Esophageal involvement is frequent and often early in SSc. Smooth muscle atrophy and autonomic dysfunction reduce lower esophageal sphincter (LES) tone and peristalsis, leading to refractory heartburn, nocturnal regurgitation, and dysphagia to both solids and liquids. Chronic microaspiration is associated with worse interstitial lung disease. [5] [6] [9]

Upper endoscopy (EGD) documents esophagitis, strictures, and Barrett’s esophagus while excluding structural causes. High-resolution manometry characterizes motility (ineffective peristalsis, absent contractility, hypotensive LES). pH-impedance monitoring quantifies both acid and non-acid reflux; gastric emptying studies should be considered in cases of early satiety, nausea, or vomiting. Suspect small intestinal bacterial overgrowth (SIBO) if there is bloating and diarrhea; breath testing or empiric therapy may be used. [5] [7] [10]

Optimization of proton pump inhibitors (PPIs) is the cornerstone of therapy; non-pharmacological measures include head-of-bed elevation, avoidance of late or heavy meals, weight reduction, and limiting alcohol, caffeine, and peppermint. [11] Prokinetics such as metoclopramide or domperidone (depending on safety profile), 5-HT4 agonists, and baclofen (for predominant regurgitation, to reduce transient LES relaxations) may be considered. [6] [11] Treat SIBO with non-absorbable or cyclic antibiotics; provide nutritional support. Surgical anti-reflux procedures should be approached with caution, with partial fundoplication preferred. In selected cases, endoscopic dilation relieves peptic strictures, ideally combined with reflux control. [5] [6] [11]

Other gastric entities in SSc include gastroparesis, presenting with nausea and early satiety. Gastric antral vascular ectasia (GAVE) leads to iron deficiency or overt bleeding and is treated with endoscopic ablation and hematimetric monitoring. [5]

AIG is an atrophic gastritis affecting the corpus and fundus, mediated by autoantibodies against parietal cells and/or intrinsic factor, associated with hypochlorhydria, hypergastrinemia, and enterochromaffin-like (ECL) cell hyperplasia. It frequently coexists with other autoimmune conditions such as Sjogren’s syndrome, Hashimoto thyroiditis, and type 1 diabetes, and may present initially with iron deficiency or PA due to vitamin B12 deficiency. [12] [13]

The diagnostic approach includes basic laboratory tests such as complete blood count, iron studies, vitamin B12, anti-parietal cell and anti-intrinsic factor antibodies, serum gastrin, and pepsinogen I/II. [14] EGD with topographic biopsies following the Sydney protocol defines atrophy and metaplasia and can guide risk assessment for type I neuroendocrine tumors or, less commonly, adenocarcinoma. [14] [15] Treatment includes correction of B12 and iron deficiency, eradication of Helicobacter pylori if present, and endoscopic surveillance; screening for associated autoimmune diseases is also recommended. [14]

Celiac disease (CD) often coexists with other autoimmune disorders and may present with chronic diarrhea, weight loss, or extraintestinal manifestations such as iron-deficiency anemia and elevated transaminases. [16] Initial screening includes anti-tissue transglutaminase IgA (tTG-IgA) antibodies along with total IgA; in IgA deficiency, tTG-IgG or deamidated gliadin peptide (DGP-IgG) should be used. [17] Multiple duodenal biopsies remain the confirmatory standard in adults; however, the 2023 ACG guidelines conditionally acknowledge a non-biopsy approach in cases with very high tTG-IgA titers, extrapolating ESPGHAN criteria, and reserve HLA-DQ2/DQ8 typing for complex diagnostic scenarios. Follow-up should document histological recovery and clinical response to a gluten-free diet. [16] [17]

In systemic lupus erythematosus (SLE), the clinical spectrum includes lupus enteritis (mesenteric vasculitis), protein-losing enteropathy (PLE), and small intestinal bacterial overgrowth (SIBO). [18] Lupus enteritis typically presents with abdominal pain, nausea, and diarrhea; CT imaging may show the “target sign” due to bowel wall edema and mucosal enhancement, and it generally responds to systemic corticosteroids. [19] Lupus-associated PLE, although uncommon, may represent an initial manifestation, characterized by hypoalbuminemia with absent or minimal proteinuria; it requires immunosuppression targeting underlying lupus activity. [20] In Sjogren’s syndrome, dysautonomia and dysmotility predispose to refractory diarrhea secondary to SIBO or bile acid malabsorption. Breath tests and non-absorbable antibiotics are useful diagnostic and therapeutic tools, alongside management of functional comorbidities. [21] [22]

Adult-onset AIE is rare but clinically relevant in cases of intractable chronic diarrhea with weight loss. Diagnostic criteria include villous atrophy with failure to respond to exclusion diets such as gluten-free regimens, with anti-enterocyte or anti-goblet cell autoantibodies often absent. [23] Histology may demonstrate crypt apoptosis and a graft-versus-host-like pattern. It is essential to exclude infectious causes, drug-induced injury (e.g., immune checkpoint inhibitors), collagenous sprue, and seronegative CD. [23] - [25] Treatment is based on induction with corticosteroids and steroid-sparing agents (azathioprine, tacrolimus/sirolimus) and, in refractory cases, biologics such as infliximab or vedolizumab, along with intensive nutritional support. Genetic characterization (e.g., immune regulatory defects) may guide targeted therapies in specific subgroups. [26] Early recognition is crucial to prevent recurrent hospitalizations and severe malnutrition. [26]

AIH may present with elevated ALT (sometimes with cholestatic features), asthenia, and arthralgias, along with hypergammaglobulinemia (IgG) and positive autoantibodies such as ANA and SMA, or anti-LKM/anti-SLA. [27] Liver biopsy is essential to confirm interface hepatitis and to exclude alternative diagnoses; scoring systems (IAIHG, simplified) help establish diagnostic probability. [28] The 2025 EASL and AASLD guidelines recommend prednisolone at 0.5 - 1 mg/kg/day or 40 - 60 mg/day as first-line therapy, combined with azathioprine at 1 - 2 mg/kg/day. Budesonide 9 mg/day is an option in non-cirrhotic patients without portal involvement. [27] [29] The therapeutic goal is a complete biochemical response (normal ALT/AST and IgG), with maintenance achieved using the steroid-sparing agent. Thiopurine methyltransferase activity should be assessed before initiating azathioprine, and adverse events must be monitored. [27] - [29]

Diagnosis is typically established with elevated alkaline phosphatase (ALP) and positive antimitochondrial antibodies (AMA-M2), without requiring liver biopsy unless there is diagnostic uncertainty or suspicion of overlap syndrome/steatohepatitis. [30] Ursodeoxycholic acid at 13 - 15 mg/kg/day indefinitely remains the therapeutic standard; biochemical response is evaluated at 12 months to stratify risk. In cases of insufficient response, a selective farnesoid X receptor agonist such as obeticholic acid may be considered, although it should be avoided in decompensated cirrhosis. Management should also address pruritus, osteoporosis surveillance, and cirrhosis-related complications. [30] [31]

PSC follows a course of chronic cholestasis and is strongly associated with ulcerative colitis. Diagnosis is based on MRCP/ERCP showing characteristic multifocal strictures and dilatations in a “beaded” pattern; if imaging is normal but suspicion remains high, liver biopsy may demonstrate small-duct PSC. Serum IgG4 should be measured to exclude IgG4-related sclerosing cholangitis (IgG4-SC). Routine use of ursodeoxycholic acid is not recommended; management focuses on treating dominant strictures endoscopically, controlling bacterial cholangitis, and surveillance for cholangiocarcinoma and IBD (periodic colonoscopy). Liver transplantation should be considered in advanced disease. [32] [33]

AIP is a fibroinflammatory form of pancreatitis that may present with obstructive jaundice, mild abdominal pain, or a pancreatic mass mimicking adenocarcinoma. [34] Two phenotypes are recognized: type 1, which represents the pancreatic manifestation of IgG4-related disease (IgG4-RD) and is typically multi-organ; and type 2, which is limited to the pancreas and lacks IgG4-RD features. Diagnosis is guided by the International Consensus Diagnostic Criteria (ICDC), which integrates five domains: pancreatic parenchymal/ductal imaging, serology, other organ involvement, histology, and steroid responsiveness (the latter being optional). [35]

First-line treatment consists of glucocorticoids—prednisone at 0.6 mg/kg/day for 2 - 4 weeks with gradual tapering. In many centers, low-dose maintenance (≈5 mg/day) for 6 - 24 months is considered to reduce relapse, which is more frequent in type 1 AIP and in the setting of proximal cholangiopathy. [36] In relapses or steroid intolerance, azathioprine or other steroid-sparing agents may be used; rituximab is effective for inducing and maintaining remission, particularly in IgG4-RD with biliary involvement. Endoscopic biliary decompression is reserved for cases with cholangitis or significant obstruction. [37]

In summary, AIP should be suspected in patients with obstructive jaundice or “idiopathic pancreatitis” with characteristic imaging findings, elevated serum IgG4, and/or multi-organ involvement. Clinical and radiologic resolution with corticosteroid therapy is a defining feature within the ICDC and aids in differentiating AIP from pancreatic neoplasia. [34] [36]