Although examples of interstitial lung disease such as diffuse alveolar haemorrhage and interstitial fibrosis were the only ones acknowledged to be associated with Henoch-Schonlein purpura(HSP) in a recent review(1), the association of HSP and pan-acinar emphysema attributable to alpha-1 antitrypsin(AAT) deficiency also deserves mention(2), especially in view of the speculative relationship between anti neutrophil cytosplasmic antibodies(ANCA) and AAT deficiency, on the one hand(2), and ANCA vs HSP on the other(3)(4). Although the precise pathogenic basis of the association of AAT deficiency and the vasculitides is unclear, according to a recent evaluation a major role of alpha-1 antitrypsin(AAT) is to inhibit the destructive capabilities of proteinase-3(PR3), the serine protease released from neutrophils and monocytes at local sites of inflammation and tissue injury. Deficiency of AAT results in an increase in blood levels of free and active PR3 which, in turn generate further tissue injury and also generate an antibody response in the form of ANCA. ANCA, in turn, compounds PR3-related vascular injury by generating a cascade which includes activation of tumour necrosis factor(TNF)-primed neutrophils, accelaration of apoptosis of TNF-primed neutrophils, and secondary necrosis of the TNF-primed neutrophils themselves. The premature release of the toxic contents of the apoptopic cells is a further episode in the catalogue of ANCA-related tissue destruction.(2). In the clinical context a literature review revealed six cases of the association of AAT deficiency and HSP, one being a child aged 1.8 years when first reported, and the other five being adults aged 27-82. In the paediatric case there was no documentation of lung disease, and, in that instance, chronic renal disease was the significant complication of AAT deficiency. Among the five adults, four had documented pan-lobular emphysema, with co-existing chronic renal disease in three of those four. The one adult in whom pulmonary status had not been documented did also have chronic renal disease but the fourth adult with pan-lobular emphysema only experienced transient proteinuria and transient haematuria(2). In the latter instance, HSP was associated with ANCA of the Immunoglobulin G(IgG) subtype(5) whereas, among the three adults in whom pan-lobular emphysema co-existed with chronic renal disease, the one patient with ANCA was characterised by the IgA subtype of ANCA(2). In all, ANCA was present in only two of the 6 patients characterised by the association of AAT deficiency and HSP(2). Both had pan-lobular emphysema, but only one had chronic renal disease. ANCA of the IgA subclass was a feature of the patient with chronic renal disease(2), and ANCA of the IgG subclass charcterised the patient who was free of chronic renal disease(5). Although IgA ANCA has been identified in as many as 82.3% of 35 chidren aged 3-16 in the acute phase of HSP(3), among 28 consecutive adult HSP patients who presented predominantly with abdominal symptoms, the prevalence of ANCA(subtype not stated) was only 32.1%(4). In the former, no relationship was found between severity of HSP and IgA ANCA(3), but in the latter HSP patients with ANCA had significantly(p=0.02) higher clinical scores, significantly higher(p=0.01)serum creatinine levels, and significantly(p=0.03)higher 24 hour urinary protein excretion than their ANCA negative counterparts(4) However, given the variability in prevalence of ANCA in HSP patients free of AAT deficiency(3)(4), and the low prevalence of ANCA when HSP is associated with AAT(2), the role of ANCA, though speculative, nevertheless remains intriguing, especially in view of the theoretical considerations evaluated by Patterson et al(2). References (1) Tizard EJ., Hamilton-Ayres MJJ Henoch-Schonlein purpura Archives of Disease in Childhood 2008:93:1-8 (2)Patterson CC., Ross P., Pope-Harman AL., Knight DA., Magro CM Alpha-1 anti-trypsin deficiency and Henoch-Schonlein purpura associated with anti-neutrophil cytoplasmic and anti-endothelial cell antibodies of immunoglobulin-A isotype Journal of Cutaneous Pathology 2005:32:300-6 (3) Ozaltin F., Bakkaloglu A., Ozen S et al The significance of IgA class of antineutrophil cytoplasmic antibodies(ANCA) in childhood Henoch-Schonlein purpura Clinical Rheumatology 2004:23:426-9 (4) Zhang Y., Wu Y-K., Ciorba MA., Ouyang Q Significance of antineutrophil cytoplasmic antibody in adult patients with Henoch-Schonlein purpura presenting mainly with gastrointestinal symptoms World Journal of Gastroenterology 2008:14:622-6 (5) Meier P., Dayer E., Lemoine R., Blanc E Henoch-Schonlein purpura with IgG PR3-ANCA in a PiZZ alpha 1- antitrypsin deficient patient Nephrology Dialysis Transplantation 2001:16:1932-5

We read with great interest the paper by Shaw “Osteoporosis in pediatrics” (Arch. Dis. Child. Ed. Pract., December issue). The author doesn’t cite celiac disease as a specific cause of osteoporosis in children, although he correctly recommends celiac screening in case of suspected secondary osteoporosis.

A diminished bone mineral density with z score lower than -1.0 standard deviation (SD) can be found in up to 50% of children with celiac disease; more severe reduction of mineral density with z score lower than -2.5 SD is generally observed only in newly diagnosed children or in adults.[1] Moreover, celiac patients, including children, are at increased risk of hip fractures and fractures of any type.[2]

Osteoporosis in celiac disease may be due not only to malabsorption, but also to abnormalities in cytokine levels.[3] Increased levels of osteoclast-triggering cytokines, such as IL-1, IL-6 and TNFalfa, have in fact been found in untreated CD patients, while the level of inhibitory cytokines such as IL-18 and IL-12 may be lowered. Normalization of cytokines levels with a gluten-free diet may explain the increased bone mineral density observed in osteopenic celiac children, particularly under 4 years, while this effect is not so obvious in adults. [1, 4] As bone mineral density can be reduced both in symptomatic and in silent celiac disease, early diagnosis is important not only in order to achieve a normal bone mineral density, but also to prevent the onset of autoimmune conditions associated to celiac disease.[5]

In conclusion, osteopenia and osteoporosis may be the only manifestation of silent/latent celiac disease, leading to an increased risk of fractures. Given the high prevalence of celiac disease, and the effectiveness of a gluten-free diet in treating and preventing its complications, it is relevant to consider celiac disease in the differential diagnosis of osteoporosis in pediatrics.

References

1 Kalayci AG, Kansu A, Girgin N, et al. Bone mineral density and importance of a gluten free diet in patients with celiac disease in childhood. Pediatrics 2001;108:E89.

2 Ludvigsson JF, Michaelsson K, Ekbom A, et al. Coeliac disease and the risk of fractures – a general population based cohort study. Aliment Pharmacol Ther 2007;25:273-85.

3 Bernstein CN, Leslie WD. The pathophysiology of bone disease in gastrointestinal disease. Eur J Gastroenterol Hepatol 2003;15:857-64.

4 Tau C, Mautalen C, De Rosa S, et al. Bone mineral density in children with celiac disease. Effect of a gluten free diet. Eur J Clin Nutr 2006;60:358-63.

5 Hill ID, Dirks MH, Liptak GS, et al. Guideline for the diagnosis and treatment of celiac disease in chldren: recommendations of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition. J Pediatr Gastroenterol Nutr 2005;40:1-19.

Dear Editor,

Dr Roberts questions the point of treating warts and molluscum which are benign and will often spontaneously resolve, and expresses concern about discussing these methods of treatment at all. In terms of the former, I regret that I did not more explicitly state that the so-called "tincture of time" is, by far, the preferred method of treating these lesions. The focus of the review is on those cases where there is a compelling reason to seek further treatment, with emphasis on sorting through the vast (and often anecdotal) literature on these treatments.

As Dr Roberts notes, the consultant dermatologists carry a heavy load in the UK, and this is perhaps equally true in the US.[1] Ironically, it was the tremendous number of "emergency" consultations that are referred to our practice for warts and molluscum that prompted me to write this article. Many patients are referred by their pediatricians for warts and molluscum that have persisted or are spreading, causing a great deal of anxiety and frustration for all parties. Importantly, many of these patients express anger towards their pediatrician and frequently feel marginalized because they were told the lesions would go away without treatment. Sometimes, the children are ostracized from school, public pools or sporting events, adding psychological stress to the entire family.[2]

Much more concerning, however, is when doctors or the patients themselves feel compelled to treat these lesions and do so in ways that may cause harm. I specifically cautioned against using imiquimod for molluscum, for example, as I have seen many adverse effects when used for this purpose. I have seen patients apply powerful acids and create painful ulcers which scar, and have seen children traumatized by curettage without anesthesia of any sort. The secondary purpose of the paper, then, is to discuss these methods openly and without bias, so that if treatment is deemed necessary, there is some context and experience for choosing an appropriate treatment in a manner that is safe for the patient.

Drs Goodyear and Taibjee raise concern that I impugn evidence-based medicine (EBM). In fact, in my five-page paper with almost 50 references from the peer-reviewed literature including heavy reliance on the Cochrane Database, I sought to explore the area where there is not yet enough evidence to make easy rational choices about treatment of these skin diseases. Indeed, on the British Association of Dermatologists website, the only treatments that were given the strength of evidence D ("There is fair evidence to support the rejection of the use of the procedure") were oral cimetidine and homeopathy.[3] There were no treatments given strength of evidence E ("There is good evidence to support the rejection of the use of the prodedure"). In fact, two of the treatments I discussed (imiquidmod and heat treatment/balneotherapy) were deemed to have insufficient evidence at this time. As a strong proponent of EBM, I try to remain vigilant for the fallacy of argumentum ad ignorantiam in all its forms, which in this case might be best put: "absence of evidence is not evidence of absence."

In sum, I overwhelmingly agree with the comments of Drs Goodyear, Taibjee, and Roberts and appreciate the opportunity to put the review in a proper light.

References:

1. Tsang MW, Resneck JS Jr. Even patients with changing moles face long dermatology appointment wait-times: a study of simulated patient calls to dermatologists. J Am Acad Dermatol 2006;55(1):54-8.

2. Braue A, Ross G, Varigos G, et al. Epidemiology and impact of childhood molluscum contagiosum: a case series and critical review of the literature. Pediatr Dermatol 2005;22:287–94.

3. BAD.org.uk/healthcare/guidelines/cw.