Enzyme Therapy in Gaucher Disease Type 1: Effect of Neutralizing Antibodies to Acid β-Glucosidase

Ponce, Elvira; Moskovitz, Jay; Grabowski, Gregory A.

doi:10.1182/blood.v90.1.43.43_43_48

Cited by 25 publications

(16 citation statements)

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“…14,15 A similar experience was found in patients treated with growth hormone therapy and with enzyme replacement in Gaucher's disease. [16][17][18] Hence, our finding is in keeping with this phenomenon and may explain some of the side effects seen in the RoSA study. In addition, modification of circulating tetracosactide concentrations by sequestration or increased clearance mediated by circulating anti-ACTH antibodies could account for treatment failure in some of the patients and 'treatment resistance' observed in one participant, who lacked a sustained improvement during tetracosactide therapy.…”

Section: Discussionsupporting

confidence: 88%

Spontaneous and tetracosactide‐induced anti‐ACTH antibodies in man

Gan

MacArthur

Mitchell

et al. 2015

Clinical Endocrinology

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SummaryContextDuring a clinical trial of regular tetracosactide depot injections, four of 13 patients with autoimmune Addison's disease (AAD) developed adverse reactions immediately following tetracosactide injections. We wished to investigate whether these adverse effects could be due to the production of circulating antitetracosactide (ACTH1–24) antibodies.DesignAnti‐ACTH binding activity was investigated using immunoblotting and ELISA on sera from participants in the trial (n = 13; baseline and after tetracosactide exposure), 131 unrelated patients with AAD, 92 patients with Graves’ disease (GD), 15 patients with isolated ACTH deficiency and 102 controls. Immunohistochemistry of human pituitary tissue sections was also performed using pooled sera.ResultsBands at approximately 4 and 6 kDa, corresponding to ACTH1–24 and full‐length ACTH1–39, respectively, were found in 10 of 13 (77%) of sera from trial patients exposed to tetracosactide, including all those who had an adverse reaction. This is in contrast with healthy control sera, which showed no binding. The same 10 subjects also showed high levels of binding to tetracosactide by ELISA, along with 21% of patients with AAD, 14% of patients with GD (both P < 0·001 compared to controls) and 1 isolated ACTH deficiency patient (7% of 15). These sera also recognized native ACTH in human pituitary sections.ConclusionOur study demonstrates that repeated administration of depot tetracosactide can lead to anti‐ACTH1–24 autoreactivity. In addition, a significant number of patients with AAD and GD also had similar, spontaneous, anti‐ACTH reactivity. The presence of these antibodies could mediate some of the adverse effects or explain the well‐described phenomenon of resistance to chronic ACTH therapy.

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Section: Discussionsupporting

confidence: 88%

Spontaneous and tetracosactide‐induced anti‐ACTH antibodies in man

Gan

MacArthur

Mitchell

et al. 2015

Clinical Endocrinology

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“…Rapid enlargement of the spleen in an adult with the disease should prompt suspicion of an associated disorder that may increase glycolipid turnover, such as hematologic malignancy, immune thrombocytopenia, or autoimmune hemolytic anemia. Splenomegaly complications [ 10 , 11 ] include hypersplenism with increased risk of infections, pain, rupture and infracts when the enlargement exceed 20-fold. In our study splenomegaly was constantly observed and complicated in one case with infracts ans abcesses ( Figure 3 , Figure 4 ).…”

Section: Discussionmentioning

confidence: 99%

Gaucher’s disease: report of 11 cases with review of literature

Essabar¹,

Meskini²,

Lamalmi³

et al. 2015

Pan Afr Med J

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Gaucher's disease (GD) is a lysosomal storage disorder due to glucocerebrosidase deficiency; it's one of the rare genetic diseases for which therapy is now available. The purpose of this work is to study the epidemiological features of the disease and to highlight the diagnostic difficulties. We performed an 11-year retrospective study of 11 patients with GD followed-up in the department of paediatric hepatology gastroenterology and nutrition of Rabat children's Hospital. We observed 11 patients with GD: 6 males and 5 females. Age at onset ranged from 3 months to 10 years with an average of 3.41 years. Mean age at diagnosis was 4 years (range 3months-14years). Parental consanguinity was noted in 85% cases. According to the clinical presentation, we classified our patients into: 9 cases of type 1 (81%) and two cases of type 2 (19%), none of the patients presented GD type 3. GD type 1: The age at diagnosis ranged from 2 years to 14 year with an average of 6 years. Main symptoms were: splenomegaly, hepatomegaly, pallor, haemorrhagic appearance (40%), bone pain (40%). The diagnosis was based on histology showing the Gaucher's cells in various tissues (100%). Enzymatic activity dosage confirmed the diagnosis of GD for 4 patients (44.5%). The treatment was always symptomatic (analgesics, transfusion). A splenectomy was performed in one case presenting with multiple splenic abscesses and high transfusion requirements. None of the patients received a specific treatment (substitutive enzymotherapy). The follow-up period ranged from 3 months to 6 years with an average follow-up of 4 years. We noticed stability in 4 cases, 2 worsening cases with bone and spleen complications. Three patients were lost to follow-up. GD type 2: we observed two cases of GD type 2 diagnosed at 3 and 18 months. The visceral symptoms were serious and the neurological features included seizures, hypertony, squint, physical developmental milestones delay. Both of them died. Gaucher's disease is not exceptional in Morocco. Type 1 is the most common type. We noted through this study some diagnostic difficulties as the diagnosis was delayed and the enzymatic dosage was performed in only 42% of the cases as well as therapeutic difficulty with no prescription of the specific treatment given the high cost of the enzyme.

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“…In humans, the effect of anti‐rhGAA antibodies on the efficacy of ERT is controversial. In patients with Gaucher disease, reduced efficacy of ERT was attributed to the enzyme‐neutralizing capacity of the induced antibodies 4, 5. In Pompe disease caused by complete absence of GAA, antibody production against rhGAA is increased due to a lack of immune tolerance, and the therapeutic response is worse 6.…”

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confidence: 99%