IgG4-Related Orbitopathy.

Immunoglobulin G4-related disease (IgG4-RD) has been increasingly recognized immune-mediated disorder affecting almost all major organs of the body having clinical, pathological, and immunohistochemical markers.1 Some of the commonly shared features include tumor-like swelling of involved organs, a lymphoplasmacytic infiltrate having IgG4-positive plasma cells, and a variable degree of fibrosis that has a characteristic “storiform” pattern along with elevated serum IgG4 levels.2 Some of the sites involved include, IgG4-related autoimmune pancreatitis, salivary gland enlargement or sclerosing sialadenitis, retroperitoneal fibrosis affecting ureters leading to hydronephrosis and renal injury, heart, hard palate, esophagus, stomach, small intestine, adrenal gland, uterus, ureter, bladder, and synovium.3 Orbitopathy due to IgG4-RD has recently been implicated as the cause of dacryoadenitis, myositis, and optic neuropathy.4 In this issue of MEAJO, Lokdarshi et al. discuss the role of IgG4-RD in their review of pathogenesis of the sclerosing lesions of the orbit and relate this to systemic sclerosing pseudo tumor-like lesions.5

Strategies in the diagnosis and treatment of orbital IgG4-RD continue to evolve. Several different diseases that have been known for many years to cause ophthalmopathy are now considered to be manifestations of IgG4-RD.4 The pathogenesis of IgG4-RD is not well understood, it appears that IgG4 seems to play a role. Among patients with the IgG4-related ophthalmic disease, bilateral lacrimal gland involvement is typical, even though the onset of clinical disease may be asynchronous. Concurrent salivary gland involvement is common. Histologic and serologic findings are similar to those seen in patients with sialadenitis and in other tissues. IgG4-RD also appears to account for 25–50% of orbital pseudotumors, including those originally diagnosed, before recognition of IgG4-RD, as orbital benign lymphoid hyperplasia.23 IgG4-RD is also recognized as a cause of orbital myositis that leads to proptosis and diplopia among patients presenting with complaints. Patients may present with enlargement of lacrimal and salivary glands (parotid and/or submandibular) or with chronic sclerosing sialadenitis and unilateral or bilateral submandibular gland enlargement. These entities were previously called Mikulicz disease (or syndrome) and Küttner's tumor and were often erroneously considered to be subcategories of Sjogren's syndrome.45

The diagnosis of IgG4-RD is based upon biopsy findings demonstrating the characteristic histopathologic findings and immunohistochemical staining.4 These findings include lymphoplasmacytic tissue infiltration of mainly IgG4-positive plasma cells and lymphocytes, accompanied by fibrosis that has storiform features and often by obliterative phlebitis. A modest tissue eosinophilia is often present. Serum IgG4 levels should be measured, and isolated elevated levels are a significant aid in diagnosis, although they are not diagnostic. The histopathological and immunohistochemical staining features of IgG4-RD are strikingly similar in different tissues, regardless of the organ or tissue involved. Patients at high risk for having IgG4-RD are those with any of the following: Pancreatitis of unknown origin, sclerosing cholangitis, bilateral lacrimal/salivary gland enlargement or retroperitoneal fibrosis, orbital pseudotumor, or proptosis.4 After the biopsy of the local organ, a computed tomography scan of the chest, abdomen, and pelvis in patients diagnosed with IgG4-RD is recommended. Some patients may require additional imaging studies and when available, positron emission tomographic scanning can also be highly effective in determining the extent of disease and should be considered at baseline prior to initiating treatment.

Optimal treatment for IgG4-RD has not been established. No randomized trials have evaluated approaches to the treatment of either IgG4-RD overall or any organ-specific disease. International consensus guideline statement is based on observational data, including case reports and case series. The goal of treatment is the induction and maintenance of remission so as to prevent progression of fibrosis and organ destruction in affected organ (s). An international panel of experts have developed recommendations for the management of IgG4-RD.6 Systemic corticosteroids are the first-line agent for remission induction in all patients with active, untreated IgG4-RD, unless contraindications to such treatment are present. Patients having active IgG4-RD require intravenous (IV) pulse corticosteroids administration as the first-line of treatment. Following a successful course of induction therapy, certain patients may benefit from maintenance therapy. Retreatment with systemic corticosteroids may be indicated in patients who relapse off of treatment following successful remission induction. Following relapse, the introduction of a steroid-sparing agent for continuation in the remission maintenance period may be considered. It is recommended to start treatment with prednisone at a dose of 40–60 mg/day. Once a significant response is evident in the affected organ system, one should consider to gradually tapering the dose of prednisone, with a planned reduction over a 2-month period. In patients who may be unable to tolerate steroids, one may consider using steroid-sparing agents. Some of the steroid-sparing agents that have been used include rituximab, azathioprine, methotrexate, and cyclophosphamide. In recent years, growing number of reports support the efficacy of B cell depletion with rituximab (1 g IV every 15 days for a total of two doses) in the treatment of IgG4-RD. Rituximab has not been evaluated in patients with IgG4-RD in a randomized trial, and its use for this indication is considered off-label use by the US Food and Drug Administration. B cell depletion leads to the targeted reduction of serum IgG4 concentrations, with relative preservation of the concentrations of other immunoglobulins and immunoglobulin subclasses. In patients for whom rituximab is not feasible, either azathioprine (2 mg/kg/day) or mycophenolate mofetil (up to 2.5 g/day as tolerated) are reasonable choices for second-line agents with potential for corticosteroid-sparing agents.