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What is IgG4?

A couple of important themes occur, however:. IgG4-RD typically has a subacute onset, meaning many patients have had active disease with no signs or symptoms for months or even years before the diagnosis is made. The result of this subacute onset is that organ damage often occurs even while the patient is feeling well, long before he or she comes to medical attention. Patients often feel well for long periods of time despite having disease in multiple organs. Fevers are rare to non-existent in IgG4-RD. Fatigue is often a common symptom, but because fatigue can be a common symptom for many conditions, patients often endure this symptom for long periods of time without a diagnosis.

Weight loss can be a prominent component of how IgG4-RD presents. The loss of anywhere between 10 and 50 pounds in IgG4-RD is often because of subclinical pancreatic dysfunction. The damaged pancreas is no longer making the appropriate amount of digestive enzymes.

As a result, patients do not absorb nutrients and calories from their food and often experience extreme weight loss that defies diagnosis for an extended period of time. The most common symptoms below are grouped according to organ:. Meninges — Patients with IgG4-RD affecting the meninges often present with headaches or dysfunction of the cranial nerves, which control eye movements, speech, swallowing, hearing, and other critical functions.

Some patients also develop double vision and the inability to move their eyes together in a coordinated fashion because of tethering of the extra-ocular muscles. Lacrimal glands — The lacrimal glands typically become enlarged. While they are normally not visible in healthy people, in patients with IgG4-related dacryoadenitis lacrimal gland disease , the glands may bulge noticeably under the eyelids. Major salivary glands — The parotid, submandibular and sublingual glands, like the lacrimal glands, often expand substantially in size, causing noticeable bulges on the sides of the face or below the chin.

The overall production of saliva is also often affected, leading to symptoms of a dry mouth. Inflammation within the thyroid gland can extend through the thyroid capsule and into surrounding tissues, particularly the airway. This can sometimes lead to airway compromise, requiring major surgery to remove the invasive inflammatory tissue that originated in the thyroid. Lungs — Patients can have symptoms of allergy and shortness of breath. The radiology features of IgG4-RD in the lung are extremely diverse and can mimic many other disorders.

The lining of the chest wall, the pleura, can also be affected by IgG4-RD. Aorta — Aortic lesions can be silent for long periods of time, until complications develop. In the thoracic aorta small branches that supply blood to the ribs and chest , the vessel wall grows thick because of internal inflammation. The presence of IgG4-RD is occasionally detected at surgery for an aortic aneurysm. In the abdomen, inflammation caused by IgG4-RD tends to affect around the aorta, rather than involve it directly. Kidneys — Kidney lesions, like those of the aorta, can also be clinically silent until advanced damage has occurred.

Signs of early kidney injury, however, can be detected on routine blood tests. The kidneys often become enlarged when affected by IgG4-RD, and renal cell carcinoma a primary kidney cancer is occasionally misdiagnosed. His serum creatinine level was 4. He was also taking tamsulosin 0. In view of the constitutional syndrome with cough, outpatient investigations had been undertaken, showing an initial creatinine level of 3.

Renal ultrasound revealed normalsized kidneys with correct corticomedullary differentiation, and a thoracic CT scan showed lesions compatible with two pulmonary masses. There was also slight peripheral infiltrate in the apical region of the RLL, with a non-specific inflammatory appearance. Another finding of note was the presence of mediastinal lymphadenopathies. A bronchoscopy was then performed, showing moderate infiltration of the subsegmental spur of the right basal segment, which was biopsied.

Bronchial aspirate samples were taken for microbiology and cytology. Ziehl-Neelsen staining was negative.

An attempt to perform a fine-needle aspiration biopsy of one of the pulmonary masses was unsuccessful due to technical problems; therefore, an in-patient mediastinoscopy was arranged with the Thoracic Surgery Department.. Finally, the patient was admitted to the Nephrology Department for study, diagnosis and treatment of acute renal failure, with progressive deterioration of renal function associated with pulmonary and lymph node involvement of unknown origin. The protein analysis showed beta-gamma bridging.

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The bone marrow aspirate ruled out monoclonal gammopathies.. We repeated the thoracic CT scan and confirmed the previously described pulmonary nodular images and mediastinal lymphadenopathies. The thoracic surgeons performed a mediastinoscopy with lymph node biopsy; lymphomatous disease was ruled out in the histology report.. Anatomic pathology study of the renal biopsy. Of the 15 glomeruli present in the sample, 9 were sclerosed and the rest had normal cells, with a slight mesangial matrix expansion.

Some thick, folded basement membranes were observed segmentally. The interlobular arteries presented a narrowed lumen caused by marked fibrosis of their inner layer.. The lymph cell infiltrate was predominantly T type.. The ultrastructural examination identified abundant electron-dense and amorphous deposits in the interior of thickened tubular basement membranes.

The only glomerulus in the ultrastructural study sample had thick, folded basement membranes, with a slight fusion of the podocytes. No electron-dense deposits were observed.. Figure 1 — Expansile interstitial fibrosis with a storiform pattern, tubular atrophy and destruction, and inflammatory infiltrate Masson trichrome x Anatomic pathology study of the mediastinal lymph node biopsies. The lymph nodes showed paracortical and follicular hyperplasia changes, as well as abundant plasma cell infiltrate..

The immunohistochemical analysis confirmed that the plasma cells were polyclonal; kappa and lambda light chains were positive. Figure 3 — Immunofluorescence for IgG with granular positivity in the tubular basement membranes and the Bowman capsule; the glomerulus is negative x The patient was treated with corticoids at a dose of 0.

Despite this, the patient is currently receiving haemodialysis, but has a good quality of life, as he is able to carry out his activities of daily living completely independently. It is likely that the extensive, chronic interstitial lesions seen in the biopsy contributed to the lack of renal recovery. A follow-up thoracic CT scan was performed after 8 months of the corticoid treatment, showing a reduction of the nodular lesions and no enlarged lymph nodes..

Figure 5 — Electron microscopy showing an atrophic tubule with thick basement membranes containing abundant electron-dense deposits x5, Our patient was referred to the Nephrology Department due to acute renal failure, while being investigated for pulmonary masses and mediastinal lymphadenopathies. The clinical-pathological correlation of this case led to the diagnosis of IgG4 nephropathy.. IgG4-related disease IgG4-RD is a systemic autoimmune process that has only recently been recognised. It usually presents as inflammatory masses in multiple locations. The clinical manifestations vary depending on disease severity and organs affected..

IgG4-RD is more prevalent among males than females, with a ratio of , and it is more frequent in patients over the age of Figure 6 — Thoracic CT scan: bilateral pulmonary nodules with air bronchograms and irregular margins. Note: Data from Okazaki and Umehara 9 and Umehara et al. Next to these comprehensive diagnostic criteria, several organ-specific criteria have been suggested, like for IgG4-related pancreatitis or for IgG4-related kidney disease.

Regardless of which criteria used, reliance on IgG4 levels poses a potential limitation, as those may be within the normal range in a considerable fraction of histologically proven patients with IgG4-RD. New biomarkers such as plasmablasts will probably improve sensitivity and specificity of such diagnostic tools. Nevertheless, until having proven evidence in larger clinical studies, scores and criteria can only support diagnosis but cannot replace expert experience in the assessment of clinical history and cautious interpretation of examination results.

Untreated IgG4-RD in vital organs such as pancreas and kidney can — even if asymptomatic — lead to irreversible organ damage within only months and therefore requires immediate treatment. Thus, watchful waiting with close follow-up examinations may be an option to be considered in certain patients with no or only mild symptoms, without signs of organ dysfunction and with IgG4-RD in locations not likely to cause major complications.

However, even highly fibrotic disease can respond to steroids. In some cases, not only surgical debulking but also endoluminal or endovascular interventions should be considered when indicated and are in some cases required as urgent surgical interventions, 50 , 55 especially when organ function is at risk. Glucocorticoids GCs have been considered the first-line therapy in IgG4-RD ever since the first description of AIP in , when prompt response to GC treatment was reported as a characteristic finding.

According to the recently published consensus statement on the treatment of IgG4-RD, the vast majority of IgG4-RD experts still regard GC as the first-line therapy for active, untreated disease. At least for IgG4-related pancreatitis, maintenance therapy seems to decrease the risk of a relapse. At the moment, most experts recommend an add-on therapy with steroid-sparing agents after relapses under GC treatment alone. RTX therapy leads to specific IgG4 reductions together with apparently very effective disease control, even in steroid refractory cases.

At the moment, evidence concerning RTX in IgG4-RD is still limited due to low patient numbers and the lack of larger prospective and especially randomized trials. IgG4-RD is a chronic, frequently relapsing disease, which often requires long-term maintenance therapy.

IgG4-Related Disease Clinic

Importantly, plasmablasts recently emerged as an apparently good indicator for disease activity, although their application as a longitudinal monitoring parameter still requires further research. Furthermore, serum IgG4, with all its limitations, as extensively described in this article, may characterize a more inflammatory and therapy-resistant type of IgG4-RD and thus also help estimate the disease activity. Regardless of the therapy modality ultimately chosen, it seems that relapses happen frequently in IgG4-RD. Up to now, there is no striking evidence of superiority for GC, alone or together with steroid-sparing drugs or for RTX in either remission induction or maintenance therapy.

Also, the question, whether timely GC discontinuation or long-term maintenance therapy with or without steroid-sparing agents is advisable after remission remains unanswered due to the lack of evidence from randomized trials. Anti-CD20 therapy approaches seem to be a promising new therapeutic option on the horizon. However, there is no consensus about dosage, frequency, and indication for RTX treatment, and especially, trials comparing RTX versus GC with or without steroid-sparing drugs are still lacking.

From the present point of view, GC are still regarded as the first-line therapy for induction and maintenance, while steroid-sparing drugs and RTX should be considered in relapsing or steroid-resistant cases as well as in patients with intolerance to GC treatment. Long-term maintenance therapy seems to be advisable at least in patients with a history of relapses and disease localizations in vital organs. IgG4-RD is a complex condition with a highly variable clinical appearance that can mimic various inflammatory and neoplastic diseases.

Its pathophysiology has still not been fully understood, though recent research suggests the existence of an antigenic trigger, initiating and perpetuating the disease. Having emerged within only 1 decade, its epidemiology is still widely unknown. IgG4-RD is probably underdiagnosed, especially in Europe and North America, where the awareness of its existence may be lower than in Asian countries, where the disease was originally discovered. Especially, the serum IgG4 levels, originally considered highly significant, have certainly lost importance in the diagnosis of IgG4-RD.

Histopathological proof is still regarded a gold standard and should be obtained if possible. Measurement of plasmablast counts in flow cytometry has recently emerged as a promising new diagnostic modality; however, more evidence in this field is certainly needed. In any case, all diagnostic findings need to be put into context with the clinical presentation of the patient carefully.

Differential diagnoses, especially malignancies, are numerous and have to be excluded before the treatment is initiated. GCs are effective in initial and relapse treatment and are widely used in maintenance therapy. From the present point of view, neither RTX nor GC treatment has been shown to be superior in therapy and the application of steroid-sparing drugs is still object to discussion.

Anyway, the true challenge in IgG4-RD is probably its long-term management, as relapses happen frequently, regardless of the therapy chosen. Thus, further advances in the treatment of IgG4-RD will most likely rather come with new parameters such as plasmablasts, which could allow monitoring of disease activity and exact timing of retreatment in order to prevent relapses before they actually happen. JZ received honoraria for educational activities and advisory board participation from Roche. The authors report no other conflicts of interest in this work.

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This article has been cited by other articles in PMC. Abstract Immunoglobulin G4-related disease IgG4-RD represents an immune-mediated fibroinflammatory condition with a characteristic histopathological appearance that can affect various organs. Introduction Immunoglobulin G4-related disease IgG4-RD is a condition characterized by an immune-mediated fibroinflammatory process with a tendency to form tumefactive lesions in various organs, occurring in a synchronous or metachronous fashion.

Epidemiology Prevalence, incidence, age, and sex Up to now, only little is known about the epidemiology of IgG4-RD and its organ manifestations.

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Organ distribution Traditionally, IgG4-related pancreatitis is regarded as the most frequent manifestation of IgG4-RD, 3 , 16 although organ distribution varies between the studies and is influenced by hospital and medical specialty. IgG4-RD and allergy Various studies from the past years have reported frequent atopic symptoms and concomitant laboratory findings among patients with IgG4-RD. T-cells and cytokines Since the discovery of IgG4-RD, a Type 2 helper T-cell Th2 -driven immunological mechanism has been proposed in its pathogenesis. Innate immunity and complement Latest studies have cast doubt over the model of IgG4-RD as a primarily T-cell-driven disease.

Future prospects Summing up, it appears that the role of innate immunity in IgG4-RD has been underestimated in the past and needs to be further clarified by future research, just like the question, whether IgG4 antibodies represent a causative factor or just a bystander in the disease. Differential diagnosis All those mentioned signs and symptoms are highly unspecific. Standard laboratory testing Besides renal, pancreatic, and liver manifestations, which may result in organ-specific laboratory findings, there is no standard laboratory parameter that would explicitly mark the presence of IgG4-RD.

Histopathology According to most experts, biopsy and histological proof is the gold standard in the diagnosis of IgG4-RD and should be acquired if anyhow possible. Imaging techniques As IgG4-RD frequently presents itself with organ enlargement and tumefactive lesions, imaging is obviously essential as malignancy is usually the main differential diagnosis.

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IgG4-related Orbital Inflammation

Diagnostic criteria In , Japanese investigators proposed comprehensive diagnostic criteria for IgG4-RD, according to which diagnosis should be based on three pillars Table 1. Therapy Indication for treatment Untreated IgG4-RD in vital organs such as pancreas and kidney can — even if asymptomatic — lead to irreversible organ damage within only months and therefore requires immediate treatment.

Initial treatment and maintenance therapy Glucocorticoids GCs have been considered the first-line therapy in IgG4-RD ever since the first description of AIP in , when prompt response to GC treatment was reported as a characteristic finding. Disease activity IgG4-RD is a chronic, frequently relapsing disease, which often requires long-term maintenance therapy.

Future prospects Regardless of the therapy modality ultimately chosen, it seems that relapses happen frequently in IgG4-RD. Conclusion IgG4-RD is a complex condition with a highly variable clinical appearance that can mimic various inflammatory and neoplastic diseases. References 1. Mod Rheumatol. IgG4-related disease: an orphan disease with many faces. Orphanet J Rare Dis. IgG4-related disease: dataset of consecutive patients.

Medicine Baltimore ; 94 15 :e Chronic pancreatitis caused by an autoimmune abnormality. Proposal of the concept of autoimmune pancreatitis. Dig Dis Sci.

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