Serum Anti-GAD (Code 30068) Notice of Assessment

Transcription

1 Serum Anti-GAD (Code 30068) Notice of Assessment June 2013 DISCLAIMER: This document was originally drafted in French by the Institut national d'ecellence en santé et en services sociau (INESSS), and that version can be consulted at It was translated into English by the Canadian Agency for Drugs and Technologies in Health (CADTH) with INESSS s permission. INESSS assumes no responsibility with regard to the quality or accuracy of the translation. While CADTH has taken care in the translation of the document to ensure it accurately represents the content of the original document, CADTH does not make any guarantee to that effect. CADTH is not responsible for any errors or omissions or injury, loss, or damage arising from or relating to the use (or misuse) of any information, statements, or conclusions contained in or implied by the information in this document, the original document, or in any of the source documentation.

2 1 GENERAL INFORMATION 1.1 Requestor: Hôtel-Dieu (CHUM) 1.2 Application Submitted: September 28, Notice Issued: April 12, 2013 Note: This notice is based on the scientific and commercial information (submitted by the requestor[s]) and on a complementary review of the literature according to the data available at the time that this test was assessed by INESSS. 2 TECHNOLOGY, COMPANY, AND LICENCES 2.1 Name of the Technology Detection of serum anti-gad (anti glutamic acid decarboylase) antibodies by radioimmunoassay (RIA) (code 30068) 2.2 Brief Description of the Technology Anti-GAD antibodies target the glutamic acid decarboylase (GAD) enzyme. 21 The technology used by the requestor for detecting anti-gad antibodies is a radioimmunoassay (RIA) designed to detect specific proteins based on the degree of competition between a radioisotope-labelled antigen and an antigen to be assayed relative to a specific antibody. The antibody binds to the labelled antigen ( 125 I-labelled human recombinant GAD65) in liquid phase. Adding a Protein A suspension precipitates the resulting antigen-antibody complees (GAD 125 I-anti-GAD), and the amount of radioactivity is measured. The precipitated immune complees are washed and centrifuged and the supernatant discarded; lastly, a gamma scintillation counter assay of the specific antibodies is conducted. The amount of radioactivity in the precipitate is proportional to the concentration of anti-gad autoantibodies in the sample (Cisbio Bioassays, 2011; Walikonis and Lennon, 1998). Other technologies, such as ELISA, are also available for this purpose. 2.3 Company or Developer: No information available 2.4 Licence(s): Not applicable 2.5 Patent, If Any: Not applicable 21 An enzyme that catalyzes the decarboylation of glutamic acid in gamma aminobutyric acid (GABA) present in high concentrations in the brain and pancreas. GAD eists in two isoforms: 67 kda and 65 kda. The latter is the predominant form in the pancreas. 1

3 2.6 Approval Status (Health Canada, FDA) The requestor indicates that the kit in question is licensed by Health Canada, but provides no additional details. The GADAb RIA Assay Kit offered by Kronus Market Development Associates Inc. is licensed by Health Canada under number The 510(k) Number assigned by the FDA as for the KRONUS GADAb RIA Assay Kit is k Weighted Value: CLINICAL INDICATIONS, PRACTICE SETTINGS, AND TESTING PROCEDURES 3.1 Targeted Patients Patients with diabetes who require confirmation of a differential diagnosis of type 1 versus type 2 diabetes. Other clinical indication: patients who require confirmation of a diagnosis of stiff-man syndrome Targeted Diseases Diabetes is a disorder of carbohydrate metabolism that manifests as hyperglycemia. It causes shortterm (infection, ketoacidosis) and long-term complications (e.g., end-stage renal disease due to vascular impairment). The categories of diabetes are type 1 (insulin-dependent diabetes), caused by autoimmune destruction of the pancreatic islet beta cells; type 2 (non-insulin-dependent or adultonset diabetes), caused by insulin resistance and inadequate insulin secretion; and gestational, owing to a glucose intolerance during pregnancy. The onset of type 1 diabetes is quite rapid, compared with the onset of type 2, and complications can develop several years before a clinical diagnosis (Sacks, 2011; PHAC, 2011; Canadian Diabetes Association, 2008). In new-onset type 1 diabetes, anti-gad antibodies are found in 70% to 80% of patients and often persist after diagnosis (Mueller et al., 2010). For diagnosis of type 1 diabetes, the presence of serum anti-gad antibodies has a sensitivity of 75% and a specificity of 100% (Fielding et al., 2007). High titers of anti-gad antibodies have been reported in 70% of patients with stiff-man syndrome, 23 a rare neurological disease (Seissler and Scherbaum, 2006) that affects mainly women. Many patients with this syndrome (30%) also have insulin-dependent diabetes (Orphanet, 2007). In Canada, 90% to 95% of diagnosed cases of diabetes are type 2, while 5% to 10% are type 1 (PHAC, 2011). 3.3 Number of Patients Targeted According to the requestor, an average 50 tests per week, or 2,500 tests per year, are projected over the net three years. 3.4 Medical Specialties Involved (and Other Professions, If Any) Endocrinology, internal medicine and clinical biochemistry 22,29 Stiff man syndrome: syndrome characterized by muscular rigidity, painful spasms and cramps 2

4 3.5 Testing Procedure The assay requires a blood sample. 4 TECHNOLOGY BACKGROUND 4.1 Nature of the Diagnostic Technology: Unique 4.2 Brief Description of the Current Technological Contet A diabetes diagnosis requires the following assays and clinical signs: a fasting plasma glucose concentration of 7.0 mmol/l; a casual plasma glucose concnetration of 11.1 mmol/l, plus symptoms of diabetes (polyuria, polydipsia and uneplained weight loss); two-hour plasma glucose concentration of 11.1 mmol/l after oral ingestion of 75 g glucose (Canadian Diabetes Association, 2008). 4.3 Brief Description of the Advantages Cited for the New Technology Anti-GAD antibodies, unlike the other autoantibodies directed against the islet cell, can be detected long after a diagnosis of type 1 diabetes. For this reason, anti-gad antibody testing is preferred when the diagnosis of latent autoimmune diabetes of adulthood (LADA) is sought in individuals with longstanding diabetes (type 2) (Winter and Schatz, 2011). 4.4 Cost of Technology and Options: Not analyzed 5 EVIDENCE 5.1 Clinical Relevance 5.2 Other Tests Replaced: Not Applicable 5.3 Diagnostic, Prognostic or Therapeutic Value 3

5 Table 1: Prevalence of Anti-GAD Antibody Positivity in Cohort, by Type of Diabetes STUDY TYPES OF DIABETES PREVALENCE Lucchetta, 2010 Type 1 diabetes 40% Katulanda, 2008 Type 1 (7%) Type 2 (89.7%) LADA (2.6%) 5.4% Type 1 diabetes 29.6% Saiz, 2008 Type 1 diabetes 18% Vigo, 2007 Type 2 diabetes 7.3% Castleden, 2006 Type 2 diabetes 7% Rodacki, 2004 Type 1 diabetes 45.8% * 42.1% 52% 40% Abbreviation: LADA = latent autoimmune diabetes in adults Four groups of patients with type 1 diabetes were established according to disease duration: * Group 1: 1 to 5 years Group 2: 6 to 10 years Group 3: 11 to 15 years Group 4: > 15 years According to the included studies, the prevalence of anti-gad antibody positivity is higher among individuals with type 1 diabetes, which confirms that this type of diabetes is of autoimmune etiology. Positivity prevalence ranges from 18% to 40% for type 1 diabetes. A narrative review of 10 representative studies spanning 7 countries has revealed that the prevalence of anti-gad autobodies in new-onset type 1 diabetes ranges from 52% to 75% of patients (Winter et al., 2002). Prevalence remains constant regardless of disease duration: one study showed no correlation between anti-gad positivity and duration of type 1 diabetes (p=0.738) (Rodacki et al., 2004). As well, the study showed no difference in the anti-gad antibody titers observed for each of four groups of different disease durations: ± 11.8; ± 12.07; ± 8.35, and ± 16.1 U/mL, respectively (p=0.686). This observation contradicts the assumption that new-onset type 1 diabetes presents a higher prevalence of anti-gad antibodies than does longstanding diabetes. Lucchetta et al. (2010) reported that 20 of 50 patients with type 1 diabetic (40%) were positive for an anti-gad antibody. They also found that the mean duration of type 1 diabetes was significantly shorter in anti-gad antibody-positive patients than in their antibody-negative counterparts (15.25 ±10.4 versus 25.9 ± 10.8 years; p<0.001). For patients with type 2 diabetes, the presence of anti-gad antibodies indicates that autoimmune destruction is active and that the disease is likely progressing toward the latent form of type 1 diabetes and, therefore, toward insulin dependence. In the study by Castleden et al. (2006), anti- GAD antibody-positive patients with type 2 diabetes were more likely to start insulin-treatment than their antibody-negative counterparts (62% versus 30% (p < 0.001)) and progressed to insulin treatment faster (13.8 years versus 17 years (p < 0.001)). Katulanda et al. (2008) reported that 5.4% of the patients with diabetes, mainly type 2, were anti-gad antibody positive. Anti-GAD antibody positivity was seen in 19.5% of those who required insulin, compared with 2.8% who did not require it (OR: 3.3; 95% CI: 1.6 to 6.8; p=0.002). 4

6 Vigo et al. (2007) tracked a cohort of 10,275 people with no clear diabetes diagnosis at the outset of the study for a period of nine years. Their goal was to investigate the predictive value of anti- GAD antibodies for the onset and progression of diabetes. Their study found no association between anti-gad antibody positivity and the development of diabetes, based on the results of an unadjusted analysis (HR: 0.93; 95% CI: 0.59 to 1.48) and on the results of analyses adjusted for age, gender, ethnicity, family history of diabetes, glucose, body mass inde, insulin use, hypertension and inflammation score (HR: 1.04; 95% CI: 0.55 to 1.96). At the end of the Vigo study follow-up, 59% of the anti-gad antibody-positive patients and 49% of their antibody-negative counterparts had received a clinical diagnosis of diabetes. Among these patients, 62% of those anti-gad antibody-positive and 9% of those anti-gad antibody-negative were on insulin. The authors indicate that anti-gad antibody positivity increases ten-fold the risk of progressing to insulin use (HR: 9.9; 95% CI: 3.4 to 28.5; p < 0.001). To summarize, the anti-gad antibody is a marker that allows confirmation of new-onset type 1 diabetes, confirms autoimmune progression of type 2 diabetes toward type 1, and recognizes the autoimmune etiology of the stiff-man syndrome. It is not effective for predicting the incidence of type 1 diabetes in a population at risk. 5.4 Clinical Validity COMPONENT PRESENCE ABSENCE NOT APPLICABLE Sensitivity Specificity Positive predictive value (PPV) Negative predictive value (NPV) Likelihood ratio (LR) Receiver operating characteristics (ROC) curve Accuracy Forty-si laboratories participated in the Diabetes Antibody Standardization Program (Bingley et al., 2003). Blood samples were obtained from 50 patients with newly diagnosed type 1 diabetes receiving insulin therapy; control samples were obtained from blood donors. The samples were tested using several anti-gad antibody assay methods. 5

7 Table 2: Clinical Performance of Anti-Gad Antibody Assays (Bingley et al., 2003) ANTI-GAD SENSITIVITY SPECIFICITY Radioimmunoassay* 88% 100% Radio-binding assay 58% to 88% 80% to 100% Immunofluorescence 60% 96% ELISA 72% 92% * Anti-GAD antibodies were assayed in association with the anti-tyrosine phosphatase (IA-2) antibody 5.5 Analytical (or Technical) Validity COMPONENT PRESENCE ABSENCE NOT APPLICABLE Repeatability Reproducibility Analytical sensitivity Analytical specificity Matri effect Concordance Correlation Other, depending on type of test Radioimmunoassay of anti-gad antibodies (Rodacki et al., 2004): Inter-assay CV: 3.5% Intra-assay CV: 3.1% No correlation between anti-gad antibody positivity and decision to start insulin therapy: r (Pearson) = ; p=0.006 (Katulanda et al., 2008) 5.6 Recommendations for Listing in Other Jurisdictions Anti-GAD antibody assays in other jurisdictions The Anti-GAD65 assay is used in Alberta 24 for the following indications: May be useful when it is difficult to distinguish type 1 diabetes from type 2 diabetes or when the probability of progression from type 2 to type 1 is high To aid in the diagnosis of stiff-man syndrome or other neurological disorders Test performed on diabetic patients with a C peptide <0.8 nmol/l or if prescribed by a neurologist 24 Alberta Health Services. Anti-GAD65 (GAD65) (website). Available at 6

8 5.6.2 Recommendations from the Type 1 Diabetes Treatment Guideline (Group Health, 2012) Islet cell autoantibody assays, including those for anti-gad antibodies, are recommended for diagnosing: diabetes among young patients (teenagers) to distinguish early type 1 diabetes from type 2 diabetes diabetes among adults who are not overweight and who are not responding to oral hypoglycemic therapy and lifestyle (diet/eercise) modifications type 1 diabetes: these antibodies must be tested simultaneously Recommendations of the American Diabetes Association and the American Association for Clinical Chemistry (Sacks et al., 2011) Islet cell autoantibodies assays: Are recommended for screening nondiabetic family members who wish to donate part of their pancreas for transplantation to a relative with end-stage type 1 diabetes; Are not recommended for diagnosis of type 1 diabetes or type 2 diabetes or of persons from the general population; May be used for classification of diabetes in adults, in prospective clinical studies, in clinical studies to determine the genetic risk for type 1 diabetes in children with typical human leukocyte antigen (HLA) at birth, and for identifying possible mechanisms of failure in treatment of type 2 diabetes (B grade recommendation). It is important that islet cell autoantibodies be measured in an accredited laboratory with an established quality-control program and participation in a proficiency-testing program ( good practice point recommendation). 6 ANTICIPATED OUTCOMES OF INTRODUCING THE TEST 6.1 Impact on Material and Human Resources: Not assessed 6.2 Economic Consequences of Introducing Test into Quebec s Health Care and Social Services System: Not assessed 6.3 Main Organizational, Ethical, or Other (Social, Legal, Political) Issues: Not assessed 7

9 7 INESSS NOTICE IN BRIEF Serum Anti-GAD Antibodies (Code 30068) Status of the Diagnostic Technology Established Innovative Eperimental (for research purposes only) Replacement of technology:, which becomes obsolete INESSS Recommendation Keep test in the Inde for the indications described in the application Remove test from the Inde Reassess test Additional Recommendation Draw connection with listing of drugs, if companion test Produce an optimal use guide Identify indicators, when monitoring is required 8

10 REFERENCES Agence de la santé publique du Canada (ASPC). Le diabète au Canada : Perspective de santé publique sur les faits et chiffres. Ottawa, ON : ASPC; Available from: Association canadienne du diabète. Lignes directrices de pratique clinique 2008 de l'association canadienne du diabète pour la prévention et le traitement du diabète au Canada. Can J Diabetes 2008;32(Suppl 1):S1-S225. Bingley PJ, Bonifacio E, Mueller PW. Diabetes Antibody Standardization Program: First assay proficiency evaluation. Diabetes 2003;52(5): Castleden HA, Shields B, Bingley PJ, Williams AJ, Sampson M, Walker M, et al. GAD antibodies in probands and their relatives in a cohort clinically selected for Type 2 diabetes. Diabet Med 2006;23(8): Cisbio Bioassays. Trousse GAD-AB (Février Modèle 13). Cisbio Bioassays; Available from: Fielding AM, Brophy S, Davies H, Williams R. Latent autoimmune diabetes in adults: Increased awareness will aid diagnosis. Ann Clin Biochem 2007;44(Pt 4): Group Health. Type 1 diabetes treatment guideline. Seattle, WA : Group Health Cooperative; Available from: Katulanda P, Shine B, Katulanda GW, Silva A, Asfir EL, Sheriff R, et al. Diabetes mellitus among young adults in Sri Lanka Role of GAD antibodies in classification and treatment: The Sri Lanka Young Diabetes study. Diabetologia 2008;51(8): Lucchetta M, Rudilosso S, Costa S, Bruttomesso D, Ruggero S, Toffanin E, et al. Anti-ganglioside autoantibodies in type 1 diabetes. Muscle Nerve 2010;41(1):50-3. Mueller PW, Achenbach P, Lampasona V, Schlosser M, Williams AJK. Type 1 diabetes autoantibodies: Prediction and diagnosis of autoimmune diabetes. Clin Lab News 2010;36(10):8-10. Orphanet. Syndrome de l homme raide (Website). Paris, France : Orphanet; Available from: Rodacki M, Zajdenverg L, Albernaz MS, Bencke-Gonçalves MR, Milech A, Oliveira JE. Relationship between the prevalence of anti-glutamic acid decarboylase autoantibodies and duration of type 1 diabetes mellitus in Brazilian patients. Braz J Med Biol Res 2004;37(11): Sacks DB, Arnold M, Bakris GL, Bruns DE, Horvath AR, Kirkman MS et al. Guidelines and recommendations for laboratory analysis in the diagnosis and management of diabetes mellitus. Diabetes Care 2011;34(6):e Saiz A, Blanco Y, Sabater L, Gonzalez F, Bataller L, Casamitjana R, et al. Spectrum of neurological syndromes associated with glutamic acid decarboylase antibodies: Diagnostic clues for this association. Brain 2008;131(Pt 10): Seissler J et Scherbaum WA. Autoimmune diagnostics in diabetes mellitus. Clin Chem Lab Med 2006;44(2):

11 Vigo A, Duncan BB, Schmidt MI, Couper D, Heiss G, Pankow JS, Ballantyne CM. Glutamic acid decarboylase antibodies are indicators of the course, but not of the onset, of diabetes in middle-aged adults: The Atherosclerosis Risk in Communities Study. Braz J Med Biol Res 2007;40(7): Walikonis JE et Lennon VA. Radioimmunoassay for glutamic acid decarboylase (GAD65) autoantibodies as a diagnostic aid for stiff-man syndrome and a correlate of susceptibility to type 1 diabetes mellitus. Mayo Clin Proc 1998;73(12): Winter WE et Schatz DA. Autoimmune markers in diabetes. Clin Chem 2011;57(2): Winter WE, Harris N, Schatz D. Immunological markers in the diagnosis and prediction of autoimmune type 1a diabetes. Clin Diabetes 2002;20(4):