instructed him to do, and had acute studies done. This is where it gets weird. Serum tryptase 10.4 ( less than 11.2) done at Mayo, but 24 hr urinary PGD2 for which the normal range is 100-280ng/L was off the charts for this patient, greater than 5000 ng/L. It was sent by Mayo to Interscience Institute, where the supervisor ordered it repeated with the same results. Normal values were obtained for 24 hr urinary n-methyl histamine, metanephrines, normetanephrine , norepinephrine, epinephrine and dopamine.

My question is this: if this is a mast cell disorder, how could there be such a discrepancy between the 24 hr urinary PGD2 and the serum tryptase immediately after a mild episode? Is there another source for PGD2 other than mast cells? Should this patient have a bone marrow aspirate and biopsy now or should we wait a number of months for another episode and look for acute laboratory data again? After all, he has been having urticaria for four years and it is ten months since he had his first anaphylactoid episode.

I will start this response with a direct answer to the most important clinical question which you asked. Yes, in my opinion, you do need to do a bone marrow biopsy (rather than aspirate) on your patient. Having said this, I will expand on this point and present the rationale for this opinion as well as look at other salient points brought up by your patient’s presentation.

Several issues of importance are illustrated in this patient’s presentation. These are the differential diagnosis, the nocturnal predisposition for the episodes, the medications the patient was taking and the disjunction between the mediators that were measured.

We'll discuss each of these.

1. The differential diagnosis of an anaphylactic episode and the distinction between anaphylaxis and those conditions which mimic an anaphylactic episode is illustrated by your workup which included not only an assay of mast cell mediators, but also a search for markers of other conditions. It is of note that you measured serotonin, catecholamines, 5-hydroxyindoleacetic acid, pancreastatin and neuropeptides. The presentation which included abdominal symptoms certainly merited obtaining this workup. It calls attention to the fact that the differential in your case includes vasointestinal polypeptide secreting tumors (pancreastatin, neuropeptides), carcinoid syndrome (serotonin, 5-hydroxyindoleacetic acid) , and paradoxical pheochromocytoma (catecholamines). I might mention, parenthetically, that I see no rationale for the measurement of plasminogen activator inhibitor antigen or T-cell subsets.

2. It is also of interest that the episodes in your patient have all been nocturnal. I would therefore mention, parenthetically, that nocturnal episodes suggest the presence of IgE anti-galactose-alpha-1,3-galactose (alpha-gal). Since your patient has no history consistent with this in terms of mammalian meat ingestion, I don't believe that this diagnosis is likely, but wanted to mention it for the sake of completeness and for the readers of this response. I don't know if you reside in an area endemic for the Lone Star tick (Amblyomma americanum), but if you do, ordering an serum specific IgE to alpha-gal would be something to consider even though, as noted, the history doesn't suggest this other than for the fact these episodes have been nocturnal.

3. You appropriately addressed the issue of the beta-adrenergic blocking agent, and I also suggest that the angiotensin-converting enzyme inhibitor be discontinued if possible. The reason for this is that your patient experienced a hypotensive reaction, and part of the endogenous compensatory response to hypotension in anaphylaxis is generated through the activity of angiotensin II. In addition, angiotensin-converting enzyme inhibitors also prevent the degradation of kinins, and kinins can play a role in the pathogenesis of anaphylactic episodes. Although the role of angiotensin enzyme inhibitors as a risk factor for anaphylaxis has only been demonstrated conclusively in reactions to hymenoptera stings (1), in my opinion, the same principles would apply in a patient exhibiting idiopathic episodes of anaphylaxis.

4. Last but not least, I would like to address the discrepancy between the prostaglandin D2 levels and the serum tryptase which you highlighted in your inquiry.

There are multiple cellular sources of prostaglandins. For example, eosinophils can be a source of this molecule (2). Nonetheless, mast cells are the major source of prostaglandin D2, and mast cell activation can be monitored in vivo by measuring prostaglandin D2 and its metabolites (3). The question then becomes, does a selective elevation of prostaglandin D2 (as compared to other mediators) have clinical import.

The concept that there can be a disjunction in levels of mast cell mediators during an episode of anaphylaxis is not new. The measurement of mediators during events has documented variations on numerous occasions. (4, 5, 6).

For example, Lin and Schwartz (4) found that 42 of 97 patient s who experienced anaphylaxis had elevations in histamine, whereas only 20 experienced elevations in tryptase. In addition, patients with elevated histamine were more likely to have urticaria, more extensive erythema, abnormal abdominal findings, and wheezing. Vadas, et al. (5) demonstrated that platelet activating factor correlated better with the manifestations of anaphylaxis than did other mediators. And Simon Brown and colleagues (6) found that interleukins 2, 6, 10, TNF-receptor 1, mast cell tryptase, and histamine were all elevated in patients with severe reactions.

However, these studies were designed to look at the sensitivity and specificity of these mediators in anaphylactic episodes in general, and not identify a specific cause of these anaphylactic events. On the other hand, elevations of prostaglandin D2 and its metabolites may play a role in identifying mastocytosis per se as the cause of such episodes (7). This can of course be of clinical importance since such patients have been shown to respond to aspirin therapy, but not to antihistamine treatment (7).

This observation is one of the salient reasons I suggested that a bone marrow biopsy be done. Because of the elevation in prostaglandin D2, mastocytosis or a mast cell activating disorder is a strong diagnostic consideration, and the only definitive way to make a diagnosis would be a bone marrow biopsy.

References:
1. Ruëff F, Przybilla B, Biló MB, Müller U, Scheipl F, Aberer W, Birnbaum J, Bodzenta-Lukaszyk A, Bonifazi F, Bucher C, Campi P, Darsow U, Egger C, Haeberli G, Hawranek T, Körner M, Kucharewicz I, Küchenhoff H, Lang R, Quercia O, Reider N, Severino M, Sticherling M, Sturm GJ, Wüthrich B, et al. Predictors of severe systemic anaphylactic reactions in patients with Hymenoptera venom allergy: Importance of baseline serum tryptase - study of the European Academy of Allergology and Clinical Immunology Interest Group on Insect Venom Hypersensitivity. Journal of Allergy and Clinical Immunology 2009; 124(5):1047-1054.

2. Luna-Gomes T, Magalhães KG, Mesquita-Santos FP, Bakker-Abreu I, Samico RF, Molinaro R, Calheiros AS, Diaz BL, Bozza PT, Weller PF, Bandeira-Melo C. Eosinophils as a novel cell source of prostaglandin D2: autocrine role in allergic inflammation. J Immunol 2011 (December 15); 187(12):6518-26.

3. Ono E, Taniguchi M, Mita1 H, Fukutomi1 Y, Higashi1 N, Miyazaki E, Kumamoto T, Akiyama K. Increased production of cysteinyl leukotrienes and prostaglandin D2 during human anaphylaxis. Clin Exp Allergy 2009 (January); 39(1):72-80.

4. Lin RY, Schwartz LB, Curry A, et al. Histamine and tryptase levels in patients with acute allergic reactions: An emergency department-based study. J Allergy Clin Immunol 2000 (Jul); 106(1 Pt 1):65-71.

5. Vadas P, Perelman B, Liss G.Platelet-activating factor, histamine, and tryptase levels in human anaphylaxis. J Allergy Clin Immunol 2013; 131:144-49.

6. Stone SF, Cotterell C, Isbister GK, Holdgate A, et al. Elevated serum cytokines during human anaphylaxis: Identification of potential mediators of acute allergic reactions J Allergy Clin Immunol 2009; 124(4):786-792.

7. Butterfield JH, Weiler CR. Prevention of mast cell activation disorder-associated clinical sequelae of excessive prostaglandin D(2) production. Int Arch Allergy Immunol 2008; 147:338.

Thank you again for your inquiry and we hope this response is helpful to you.

Sincerely,
Phil Lieberman, M.D.

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