Granulomatosis With Polyangiitis and Other Systemic Inflammatory Diseases

Epidemiology, Etiology, and Pathogenesis

GPA is a rare disorder, with an annual incidence of 5–10 per million population, no sex predilection, and is more common in Caucasians. While it commonly presents between the ages of 65 and 70, GPA can affect patients of all ages.

GPA is considered a hypersensitivity disorder on the basis of its histologic manifestations. The etiology remains obscure, although inhaled and autoimmune antigens as well as chronic bacterial infestations have been postulated as triggers. Familial studies have shown that patients with a first-degree relative with GPA have a 1.56 increased relative risk of developing the disease. Furthermore, a higher frequency of certain human leukocyte antigen (HLA) markers (B2, B8, DR1, DR2, and DqW7) has been reported in patients with GPA. The pathogenesis of GPA is complex and not yet fully explained. It involves the generation of ANCA to proteinase-3 (PR3-ANCA) in 80%–90% of patients. This triggers a cascade that eventually causes the necrotizing systemic vasculitis.

Systemic Manifestations

Patients with clinically active disease typically present with constitutional symptoms, including general malaise, fever, myalgia, migratory arthralgia, anorexia, and weight loss. A prodromal syndrome may continue for several months with no clear organ involvement. Patients can also exhibit fulminant symptoms, such as respiratory insufficiency and rapidly progressing renal failure. The most commonly affected organs are the upper and lower respiratory tracts, followed by the kidneys; however, GPA has been reported to affect almost any organ.

Necrotizing inflammation of the upper respiratory mucosa can lead to destruction of the nasal septum, nasal arch, and bones of the paranasal sinuses, with resulting extension into the orbits. ^{, ,} Involvement of the lower respiratory tract leads to a productive cough and hemoptysis. Chest radiography and computed tomographic (CT) scan findings are variable, but characteristic findings are diffuse nodules that may cavitate, focal segmental opacities, and atelectasis. Renal involvement usually occurs in about 80% of patients, and it can be a presenting sign in approximately 20% of patients. Apart from the typical pulmonary and renal disease, focal vasculitis affecting the smaller arteries and occasionally the veins of other organ systems is frequently observed.

The diagnosis of GPA is facilitated by the detection of ANCA in patients with systemic vasculitis. Two types of autoantibodies have been identified and are characterized by their staining pattern of neutrophils: c-ANCA (cytoplasmic staining) and p-ANCA (perinuclear staining). ^, GPA is strongly linked to the PR3-ANCA, which usually exhibits the c-ANCA pattern. While 90% of clinically identified GPA patients can be positive for PR3-ANCA, up to 20% are also positive for myeloperoxidase-ANCA, which usually exhibits the p-ANCA staining pattern. A negative blood test does not rule out GPA, as a minority of patients with active generalized disease and those with limited forms of GPA may be ANCA-negative.

The clinical course of classic GPA is characterized as one of rapid progression. The average survival time after diagnosis in untreated patients is 5 months, with a 1-year mortality of 82% and a 2-year mortality of 90%.

Ocular Manifestations

The ocular manifestations of classic GPA were first described by Cutler and Blatt in 1956. The incidence of ocular involvement is generally cited to be about 40%, with ranges of 28%–58% having also been reported. This high prevalence results partly from the proximity of the orbit to the upper airways, but isolated ocular involvement may occur as part of a focal necrotizing vasculitis.

Orbital disease is the most common ocular manifestation, followed by anterior segment involvement. ^, In patients with orbital disease, lacrimal gland involvement has been shown to be a positive prognostic factor. Patients with orbital disease without lacrimal gland involvement are associated with a higher rate of systemic disease, a severe clinical course not uncommonly associated with other ophthalmic manifestations (e.g., necrotizing scleritis, peripheral ulcerative keratitis [PUK], orbital destruction), a relatively unfavorable outcome with high level of morbidity (optic nerve atrophy, anophthalmos, strabismus), and higher rates of recurrence. Patients with lacrimal gland involvement, on the other hand, have a more favorable prognosis and present with a milder disease manifestation. Affected patients may have conjunctivitis, marginal conjunctivitis, corneoscleral ulceration, episcleritis, and/or scleritis ( Fig. 60.1 ). ^, Prolonged conjunctival inflammation may progress to cicatricial changes on the ocular surface as well as corneal thinning and subsequent perforation. Corneoscleral involvement is most often bilateral and usually begins with perilimbal infiltrates similar to those seen in staphylococcal hypersensitivity. These infiltrates may ulcerate, with the process extending concentrically to form a ring ulcer or centrally causing perforation.

PUK is the most severe corneal complication of GPA. The pathogenesis of the marginal corneal ulcers is uncertain, but it is believed that the inflammatory milieu leads to collagenase production, local ischemia, and subsequent ulceration. The perilimbal keratitis is often associated with an adjacent scleritis resulting from an occlusive vasculitis of intrascleral portions of the anterior ciliary arteries, perilimbal arteries, or both.

The histopathology of keratitis in GPA involves necrosis of the epithelium and superficial stroma, along with formation of chronic granulation tissue lining the ulcer base. The corneal stroma is filled with acute and chronic inflammatory cells with occasional epithelioid and giant cells surrounding the ulcer.

Scleritis, which is a frequent ocular manifestation of GPA, is another example of a focal vasculitis. The scleritis is usually nodular and necrotizing. The anterior sclera is primarily involved, and the inflammation is often adjacent to an area of marginal keratitis. Stromal keratitis is a rarely described feature of GPA. Necrotizing granulomas of the ciliary body are also seen and may be a distinctive feature of the disease.

In general, local treatment of the anterior segment in GPA is unsuccessful. Management should be directed at systemic therapy. Corneal perforation should be managed acutely with cyanoacrylate glue, conjunctival flap, lamellar patch graft, or penetrating keratoplasty.

GPA may also cause posterior segment, orbital, and neuro-ophthalmic disease. ^{, ,} Posterior segment involvement is uncommon but, when it is present, usually takes the form of a retinal vasculitis. ^, Other posterior segment complications include disseminated retinitis, posterior uveitis, serous choroidal and retinal detachments, and vitreous hemorrhage. ^{, ,}

Orbital disease accounts for up to 50% of the ocular manifestations; it is usually a result of contiguous spread from diseased paranasal sinuses, and it is rarely bilateral. Patients present with proptosis in 15%–20% of GPA cases, often accompanied by chemosis and other signs or symptoms of orbital congestion. ^, Adnexal involvement may take the form of dacryoadenitis, eyelid necrosis, nasolacrimal duct obstruction, florid xanthelasma, or granulomas of the eyelid. ^, Neuro-ophthalmic disease presents in the form of an optic neuropathy secondary to orbital disease, a posterior ciliary vasculitis, or increased intracranial pressure secondary to cerebral involvement.

Harper et al. explored the relationship between ocular and systemic disease and found that at the time of presentation of ocular symptoms, most patients had systemic manifestations, but only 50% of these patients had a prior diagnosis of GPA. In addition, ocular inflammation led to the diagnosis of GPA in 68% of patients. This emphasizes the importance of recognizing this potentially fatal disease in patients with scleritis or ocular inflammatory lesions with or without obvious systemic manifestations of GPA.

Management

The current first-line treatment for mild GPA is a combination of glucocorticoids and methotrexate, as the latter has been shown to be noninferior to cyclophosphamide in inducing remission with a more favorable side-effect profile. Cyclophosphamide is reserved for mild cases that are unresponsive to methotrexate, as well as for moderate to severe disease. Combined corticosteroid and cyclophosphamide successfully induces remission in 75%–93% of these patients. ^,

An alternative treatment regime for moderate to severe cases is rituximab, a CD20-targeting humanized monoclonal antibody, combined with corticosteroids. It has also been successful in the treatment of progressive PUK, scleritis, and refractory orbital inflammation. Rituximab achieved a higher rate of disease control in PUK patients when compared to cyclophosphamide. In patients with c-ANCA associated retinal vasculitis, Rituximab has been shown to be likely superior as a first line therapy in relapsing cases. Its reasonable side-effect profile has made it a palatable alternative.

Epidemiology, Etiology, and Pathogenesis

The pathogenesis of IBD remains unclear, but generic and immune factors have been implicated. Twin studies have shed light on the genetic influence on IBD, with the evidence pointing to a greater role in CD. Observed differences in first degree relatives and ethnic groups have provided further support for the role of genetic factors. The IBD1 gene on chromosome 16 encodes for the NOD2 protein, which has been associated with an increased susceptibility to ileal CD. The NOD2 protein drives an altered innate immune response to bacteria. ^, The immune response has also been implicated in the pathogenesis of IBD, with the two basic themes being the dysregulation of the innate and adaptive immune responses against bacteria in the intestinal lumen or their products, and immune responses to organisms in the intestine that do not cause a response under normal circumstances. A positive response to immunosuppressive agents also supports an immunologic association. It is likely that the genetics of IBD are complex with more than one susceptibility locus and that many gene–gene and gene–environment interactions are pivotal in the pathogenesis of IBD. Other factors associated with the development of IBD include smoking, diet, appendectomy, and perinatal events.