Efficacy and safety of thalidomide in patients with inflammatory ...

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LETTERS TO THE EDITOR 997

J ALLERGY CLIN IMMUNOL VOLUME 132, NUMBER 4

increased intrathecal mast cell activity. Although mast cells are found in diverse parenchymal regions in other animals, human neuropathologic studies show localization in mainly the dura mater and regions devoid of blood-brain barrier.6 Neuropathologic studies of patients with mastocytosis are lacking. The clinical observation that disodium cromoglycate might improve brain fog7 despite its inability to penetrate the bloodbrain barrier is consistent with the hypothesis that peripheral mast cell activity is important in the pathophysiology of neuropsychological symptoms. Along these lines, a recent series of patients without mastocytosis demonstrated a high correlation between gastrointestinal mucosal mast cell density and the presence of headache.8 However, other authors have noted a lack of association between serum tryptase levels and neuropsychological measures.1 The limitations of our study include the small number of patients, inclusion of only female patients, and the limited detection threshold of our assay. Evidence for intrathecal mast cell activity might very well be detected with a higher-sensitivity technique. In the one other study that has looked at tryptase levels in CSF, differences were found in patients with multiple sclerosis that were less than the detection threshold of our assay.5 Future studies should address the penetration of peripheral mast cell mediators across the blood-brain barrier and correlations with neuropsychological measures. This would be important because mast cell degranulation has a recognized capacity to disrupt the blood-brain barrier, directly modulate neuronal function, and change behavioral states.9 Multiple mast cell–derived mediators can influence neuronal activity, including serotonin, histamine, cytokines, and lipid-derived factors.9 Jonathan H. Smith, MDa Melissa R. Snyder, PhDb Catherine R. Weiler, MDc F. Michael Cutrer, MDa Joseph H. Butterfield, MDc From the Departments of aNeurology, bLaboratory Medicine and Pathology, and cAllergic Disease, Mayo Clinic, Rochester, Minn. E-mail: [email protected]. Supported by a foundation grant awarded by the Mastocytosis Society. Disclosure of potential conflict of interest: J. H. Smith, M. R. Snyder, C. R. Weiler, and F. M. Cutrer have received a foundation grant from the Mastocytosis Society. J. H. Butterfield has received a foundation grant from the Mastocytosis Society and receives royalties according to licensing agreements with MedImmune, Amgen, Janssen Biotech, Wyeth-Ayerst, and Actelion for the use of HMC-1 cells.

REFERENCES 1. Hermine O, Lortholary O, Leventhal PS, Catteau A, Soppelsa F, Baude C, et al. Case-control cohort study of patients’ perceptions of disability in mastocytosis. PLoS One 2008;3:e2266. 2. Rogers MP, Bloomingdale K, Murawski BJ, Soter NA, Reich P, Austen KF. Mixed organic brain syndrome as a manifestation of systemic mastocytosis. Psychosom Med 1986;48:437-47. 3. Escribano L, Alvarez-Twose I, Sanchez-Munoz L, Garcia-Montero A, Nunez R, Almeida J, et al. Prognosis in adult indolent systemic mastocytosis: a long-term study of the Spanish Network on Mastocytosis in a series of 145 patients. J Allergy Clin Immunol 2009;124:514-21. 4. Moura DS, Sultan S, Georgin-Lavialle S, Barete S, Lortholary O, Gaillard R, et al. Evidence for cognitive impairment in mastocytosis: prevalence, features and correlations to depression. PLoS One 2012;7:e39468. 5. Rozniecki JJ, Hauser SL, Stein M, Lincoln R, Theoharides TC. Elevated mast cell tryptase in cerebrospinal fluid of multiple sclerosis patients. Ann Neurol 1995;37: 63-6. 6. Dropp JJ. Mast cells in the human brain. Acta Anatomica 1979;105:505-13. 7. Soter NA, Austen KF, Wasserman SI. Oral disodium cromoglycate in the treatment of systemic mastocytosis. N Engl J Med 1979;301:465-9.

8. Yeom JS, Choi MB, Seo JH, Park JS, Lim JY, Park CH, et al. Relationship between headache and mucosal mast cells in pediatric Helicobacter pylori-negative functional dyspepsia. Cephalalgia 2013;33:323-9. 9. Nautiyal KM, Ribeiro AC, Pfaff DW, Silver R. Brain mast cells link the immune system to anxiety-like behavior. Proc Natl Acad Sci U S A 2008;105:18053-7. Available online June 27, 2013. http://dx.doi.org/10.1016/j.jaci.2013.04.060

Efficacy and safety of thalidomide in patients with inflammatory manifestations of chronic granulomatous disease: A retrospective case series To the Editor: The prognosis of patients with chronic granulomatous disease (CGD) has improved in recent years thanks to earlier recognition and prevention of infectious complications.1 In this context an important concern remains the management of inflammatory manifestations (ie, colitis, interstitial pneumonitis, cystitis, or neutrophilic dermatosis). Gastrointestinal tract disorders, the prevalence of which can be as high as 60% and mimic Crohn disease (fistulae, perforations, and aseptic abscesses),2 can affect the quality of life and prognosis of these patients. Immunosuppressive agents (corticosteroids and azathioprine) are associated with significant adverse effects, mostly infections. Moreover, in a series of 5 patients treated with anti–TNF-a agents,3 infections were more frequent, and 2 deaths occurred despite effectiveness in severe colitis, thus raising concerns regarding their safety in such patients. The alternative in severe cases is allogeneic hematopoietic stem cell transplantation (HSCT).4 However, this procedure can be associated with significant mortality. In this retrospective study we report the clinical efficacy and safety profile of thalidomide, an immunomodulatory agent with TNF-a antagonist properties, in the inflammatory manifestations of CGD. Of 119 patients followed in the Centre de R!ef!erence des D!eficits Immunitaires H!er!editaires5 between 1968 and 2011, 70 (58.8%) experienced at least 1 inflammatory manifestation. Eight patients (7 male patients with mutations in CYBB and 1 female patient with a mutation in NCF1) received thalidomide for inflammatory manifestations (Table I). Their median age at diagnosis of CGD was 13 months (range, 1-188 months). Inflammatory conditions were colitis (n 5 6, see Fig E1 in this article’s Online Repository at www.jacionline.org), interstitial lung disease or nodular consolidation (n 5 4), neutrophilic dermatosis (n 5 1), and histologically proved granulomatous hepatitis (n 5 1). Inflammatory lung disease presented with 2 distinct patterns: mass-like nodular consolidation (patients 3 and 6, see Figs E2 and E3 in this article’s Online Repository at www. jacionline.org) and interstitial lung disease (patients 4 and 5, see Fig E4 in this article’s Online Repository at www. jacionline.org). The nodular consolidations corresponded to granuloma pathologically, and no evidence of infectious pneumonia was found at the time of their occurrence. Overall, 4 patients had only 1 inflammatory manifestation (colitis, n 5 3; granulomatous hepatitis, n 5 1), and 4 patients presented with 2 manifestations (colitis and pneumonia, n 5 3; pneumonia and neutrophilic dermatosis, n 5 1), leading to a total of 12 inflammatory flares.

998 LETTERS TO THE EDITOR

J ALLERGY CLIN IMMUNOL OCTOBER 2013

TABLE I. Assessment of efficacy and tolerance of thalidomide Patient no. 1

2

3

4

Sex/inheritance

M/X-linked (gp91phox)

M/X- linked (gp91phox)

M/X- linked (gp91phox)

M/X- linked (gp91phox)

Past infectious disease

BCGitis, colitis (Salmonella dublin)

Pulmonary aspergillosis, pneumonia, septicemia (Salmonella typhimurium), adenitis (Staphylococcus aureus)

Adenitis (Staphylococcus aureus), colitis (Salmonella paratyphi B), pleuropneumonia, mandibular osteitis

No./type of sites of granulomatous manifestations

1/Colitis, stomatitis

1/Colitis

Cutaneous abscesses (Serratia marcescens), mediastinitis (Propionibacterium acnes), pulmonary aspergillosis 2/Colitis Nodular lung lesions

Symptoms

Abdominal pain, diarrhea, aphtosis

Abdominal pain, diarrhea, rectal bleeding

Dyspnea, Pancoast-Tobias syndrome, diarrhea

Diarrhea, aphtosis, dyspnea

Age at thalidomide initiation (y) Duration of inflammatory symptoms (y)/no. of flares before thalidomide Other therapies before thalidomide

Initial/maximal thalidomide dosage (mg/d) Clinical efficacy

Time to first improvement (mo) Corticosteroids (mg/kg/d) at thalidomide’s initiation Duration of corticosteroid use (mo) Adverse effects Duration of thalidomide’s use/follow-up (mo) Outcome

2/Colitis, stomatitis Reticulonodular pneumonia

25

17

22

34

3/6

4/