The guidance aims to address delays in recognition and improve timely initiation of treatment in this rare condition.
The European Reference Network for Rare Connective Tissue Diseases has released guidance for clinicians to consider IgG4-related disease in a bid to promote earlier diagnosis and treatment.
Recognising these red flags in primary and secondary care is crucial for early referral to specialists, especially given the potential for significant organ damage, such as fibrosis or loss of organ function, early detection and appropriate treatment can prevent irreversible damage.
European researchers published the guidance in The Lancet Rheumatology this month, describing it as the “first set of red flags for IgG4-related disease”.
“These red flags are based on expert opinion rather than on established evidence and highlight an important knowledge gap in the field of IgG4-related disease,” they wrote.
“These red flags require validation in longitudinal cohorts. Although the absence of evidence in support of our results prevents them from being conclusive, this work provides important recommendations for future research and represents an opportunity to increase disease awareness among non-specialists.”
The researchers said primary care physicians and specialists might not regularly encounter IgG4-RD, but it was important to remain vigilant for these red flags, especially when a patient presents with unexplained swelling, organ dysfunction, or other symptoms that do not fit a common diagnostic pattern.
The five red flags include:
- Swelling in one or more organ systems: This is often one of the most common and earliest signs of IgG4-RD. The disease can cause enlargement or swelling in various organs, such as the salivary glands, lymph nodes, pancreas and kidneys.
- Pancreatic and biliary tree Involvement: The pancreas is often affected, sometimes presenting as autoimmune pancreatitis. Biliary tract involvement, such as sclerosing cholangitis, is also common in IgG4-RD.
- Increased serum IgG4 levels: Elevated serum IgG4 levels are often seen in IgG4-RD but are not specific to the condition. A rise in IgG4 levels should prompt further investigation, especially when clinical signs are suggestive of IgG4-RD.
- IgG4 plus plasma cell tissue infiltration: Histologic evidence of IgG4-positive plasma cell infiltration in affected tissues is a hallmark of the disease. This can be seen on biopsy samples from affected organs, although the researchers said obtaining such a sample might not always be feasible in early stages.
- Obliterative phlebitis: Inflammation and fibrosis of small veins can be detected in certain organs like the pancreas or retroperitoneum. It is a key histopathological feature of IgG4-RD and can help distinguish it from other conditions.
As part of the development of the guidance, a task force of 28 clinicians with expertise in IgG4-RD, two primary care physicians, two statisticians, and two patient representatives was assembled.
The methodological approach included a systematic literature review; evaluation of selected items among the experts based on the results of the systematic literature review; and a level of agreement exercise to define red flags of IgG4-related disease.
The systematic review aimed to collect evidence indicating signs and symptoms that should raise suspicion of IgG4-related disease in a primary care setting. Studies providing diagnostic accuracy of such signs and symptoms from medical history, laboratory and imaging results published between January 2012 and December 2022.
Overall, 4477 records were retrieved, and after removal of duplicates, 2747 titles and abstracts were screened from which nine full texts were examined and subsequently seven studies included in the main qualitative analysis.
Five diagnostic precision studies provided estimates of sensitivity, specificity, predictive values, or other measures of diagnostic accuracy, while two cohort studies provided large amounts of multicentric and adequately described data focusing on symptoms at presentation of IgG4-RD.
The authors said raising suspicion of IgG4-related disease would “foster early referral to tertiary care centres for diagnostic confirmation and timely treatment with effective therapies”.
“Further studies should include analysis of primary care data from patients ultimately diagnosed with IgG4-related disease,” they concluded.
“This information would help to identify the reasons for the consultation that eventually led to the suspicion of IgG4-related disease and uncover knowledge gaps, resource constraints, and organisational barriers in this specific setting.
“Future potential red flags are likely to change as further evidence of sociodemographic and risk factors emerge.”
