Chronic pancreatitis (CP) is a continuing or relapsing inflammatory disease of the pancreas. In approximately one-third of all cases, no aetiological factor can be found, and these patients are classified as having idiopathic disease. Pathophysiologically, autodigestion and inflammation may be caused by either increased proteolytic activity or decreased protease inhibition. Several studies have demonstrated mutations in the cationic trypsinogen gene (PRSS1) in patients with hereditary or idiopathic CP. It is thought that these mutations result in increased trypsin activity within the pancreatic parenchyma. Most patients with idiopathic or hereditary CP, however, do not have mutations in PRSS1 (ref. 4). Here we analysed 96 unrelated children and adolescents with CP for mutations in the gene encoding the serine protease inhibitor, Kazal type 1 (SPINK1), a pancreatic trypsin inhibitor. We found mutations in 23% of the patients. In 18 patients, 6 of whom were homozygous, we detected a missense mutation of codon 34 (N34S). We also found four other sequence variants. Our results indicate that mutations in SPINK1 are associated with chronic pancreatitis.

Accumulation of CFTR variants in CP is less pronounced than reported previously, with ORs between 2.7 and 4.5. Only CF-causing variants reached statistical significance. Compound and trans-heterozygosity is an overt risk factor for the development of CP, but the number of CFTR compound heterozygotes in particular is rather low. In summary, the study demonstrates the complexity of genetic interactions in CP and a minor influence of CFTR alterations in CP development.

Chronic pancreatitis is a common inflammatory disease of the pancreas. Mutations in the genes encoding cationic trypsinogen (PRSS1) and the pancreatic secretory trypsin inhibitor (SPINK1) are associated with chronic pancreatitis. Because increased proteolytic activity owing to mutated PRSS1 enhances the risk for chronic pancreatitis, mutations in the gene encoding anionic trypsinogen (PRSS2) may also predispose to disease. Here we analyzed PRSS2 in individuals with chronic pancreatitis and controls and found, to our surprise, that a variant of codon 191 (G191R) is overrepresented in control subjects: G191R was present in 220/6,459 (3.4%) controls but in only 32/2,466 (1.3%) affected individuals (odds ratio 0.37; P = 1.1 x 10(-8)). Upon activation by enterokinase or trypsin, purified recombinant G191R protein showed a complete loss of trypsin activity owing to the introduction of a new tryptic cleavage site that renders the enzyme hypersensitive to autocatalytic proteolysis. In conclusion, the G191R variant of PRSS2 mitigates intrapancreatic trypsin activity and thereby protects against chronic pancreatitis.

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To the Editor: I have several concerns about the metaanalysis by Dr Gould and colleagues 1 about positron emission tomography (PET) imaging for diagnosis of pulmonary nodules. First, the prevalence of malignancy in the articles that they included was extremely high (55%-100%; mean, 72%), suggesting that the types of lesions that have been evaluated thus far with PET imaging are those with a very high likelihood of malignancy. The accuracy of PET imaging may be far lower in a population in whom the risk of malignancy is lower. The sensitivity might be lower because of a milder spectrum of disease in patients with a lower risk of malignancy, and the specificity might be lower because of more overlapping PET findings in small lesions of varying etiologies. 2 Thus, the results of their review are only applicable to a population of patients with a very high prevalence of cancer. Until additional studies provide evidence that PET imaging is accurate in a population with a low prevalence of cancer, it is premature to suggest application of PET imaging in this group, as the authors have done.Second, Gould et al did not sufficiently address the issue of heterogeneity of the different studies in their meta-analysis. The data appear fairly consistent with respect to sensitivity but appear extremely variable with respect to specificity, and it is not appropriate to average the specificity estimates when the results are so inconsistent. While I believe that specificity is less important if patients would otherwise proceed to surgery in the absence of PET imaging, if PET imaging were applied to a low-risk population as the authors suggest, the false-positive rate would become quite important.Finally, the authors apply receiver operating characteristic (ROC) curve methods to the data, but it does not appear that the different accuracy reported by the different studies has much to do with threshold differences. Was there truly a significant correlation between the sensitivity and the false-positive rate? I would guess that sorting the studies in Figure 1 by sensitivity would not show an inverse relationship between sensitivity and specificity but rather would confirm that there is simply a lot of heterogeneity with respect to specificity. ROC curve methodology is complex and difficult to understand, and I think it is best used to compare the results of more than 1 test. In this case, the ROC curve does not provide accurate information for the clinician who would like to know what performance they can hope to obtain from this test. It seems clear that the sensitivity of PET imaging (in a high-risk population) is high but that the specificity is more difficult to estimate.

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ObjectivesThe rarity of early diffuse cutaneous systemic sclerosis (dcSSc) makes randomised controlled trials very difficult. We aimed to use an observational approach to compare effectiveness of currently used treatment approaches.MethodsThis was a prospective, observational cohort study of early dcSSc (within three years of onset of skin thickening). Clinicians selected one of four protocols for each patient: methotrexate, mycophenolate mofetil (MMF), cyclophosphamide or ‘no immunosuppressant’. Patients were assessed three-monthly for up to 24 months. The primary outcome was the change in modified Rodnan skin score (mRSS). Confounding by indication at baseline was accounted for using inverse probability of treatment (IPT) weights. As a secondary outcome, an IPT-weighted Cox model was used to test for differences in survival.ResultsOf 326 patients recruited from 50 centres, 65 were prescribed methotrexate, 118 MMF, 87 cyclophosphamide and 56 no immunosuppressant. 276 (84.7%) patients completed 12 and 234 (71.7%) 24 months follow-up (or reached last visit date). There were statistically significant reductions in mRSS at 12 months in all groups: −4.0 (−5.2 to −2.7) units for methotrexate, −4.1 (−5.3 to −2.9) for MMF, −3.3 (−4.9 to −1.7) for cyclophosphamide and −2.2 (−4.0 to −0.3) for no immunosuppressant (p value for between-group differences=0.346). There were no statistically significant differences in survival between protocols before (p=0.389) or after weighting (p=0.440), but survival was poorest in the no immunosuppressant group (84.0%) at 24 months.ConclusionsThese findings may support using immunosuppressants for early dcSSc but suggest that overall benefit is modest over 12 months and that better treatments are needed.Trial registration numberNCT02339441.