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IgG4-related disease for hematologists
ing angiomatoid transformation of the spleen (SANT) is known to be enriched with IgG4+ plasma cells, but whether this condition is part of the spectrum of IgG4-RD remains unclear, as many patients with sclerosing angiomatoid transformation of the spleen do not exhibit other features of IgG4-RD.73 The inability to biopsy splenic tissue short of full splenectomy hinders the histo- logical characterization of IgG4-RD in this organ.
Imaging and staging
Once histopathological confirmation of the diagnosis has been obtained, the disease can be staged by computed tomography of the chest, abdomen and pelvis.74 Although the orbit is a commonly involved organ in IgG4-RD, the absence of dacryoadenitis is suggestive that there is no underlying orbital pseudotumor and therefore dedicated head or orbital computed tomography is not always neces- sary.75 Positron emission tomography/computed tomogra- phy showed greater sensitivity for the detection of disease in arteries, salivary glands and lymph nodes in a study of 21 patients but further evaluation is needed to clarify which patients benefit from the combined tomographic method over conventional imaging.76 It is important to check the uri- nary albumin/creatinine ratio and serum C3/C4 levels to assess for renal involvement. IgG4-RD often behaves indo- lently, but accurate diagnosis and staging are crucial because some patients have asymptomatic but potentially organ- or life-threatening disease such as retroperitoneal fibrosis, peri-aortitis or coronary arteritis, the last of which may develop suddenly. Moreover, fibrotic disease is typically irreversible, so early treatment is important.
Case continued
Given the patient’s multi-organ involvement, particularly of the coronary arteries, he was treated with two doses of rituximab 1 g administered intravenously 2 weeks apart. His IgG4 level improved from 11.6 g/L to 5.84 g/L after 6 months. A repeat computed tomography scan of the chest and abdomen showed improvement of his coronary artery vasculitis, pulmonary nodules and lymphadenopathy and his post-treatment IgG4-RD Responder Index activity score was 3.
Treatment
Steroids are the first-line therapy for most patients, with an overall response rate of 93% and complete response rate of 66% in a phase 2 trial of 44 patients with IgG4-RD from Japan.77 The regimen used in this trial was pred- nisone 0.6 mg/kg/day initially with a gradual decrease of 5 mg every 2 weeks.77 Patients with higher eosinophil count, lacrimal gland involvement, five or more organs involved, and higher IgG4-RD Responder Index scores were at higher risk of glucocorticoid failure in a Chinese cohort of 215 patients.78 Some suggest a maintenance dosage of prednisone 5 mg daily for autoimmune pancre- atitis specifically, which, as one would expect, decreases relapse rates compared to placebo.79 However, the toxicity associated with steroids is well known, with 40% of patients experiencing new or worsening diabetes. Blood glucose levels should be checked regularly in all patients receiving steroid therapy and many of our patients are also followed by a diabetes specialist. Disease-modifying anti-rheumatic drugs are not very effective for induction of remission but may have a role in maintenance of remis-
sion for some patients.80-82 In the absence of prospective clinical trials, an international consensus guideline on IgG4-RD treatment had only a 46% expert agreement on whether disease-modifying anti-rheumatic drugs should be started from the outset of treatment or not.83
Rituximab has been shown to be highly effective for IgG4-RD, with a response rate of 97% (29 out of 30 patients) in one prospective trial.74 The majority of patients did not require concomitant corticosteroids from the time of enrollment. However, rituximab is difficult to access due to cost, particularly outside of the USA, and remissions are often short-lived. In a French database study of 33 patients who received rituximab, a clinical response was seen in 29/31 (93.5%) patients, but 13/31 (41.9%) responders relapsed during a mean follow up of 24.8 months (with the relapses occurring at a mean of 19 months after rituximab therapy).84 The severe infection rate was estimated to be 12.1/100 patient years and three patients had hypogammaglobulinemia <5 g/L. In our prac- tice, we often keep patients on a low dose of maintenance prednisone to maintain remission after rituximab treat- ment.
A number of emerging therapeutic options show prom- ise. An open label, phase 2 clinical trial of a humanized anti-CD19 antibody (Xmab®5871) showed that this treat- ment decreased the IgG-RD Responder Index score by ≥2 points in 12/12 patients who completed the study.85 Successful use of lymphoma chemoimmunotherapy regi- mens such as fludarabine and rituximab and bendamus- tine and rituximab have been reported for two steroid- and rituximab-refractory cases.28 Whether these patients needed T-cell directed therapy or simply more potent immunosuppression than can be achieved by steroids or rituximab alone requires further exploration. Elotuzumab is an enticing agent because of the expression of SLAMF7 both on circulating plasmablasts and on the CD4+ cyto- toxic T lymphocytes thought to drive the disease process. Anti-IgE therapy with omalizumab is also a potential tar- get for those with severe atopic disease or asthma and ele- vated IgE levels.
Conclusions
IgG4-RD is an important condition for hematologists to recognize, both because of its common hematologic man- ifestations of lymphadenopathy, eosinophilia and poly- clonal hypergammaglobulinemia, as well as its overlap with other hematologic inflammatory and neoplastic dis- eases. When IgG4-RD is suspected, measurement of serum IgG subclasses is a simple, non-invasive screening test; levels >5 g/L (normal <1.35 g/L) are highly suspicious for IgG4-RD. Regardless of serum IgG4 level, the defini- tive diagnosis requires histology, preferably in an affected organ other than lymph node or bone marrow, to confirm IgG4-RD and to exclude its many mimics. Early recogni- tion and treatment with steroids, rituximab, or other immunosuppressive therapies, is essential to prevent com- plications such as fibrosis, peri-aortitis, and renal failure.
Key points
• IgG4-RD is an important cause of eosinophilia, lym- phadenopathy and polyclonal hypergammaglobulinemia.
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