The head and neck are the most common sites of involvement at initial presentation of granulomatosis with polyangiitis (GPA [Wegener’s granulomatosis]). Head and neck manifestations occur initially in 73% of patients, and eventually, up to 92% of patients with GPA are affected.¹ Many of these compromise the upper airway. Although treatment is multidisciplinary, the effects on the airway make it important to understand upper airway presentations and treatments. This article examines upper airway disease presentations, their assessment, and their advocated interventions.

DISEASE COURSE

Because head and neck involvement may be associated with a less aggressive form of GPA, outcomes for patients with predominantly head and neck involvement may be better compared with those who have involvement of other systems.²

The natural course of GPA may be indolent or rapidly progressive. Regardless, left untreated, it progresses to a generalized systemic disease that often leads to significant morbidity and likely mortality. Most patients (96%) achieve remission with immunosuppressive therapy, but nearly half (49%) have at least one relapse.¹ For this reason, systemic immunosuppressive medications play a dominant role in systemic and localized head and neck disease control. Patients often require maintenance medications along with additional therapies during disease exacerbation.³ Therefore, key partnerships between internists, rheumatologists, and otolaryngologists are paramount in the treatment and follow-up of these patients.

DIAGNOSIS: MAINSTAY IS SEROLOGIC EVALUATION

The differential diagnosis of GPA includes infection, lymphoproliferative disease (T-cell lymphoma), systemic lupus erythematosus, rheumatoid arthritis, sarcoidosis, and other granulomatous diseases such as eosinophilic GPA (Churg-Strauss syndrome), polyarteritis nodosa, and microscopic polyangiitis. Appropriate diagnosis is critical because treatment of these entities varies drastically.

The mainstay of GPA diagnosis is serologic evaluation for a cytoplasmic pattern of antineutrophil cytoplasmic antibodies (cANCA), which are reactive toward proteinase-3 (PR3) or myeloperoxidase (MPO). Testing for cANCA yields a pooled sensitivity of 91% and specificity of 99%. Sensitivity falls significantly (63%) when the disease is in nonacute stages, while the specificity remains high.⁴ These cANCA test characteristics allow a high positive predictive value for this rare disease.

Biopsy is typically reserved for cases in which serologic ANCA testing is nondiagnostic. Biopsy tissue may be readily accessible from the head and neck, but these biopsies may bear significant false-negative rates.^4–6 Diagnosis requires demonstration of palisading granulomas as vascular or extravascular lesions within the upper respiratory tract tissues. The specific site biopsied from within the head and neck has been shown to influence diagnostic yield, with sinonasal biopsies producing the highest yield.

SINONASAL MANIFESTATIONS

The nose and paranasal sinuses are the most frequently affected sites in the head and neck, noted in 64% to 80% of patients. Additionally, the nose is the only site of involvement in 30% of patients.⁷ Given the high frequency of sinonasal manifestations, GPA should be considered as a potential diagnosis among patients with persistent sinonasal disease.

Pathophysiology and disease course

The pathophysiologic mechanisms leading to the changes in the sinonasal tract in GPA have not been established. GPA is believed to be an immunologic disease that manifests as a vasculitis of small- and medium-sized vessels. Multiple potential causative factors have been identified, including fibrinoid necrosis of small blood vessels, epithelial granulomas, chronic inflammation, and prior surgical intervention.^8,9 The acute and chronic inflammation, coupled with the epithelioid granuloma formation, damages adjacent small- to medium-sized vessels. The vasculitis leads to diminished blood flow and subsequent avascular necrosis, which may promote tissue necrosis and bone destruction. This destructive process typically starts in the midseptum supplied by Kiesselbach plexus and in the turbinates. The process then eventually spreads to the paranasal sinuses.⁸

Patient evaluation

Examination of the nasal cavities is typically performed by rigid or flexible nasal endoscopy and often reveals nasal crusting, friable erythematous mucosa, granulation, and even signs of sinusitis. All or part of the cartilaginous septum may be involved, leading to significant septal defects. As the degree of cartilage destruction increases, nasal dorsal support decreases, leading to a visible depression of the external nose known as a “saddle-nose” deformity, which is present in 23% of patients with GPA.^7,10

Imaging assessment by computed tomography (CT) is needed to establish disease extent and involvement. Atypical findings may include bony erosion and destruction of the septum and turbinates; erosion of bony partitions within the ethmoid sinuses; neo-osteogenesis of the maxillary, frontal, and sphenoid sinuses; and complete bony obliteration of the maxillary, frontal, and sphenoid sinuses.^9,11

Clinical presentation

Sinonasal disease indicates the degree of disease activity.¹² Clinical findings may vary, but they have a significant impact on quality of life in these patients.¹³ Most patients with active disease present with nasal crusting (69%), chronic rhinosinusitis (CRS) symptoms (61%), nasal obstruction (58%), and serosanguinous nasal discharge (52%).¹⁰ Patients may also complain of foul-smelling rhinorrhea, recurrent epistaxis, hyposmia, anosmia, and epiphora (from granulomatous compression or obstruction of the lacrimal system). In a series of 120 patients with GPA, Cannady et al found that four (3.3%) patients had mucoceles and three (2.5%) had orbital pseudotumor.¹⁰

Any structure in the sinonasal cavity, including mucosa, septum, turbinates, and sinuses proper, may be affected because of the vasculitic involvement of mucosal blood vessels that causes diminished blood flow and subsequent necrosis. The area of the anterior septum supplied by Kiesselbach plexus is the most common site of active nasal disease, which can eventually lead to the common presentation of an anterior nasal septal perforation.

Otologic disease secondary to sinonasal GPA

Otologic involvement is observed in 19% to 38% of patients with GPA.^14,15 Most patients with GPA who exhibit otologic symptoms have middle ear or mastoid disease. It typically appears as chronic otitis media (COM) with conductive hearing loss.¹⁶ In most cases, the otologic involvement is secondary to Eustachian tube dysfunction caused by the presence of extensive disease in the nasopharynx.

Additionally, chronic mastoiditis can result from direct mastoid involvement with GPA. Facial nerve palsy secondary to infective bony destruction is a rare but repeatedly reported complication of GPA.^14,15

Inner ear involvement is a relatively common otologic presentation of GPA. Patients may experience sensorineural hearing loss (SNHL) as well as vertigo, which may mimic Cogan syndrome. Importantly, patients may exhibit inner ear involvement with or without middle ear and mastoid disease. The SNHL observed in patients with GPA may be responsive to steroid or immunosuppressive therapy.

Refractory CRS in GPA is a complex problem for which aggressive surgical intervention is often counterproductive. Unfortunately, traditional medical therapies are also often inadequate to treat progressive sinonasal symptomatology. As the nasal tissue becomes devascularized, loss of normal mucociliary function aggravates the sinus pathology, and clinical symptoms may worsen. Simple antibiotic regimens used to manage uncomplicated sinusitis are often inadequate in these patients. The subsequent progression to frank necrosis in localized regions creates an intranasal foreign body, allowing bacterial colonization, which is often refractory to antibiotics because of the inability of drug tissue penetration into these devascularized nasal structures.^12,17

Medical management must be tailored to be effective in this complex intranasal milieu. Successful treatment requires a multifaceted and often prolonged treatment course. A high index of suspicion should be maintained for Staphylococcus aureus. As a rule, endoscopically obtained cultures should be used to guide antibiotic selection. Several weeks of culture-directed antibiotics followed by topical antibiotic irrigations (eg, mupirocin irrigations) can be useful to reduce the frequency of sinonasal exacerbations.

Frequent saline irrigations using high-volume, high-flow irrigation devices (as opposed to low-volume, low-flow applicators such as nasal spray bottles) can be an excellent adjunct to maintenance therapy and are effective in clearing debris and augmenting mucociliary clearance in affected nasal cavities and those with septal perforations. Occasional in-office endoscopic debridement of large crusts adherent to intranasal structures or the edges of a septal perforation can also help to improve obstructive symptoms.

Surgery for refractory cases. Surgery should be reserved for refractory cases unresponsive to maximal medical efforts or those cases with impending complications (ie, mucoceles). Overall, only 16% of patients with sinonasal GPA required surgical intervention in a large series of 120 patients at our institution. In this series, one-third of all patients had undergone previous functional nasal surgery at an outside institution without resolution of symptoms. Anecdotal evidence suggests that surgery for GPA can contribute to additional scarring and lead to protracted sinonasal symptoms.^10,18

The decision to perform surgery is individualized and based on severity of the disease process, patient expectations, and surgeon expertise. In our experience at Cleveland Clinic, functional endoscopic sinus surgery in the setting of GPA is a surgical challenge, given extensive alteration of the sinonasal anatomy from previous surgery, prior and ongoing inflammation, chronic crusting, and scarring. Consequently, it has been our practice to employ conservative efforts prior to consideration of surgery. A complete surgical cure is exceedingly rare, and the patient should be counseled about the possible need for revision surgery and ongoing nonsurgical therapies. Meticulous postoperative care with weekly postoperative debridement, saline or antibiotic irrigations, and culture-directed antibiotics, is essential during the early postoperative recovery phase.

Management of epiphora. The most common ophthalmologic findings in patients with GPA include chronic epiphora and orbital pseudotumor. With the advent of advanced endoscopic techniques, the otolaryngologist plays a greater role in the surgical management of these ophthalmologic disease entities. In a series reported by Cannady et al,¹⁰ endoscopic dacrocystorhinostomy was performed successfully in seven patients, including one revision.

Nasal reconstruction for saddle-nose deformity: effective in selected patients. The progressive loss of septal support that occurs with the enlarging anterior septal perforation often results in significant collapse of the cartilaginous midvault of the nose. The tip cartilages in turn also begin to lose projection, resulting in a shortened nose with the characteristic saddle-nose deformity. The psychologic impact of this disfiguring facial abnormality is significant. The loss of midvault support also results in worsening nasal obstruction and increases the incidence of anosmia as the superior nasal vault becomes obstructed. For these reasons, patients often seek referral for potential reconstruction.

Despite the potential benefits, the general consensus in the medical community has been that surgical procedures on the nose should be avoided in GPA patients.¹⁷ Most nasal destruction in these patients is the consequence of poor tissue perfusion from the active vasculitis. Poor wound healing, reconstructive graft resorption, and worsening necrosis have been observed in patients who have undergone ill-advised surgical procedures.

These poor outcomes do not, however, preclude the potential for safe and effective surgical intervention. In three small published series, good surgical outcomes were achieved but the procedures were done in very highly selected patients and were modified to address the specific clinical issues seen in GPA patients.^19–21 The critical step in achieving a good outcome is working closely with the patient’s rheumatologist to identify an appropriate clinical window during which the patient’s disease process is in a period of relative remission. The second major factor is to modify the surgical techniques to take into account the very poor vascular framework of the recipient nasal bed.

Management of COM. Because the COM in patients with GPA is frequently secondary to nasopharyngeal disease, systemic control of GPA is the first priority. Systemic control is also the first-line treatment for patients with mixed or sensorineural hearing loss, or with vertigo. For continued or symptomatic middle ear effusions that do not resolve with systemic therapy, placement of a ventilation tube may be considered. In patients with significant hearing loss, hearing amplification devices may be warranted.^15,22 Cochlear implant devices in GPA patients are experimental and may pose undue risks of meningitis.

SUBGLOTTIC STENOSIS AND TRACHEAL MANIFESTATIONS

Subglottic stenosis affects 10% to 20% of patients with GPA.^1,23,24 Because of its potential life-threatening airway complications, patients should be carefully assessed for this disease manifestation. It may be the only manifestation of GPA or may be part of a spectrum of other disease manifestations. Therefore, the work-up for subglottic stenosis of unknown etiology should always include an evaluation for GPA.

Pathophysiology and disease course

The etiology of subglottic stenosis in GPA is not well understood. Theories primarily involve the vulnerability of the subglottic tissues to damage, chronic inflammation, and scarring.²⁵ The combination of vasculitis in the setting of active inflammation may synergistically produce a hyperactive reparative mechanism in GPA patients that leads to cartilaginous fibrotic scarring and stenosis. Wound healing can be divided into the phases of inflammation, proliferation, and remodeling. An imbalance or exaggerated response of any of these levels (and likely all) produces an abnormal healing response.²⁶ Similarly, each of these phases may be targeted to improve the healing process.

Patient evaluation

The presence of subglottic stenosis must be considered in a GPA patient with respiratory symptoms. As part of the routine initial evaluation, an office-based nasopharyngeal/laryngeal endoscopy using a flexible laryngoscope should be performed to assess the presence and severity of luminal airway narrowing. Flexible laryngoscopy reveals a circumferential narrowing of the subglottis. The stenotic tissue may vary from friable with erythematous and inflamed mucosa to a rigid mature fibrotic band, depending on the inflammatory state of the stenosis.^18,27

Subclinical stenosis may be identified with routine endoscopy. An appropriate baseline is needed to follow the progression of disease and to adjust the timing of any potential intervention. The ability to digitally record a patient’s examination allows further tracking of disease and is commonly used in our practices.

Although flexible fiberoptic examination is critical in diagnosis and follow-up, intraoperative direct laryngoscopy using rigid laryngoscopes and telescopes provides the optimum view of the subglottis. In particular, this view provides greater information on the length and degree of the stenosis and allows evaluation of potential stenotic segments in the inferior trachea.

Spiral CT with 3-dimensional reconstruction of the laryngotracheal lumen and virtual bronchoscopy may provide information that complements laryngoscopy. CT may permit assessment of the entire tracheobronchial pathway. Because 15% to 55% of GPA patients have additional bronchial stenotic segments, assessment of the entire airway is important.^28,29

Diagnosis of GPA in patients younger than 20 years is associated with the development of subglottic stenosis.^23,30 The GPA patient with subglottic stenosis may or may not have other active systemic symptoms. The efficacy of systemic therapy often does not correlate with the degree of subglottic stenosis. Importantly, when systemic disease enters remission, the subglottic stenosis may remain due to residual scarring of the subglottis.³¹

Patients with subglottic stenosis may present with hoarseness, cough, wheeze, stridor, or dyspnea on exertion.^27,32 The stridor and wheeze may be confused with the wheeze of asthma, often leading to misdiagnosis.¹⁷

Subglottic stenosis likely begins at a small degree and increases gradually, allowing the patient to adjust his or her breathing pattern until a critical stenotic airway area is reached. Typically, and dependent on their pulmonary health, patients are asymptomatic until about 75% airway stenosis (60% in children).^33,34 At this point, symptoms may become evident and correlate with the degree of stenosis, ranging from cough and mild shortness of breath to life-threatening stridor and obstruction. Importantly, as the airway caliber narrows, mucous plugging becomes a greater concern, as it can cause acute stridulous exacerbations and airway obstruction.

A significant proportion of patients with GPA who have subclinical asymptomatic stenosis may not receive laryngeal examination. Patients who have suspicious clinical histories should be referred for evaluation of subglottic stenosis prior to symptom worsening.

Patients with significant (approximately 80%) stenosis can present with respiratory symptoms that may be life-threatening. Because airway management in this setting is substantially more difficult, the goal should be to obtain a diagnosis and perform intervention before this advanced presentation develops.

Pauzner et al described a possible association between GPA tracheal stenosis and pregnancy.³⁵ Women of childbearing age who have GPA should be counseled about this possible association and the need for close follow-up during the partum and postpartum periods.

Treatment is controversial

The treatment of subglottic stenosis of GPA requires multidisciplinary management by the rheumatologist, otolaryngologist, and pulmonologist. Systemic manifestations of disease are managed by immunosuppressive therapy, but up to 80% of patients may require surgical management of subglottic stenosis, and the remaining 20% will respond to systemic medical therapy.^22,23,36,37 Overall, the treatment of this disease is controversial and varies by center. The therapeutic arsenal consists of conventional immunosuppressive therapy, endoscopic dilation, endoscopic or laser excision, and surgical resection of the stenotic segment followed by reconstruction.

Tracheotomy. Historically, tracheotomies were performed in approximately one-half of patients with airway manifestations of GPA when the patient had active disease or when airway patency could not be adequately maintained. Most of these patients were eventually decannulated.^23,25 At present, tracheotomy is performed infrequently and is reserved for patients who have either a severely tenuous airway (with tracheotomy the only safe option available to obtain a secure airway) or who express a preference for tracheotomy. In a recent study by Hoffman et al,³⁸ tracheotomy was avoided in 21 patients through the use of stenosis dilation procedures.

Dilation. Endoscopic subglottic dilation is the currently advocated method of treatment, and has shown promising results. In two studies with a total of 41 GPA patients who were able to avoid tracheotomy and open surgical procedures, 24% underwent decannulation of previously placed tracheotomies and 24% required only one procedure at an average follow-up of 3.4 and 5 years per study. In these studies, the technique of intralesional corticosteroid with mechanical dilation (ILCD) was performed.^31,36,38

Preferred: Dilation plus medical therapy

Because of the inflammatory etiology of this condition, surgical intervention has the risk of potentially worsening the stenosis. However, combining dilation of the stenosis with aggressive local medical treatment to prevent scar formation and cellular proliferation has been shown to be effective and safe. This treatment modality was recently recommended as the preferred therapy based on a number of relatively small clinical trials for subglottic stenosis, without the benefit of large controlled trials.

Our patient population consists of two subsets: (1) those who respond well to ILCD and systemic medical therapy, requiring a minimal number of dilations before no longer needing procedures because of a possible “burn out” of the subglottic disease, and (2) those who continue to have recurrence of stenosis, requiring repeat ILCD. The latter group requires close long-term observation.

To counter the effects of the exaggerated healing reaction of inflammation (early) and proliferation (late) following injury, two medications are applied to the area of repaired stenosis. The stenotic lesion is first injected submucosally with a long-acting corticosteroid suspension such as methylprednisolone. The solution is injected along the submucosal-perichondrial plane. Incisions are made in a star-like fashion, employing sharp metal microlaryngeal blades or, less commonly, the carbon dioxide laser. These incisions release the constricting stenotic ring and break it up, widening the diameter of the airway and simultaneously preserving islands of intact mucous membrane between the incisions. This epithelium is intended to regenerate and resurface the expanded lumen. Progressive serial dilations are performed using semirigid, flexible, smooth dilators or high-pressure balloon dilation. The next stage involves repeated topical applications of mitomycin-C to further inhibit fibrosis and restenosis by inhibiting cellular proliferation of the vigorous injury cycles of these lesions. Application of mitomycin-C to the dilated area of a laryngotracheal stenosis has been associated with a decreased rate of stenosis relapse.³⁹

Our group at Cleveland Clinic has never used laser surgery alone without dilation on the subglottic stenosis caused by GPA. Incidentally, patients treated with laser surgery in other institutions prior to their referral to the Cleveland Clinic have developed complicating secondary stenoses that required more extensive surgical intervention to overcome the severe secondary superimposed damage. In theory, use of the laser may create unnecessary thermal injury that likely worsens local damage. These patients required laryngotracheal reconstructive procedures or had to undergo establishment of permanent tracheotomies.

CONCLUSION

Granulomatosis with polyangiitis is a rare disease that may manifest in multiple areas of the head and neck. Careful attention to diagnosis and management is critical, as these patients tend to have progressive disease with debilitating sequelae. The rheumatologist, otolaryngologist, and internist should identify patients with any constellation of symptoms that may be typical of GPA. A collaborative effort to diagnose, treat, and follow these patients is paramount to successful disease management.

The head and neck are the most common sites of involvement at initial presentation of granulomatosis with polyangiitis (GPA [Wegener’s granulomatosis]). Head and neck manifestations occur initially in 73% of patients, and eventually, up to 92% of patients with GPA are affected.¹ Many of these compromise the upper airway. Although treatment is multidisciplinary, the effects on the airway make it important to understand upper airway presentations and treatments. This article examines upper airway disease presentations, their assessment, and their advocated interventions.

DISEASE COURSE

Because head and neck involvement may be associated with a less aggressive form of GPA, outcomes for patients with predominantly head and neck involvement may be better compared with those who have involvement of other systems.²

The natural course of GPA may be indolent or rapidly progressive. Regardless, left untreated, it progresses to a generalized systemic disease that often leads to significant morbidity and likely mortality. Most patients (96%) achieve remission with immunosuppressive therapy, but nearly half (49%) have at least one relapse.¹ For this reason, systemic immunosuppressive medications play a dominant role in systemic and localized head and neck disease control. Patients often require maintenance medications along with additional therapies during disease exacerbation.³ Therefore, key partnerships between internists, rheumatologists, and otolaryngologists are paramount in the treatment and follow-up of these patients.

DIAGNOSIS: MAINSTAY IS SEROLOGIC EVALUATION

The differential diagnosis of GPA includes infection, lymphoproliferative disease (T-cell lymphoma), systemic lupus erythematosus, rheumatoid arthritis, sarcoidosis, and other granulomatous diseases such as eosinophilic GPA (Churg-Strauss syndrome), polyarteritis nodosa, and microscopic polyangiitis. Appropriate diagnosis is critical because treatment of these entities varies drastically.

The mainstay of GPA diagnosis is serologic evaluation for a cytoplasmic pattern of antineutrophil cytoplasmic antibodies (cANCA), which are reactive toward proteinase-3 (PR3) or myeloperoxidase (MPO). Testing for cANCA yields a pooled sensitivity of 91% and specificity of 99%. Sensitivity falls significantly (63%) when the disease is in nonacute stages, while the specificity remains high.⁴ These cANCA test characteristics allow a high positive predictive value for this rare disease.

Biopsy is typically reserved for cases in which serologic ANCA testing is nondiagnostic. Biopsy tissue may be readily accessible from the head and neck, but these biopsies may bear significant false-negative rates.^4–6 Diagnosis requires demonstration of palisading granulomas as vascular or extravascular lesions within the upper respiratory tract tissues. The specific site biopsied from within the head and neck has been shown to influence diagnostic yield, with sinonasal biopsies producing the highest yield.

SINONASAL MANIFESTATIONS

The nose and paranasal sinuses are the most frequently affected sites in the head and neck, noted in 64% to 80% of patients. Additionally, the nose is the only site of involvement in 30% of patients.⁷ Given the high frequency of sinonasal manifestations, GPA should be considered as a potential diagnosis among patients with persistent sinonasal disease.

Pathophysiology and disease course

The pathophysiologic mechanisms leading to the changes in the sinonasal tract in GPA have not been established. GPA is believed to be an immunologic disease that manifests as a vasculitis of small- and medium-sized vessels. Multiple potential causative factors have been identified, including fibrinoid necrosis of small blood vessels, epithelial granulomas, chronic inflammation, and prior surgical intervention.^8,9 The acute and chronic inflammation, coupled with the epithelioid granuloma formation, damages adjacent small- to medium-sized vessels. The vasculitis leads to diminished blood flow and subsequent avascular necrosis, which may promote tissue necrosis and bone destruction. This destructive process typically starts in the midseptum supplied by Kiesselbach plexus and in the turbinates. The process then eventually spreads to the paranasal sinuses.⁸

Patient evaluation

Examination of the nasal cavities is typically performed by rigid or flexible nasal endoscopy and often reveals nasal crusting, friable erythematous mucosa, granulation, and even signs of sinusitis. All or part of the cartilaginous septum may be involved, leading to significant septal defects. As the degree of cartilage destruction increases, nasal dorsal support decreases, leading to a visible depression of the external nose known as a “saddle-nose” deformity, which is present in 23% of patients with GPA.^7,10

Imaging assessment by computed tomography (CT) is needed to establish disease extent and involvement. Atypical findings may include bony erosion and destruction of the septum and turbinates; erosion of bony partitions within the ethmoid sinuses; neo-osteogenesis of the maxillary, frontal, and sphenoid sinuses; and complete bony obliteration of the maxillary, frontal, and sphenoid sinuses.^9,11

Clinical presentation

Sinonasal disease indicates the degree of disease activity.¹² Clinical findings may vary, but they have a significant impact on quality of life in these patients.¹³ Most patients with active disease present with nasal crusting (69%), chronic rhinosinusitis (CRS) symptoms (61%), nasal obstruction (58%), and serosanguinous nasal discharge (52%).¹⁰ Patients may also complain of foul-smelling rhinorrhea, recurrent epistaxis, hyposmia, anosmia, and epiphora (from granulomatous compression or obstruction of the lacrimal system). In a series of 120 patients with GPA, Cannady et al found that four (3.3%) patients had mucoceles and three (2.5%) had orbital pseudotumor.¹⁰

Any structure in the sinonasal cavity, including mucosa, septum, turbinates, and sinuses proper, may be affected because of the vasculitic involvement of mucosal blood vessels that causes diminished blood flow and subsequent necrosis. The area of the anterior septum supplied by Kiesselbach plexus is the most common site of active nasal disease, which can eventually lead to the common presentation of an anterior nasal septal perforation.

Otologic disease secondary to sinonasal GPA

Otologic involvement is observed in 19% to 38% of patients with GPA.^14,15 Most patients with GPA who exhibit otologic symptoms have middle ear or mastoid disease. It typically appears as chronic otitis media (COM) with conductive hearing loss.¹⁶ In most cases, the otologic involvement is secondary to Eustachian tube dysfunction caused by the presence of extensive disease in the nasopharynx.

Additionally, chronic mastoiditis can result from direct mastoid involvement with GPA. Facial nerve palsy secondary to infective bony destruction is a rare but repeatedly reported complication of GPA.^14,15

Inner ear involvement is a relatively common otologic presentation of GPA. Patients may experience sensorineural hearing loss (SNHL) as well as vertigo, which may mimic Cogan syndrome. Importantly, patients may exhibit inner ear involvement with or without middle ear and mastoid disease. The SNHL observed in patients with GPA may be responsive to steroid or immunosuppressive therapy.

Refractory CRS in GPA is a complex problem for which aggressive surgical intervention is often counterproductive. Unfortunately, traditional medical therapies are also often inadequate to treat progressive sinonasal symptomatology. As the nasal tissue becomes devascularized, loss of normal mucociliary function aggravates the sinus pathology, and clinical symptoms may worsen. Simple antibiotic regimens used to manage uncomplicated sinusitis are often inadequate in these patients. The subsequent progression to frank necrosis in localized regions creates an intranasal foreign body, allowing bacterial colonization, which is often refractory to antibiotics because of the inability of drug tissue penetration into these devascularized nasal structures.^12,17

Medical management must be tailored to be effective in this complex intranasal milieu. Successful treatment requires a multifaceted and often prolonged treatment course. A high index of suspicion should be maintained for Staphylococcus aureus. As a rule, endoscopically obtained cultures should be used to guide antibiotic selection. Several weeks of culture-directed antibiotics followed by topical antibiotic irrigations (eg, mupirocin irrigations) can be useful to reduce the frequency of sinonasal exacerbations.

Frequent saline irrigations using high-volume, high-flow irrigation devices (as opposed to low-volume, low-flow applicators such as nasal spray bottles) can be an excellent adjunct to maintenance therapy and are effective in clearing debris and augmenting mucociliary clearance in affected nasal cavities and those with septal perforations. Occasional in-office endoscopic debridement of large crusts adherent to intranasal structures or the edges of a septal perforation can also help to improve obstructive symptoms.

Surgery for refractory cases. Surgery should be reserved for refractory cases unresponsive to maximal medical efforts or those cases with impending complications (ie, mucoceles). Overall, only 16% of patients with sinonasal GPA required surgical intervention in a large series of 120 patients at our institution. In this series, one-third of all patients had undergone previous functional nasal surgery at an outside institution without resolution of symptoms. Anecdotal evidence suggests that surgery for GPA can contribute to additional scarring and lead to protracted sinonasal symptoms.^10,18

The decision to perform surgery is individualized and based on severity of the disease process, patient expectations, and surgeon expertise. In our experience at Cleveland Clinic, functional endoscopic sinus surgery in the setting of GPA is a surgical challenge, given extensive alteration of the sinonasal anatomy from previous surgery, prior and ongoing inflammation, chronic crusting, and scarring. Consequently, it has been our practice to employ conservative efforts prior to consideration of surgery. A complete surgical cure is exceedingly rare, and the patient should be counseled about the possible need for revision surgery and ongoing nonsurgical therapies. Meticulous postoperative care with weekly postoperative debridement, saline or antibiotic irrigations, and culture-directed antibiotics, is essential during the early postoperative recovery phase.

Management of epiphora. The most common ophthalmologic findings in patients with GPA include chronic epiphora and orbital pseudotumor. With the advent of advanced endoscopic techniques, the otolaryngologist plays a greater role in the surgical management of these ophthalmologic disease entities. In a series reported by Cannady et al,¹⁰ endoscopic dacrocystorhinostomy was performed successfully in seven patients, including one revision.

Nasal reconstruction for saddle-nose deformity: effective in selected patients. The progressive loss of septal support that occurs with the enlarging anterior septal perforation often results in significant collapse of the cartilaginous midvault of the nose. The tip cartilages in turn also begin to lose projection, resulting in a shortened nose with the characteristic saddle-nose deformity. The psychologic impact of this disfiguring facial abnormality is significant. The loss of midvault support also results in worsening nasal obstruction and increases the incidence of anosmia as the superior nasal vault becomes obstructed. For these reasons, patients often seek referral for potential reconstruction.

Despite the potential benefits, the general consensus in the medical community has been that surgical procedures on the nose should be avoided in GPA patients.¹⁷ Most nasal destruction in these patients is the consequence of poor tissue perfusion from the active vasculitis. Poor wound healing, reconstructive graft resorption, and worsening necrosis have been observed in patients who have undergone ill-advised surgical procedures.

These poor outcomes do not, however, preclude the potential for safe and effective surgical intervention. In three small published series, good surgical outcomes were achieved but the procedures were done in very highly selected patients and were modified to address the specific clinical issues seen in GPA patients.^19–21 The critical step in achieving a good outcome is working closely with the patient’s rheumatologist to identify an appropriate clinical window during which the patient’s disease process is in a period of relative remission. The second major factor is to modify the surgical techniques to take into account the very poor vascular framework of the recipient nasal bed.

Management of COM. Because the COM in patients with GPA is frequently secondary to nasopharyngeal disease, systemic control of GPA is the first priority. Systemic control is also the first-line treatment for patients with mixed or sensorineural hearing loss, or with vertigo. For continued or symptomatic middle ear effusions that do not resolve with systemic therapy, placement of a ventilation tube may be considered. In patients with significant hearing loss, hearing amplification devices may be warranted.^15,22 Cochlear implant devices in GPA patients are experimental and may pose undue risks of meningitis.

SUBGLOTTIC STENOSIS AND TRACHEAL MANIFESTATIONS

Subglottic stenosis affects 10% to 20% of patients with GPA.^1,23,24 Because of its potential life-threatening airway complications, patients should be carefully assessed for this disease manifestation. It may be the only manifestation of GPA or may be part of a spectrum of other disease manifestations. Therefore, the work-up for subglottic stenosis of unknown etiology should always include an evaluation for GPA.

Pathophysiology and disease course

The etiology of subglottic stenosis in GPA is not well understood. Theories primarily involve the vulnerability of the subglottic tissues to damage, chronic inflammation, and scarring.²⁵ The combination of vasculitis in the setting of active inflammation may synergistically produce a hyperactive reparative mechanism in GPA patients that leads to cartilaginous fibrotic scarring and stenosis. Wound healing can be divided into the phases of inflammation, proliferation, and remodeling. An imbalance or exaggerated response of any of these levels (and likely all) produces an abnormal healing response.²⁶ Similarly, each of these phases may be targeted to improve the healing process.

Patient evaluation

The presence of subglottic stenosis must be considered in a GPA patient with respiratory symptoms. As part of the routine initial evaluation, an office-based nasopharyngeal/laryngeal endoscopy using a flexible laryngoscope should be performed to assess the presence and severity of luminal airway narrowing. Flexible laryngoscopy reveals a circumferential narrowing of the subglottis. The stenotic tissue may vary from friable with erythematous and inflamed mucosa to a rigid mature fibrotic band, depending on the inflammatory state of the stenosis.^18,27

Subclinical stenosis may be identified with routine endoscopy. An appropriate baseline is needed to follow the progression of disease and to adjust the timing of any potential intervention. The ability to digitally record a patient’s examination allows further tracking of disease and is commonly used in our practices.

Although flexible fiberoptic examination is critical in diagnosis and follow-up, intraoperative direct laryngoscopy using rigid laryngoscopes and telescopes provides the optimum view of the subglottis. In particular, this view provides greater information on the length and degree of the stenosis and allows evaluation of potential stenotic segments in the inferior trachea.

Spiral CT with 3-dimensional reconstruction of the laryngotracheal lumen and virtual bronchoscopy may provide information that complements laryngoscopy. CT may permit assessment of the entire tracheobronchial pathway. Because 15% to 55% of GPA patients have additional bronchial stenotic segments, assessment of the entire airway is important.^28,29

Diagnosis of GPA in patients younger than 20 years is associated with the development of subglottic stenosis.^23,30 The GPA patient with subglottic stenosis may or may not have other active systemic symptoms. The efficacy of systemic therapy often does not correlate with the degree of subglottic stenosis. Importantly, when systemic disease enters remission, the subglottic stenosis may remain due to residual scarring of the subglottis.³¹

Patients with subglottic stenosis may present with hoarseness, cough, wheeze, stridor, or dyspnea on exertion.^27,32 The stridor and wheeze may be confused with the wheeze of asthma, often leading to misdiagnosis.¹⁷

Subglottic stenosis likely begins at a small degree and increases gradually, allowing the patient to adjust his or her breathing pattern until a critical stenotic airway area is reached. Typically, and dependent on their pulmonary health, patients are asymptomatic until about 75% airway stenosis (60% in children).^33,34 At this point, symptoms may become evident and correlate with the degree of stenosis, ranging from cough and mild shortness of breath to life-threatening stridor and obstruction. Importantly, as the airway caliber narrows, mucous plugging becomes a greater concern, as it can cause acute stridulous exacerbations and airway obstruction.

A significant proportion of patients with GPA who have subclinical asymptomatic stenosis may not receive laryngeal examination. Patients who have suspicious clinical histories should be referred for evaluation of subglottic stenosis prior to symptom worsening.

Patients with significant (approximately 80%) stenosis can present with respiratory symptoms that may be life-threatening. Because airway management in this setting is substantially more difficult, the goal should be to obtain a diagnosis and perform intervention before this advanced presentation develops.

Pauzner et al described a possible association between GPA tracheal stenosis and pregnancy.³⁵ Women of childbearing age who have GPA should be counseled about this possible association and the need for close follow-up during the partum and postpartum periods.

Treatment is controversial

The treatment of subglottic stenosis of GPA requires multidisciplinary management by the rheumatologist, otolaryngologist, and pulmonologist. Systemic manifestations of disease are managed by immunosuppressive therapy, but up to 80% of patients may require surgical management of subglottic stenosis, and the remaining 20% will respond to systemic medical therapy.^22,23,36,37 Overall, the treatment of this disease is controversial and varies by center. The therapeutic arsenal consists of conventional immunosuppressive therapy, endoscopic dilation, endoscopic or laser excision, and surgical resection of the stenotic segment followed by reconstruction.

Tracheotomy. Historically, tracheotomies were performed in approximately one-half of patients with airway manifestations of GPA when the patient had active disease or when airway patency could not be adequately maintained. Most of these patients were eventually decannulated.^23,25 At present, tracheotomy is performed infrequently and is reserved for patients who have either a severely tenuous airway (with tracheotomy the only safe option available to obtain a secure airway) or who express a preference for tracheotomy. In a recent study by Hoffman et al,³⁸ tracheotomy was avoided in 21 patients through the use of stenosis dilation procedures.

Dilation. Endoscopic subglottic dilation is the currently advocated method of treatment, and has shown promising results. In two studies with a total of 41 GPA patients who were able to avoid tracheotomy and open surgical procedures, 24% underwent decannulation of previously placed tracheotomies and 24% required only one procedure at an average follow-up of 3.4 and 5 years per study. In these studies, the technique of intralesional corticosteroid with mechanical dilation (ILCD) was performed.^31,36,38

Preferred: Dilation plus medical therapy

Because of the inflammatory etiology of this condition, surgical intervention has the risk of potentially worsening the stenosis. However, combining dilation of the stenosis with aggressive local medical treatment to prevent scar formation and cellular proliferation has been shown to be effective and safe. This treatment modality was recently recommended as the preferred therapy based on a number of relatively small clinical trials for subglottic stenosis, without the benefit of large controlled trials.

Our patient population consists of two subsets: (1) those who respond well to ILCD and systemic medical therapy, requiring a minimal number of dilations before no longer needing procedures because of a possible “burn out” of the subglottic disease, and (2) those who continue to have recurrence of stenosis, requiring repeat ILCD. The latter group requires close long-term observation.

To counter the effects of the exaggerated healing reaction of inflammation (early) and proliferation (late) following injury, two medications are applied to the area of repaired stenosis. The stenotic lesion is first injected submucosally with a long-acting corticosteroid suspension such as methylprednisolone. The solution is injected along the submucosal-perichondrial plane. Incisions are made in a star-like fashion, employing sharp metal microlaryngeal blades or, less commonly, the carbon dioxide laser. These incisions release the constricting stenotic ring and break it up, widening the diameter of the airway and simultaneously preserving islands of intact mucous membrane between the incisions. This epithelium is intended to regenerate and resurface the expanded lumen. Progressive serial dilations are performed using semirigid, flexible, smooth dilators or high-pressure balloon dilation. The next stage involves repeated topical applications of mitomycin-C to further inhibit fibrosis and restenosis by inhibiting cellular proliferation of the vigorous injury cycles of these lesions. Application of mitomycin-C to the dilated area of a laryngotracheal stenosis has been associated with a decreased rate of stenosis relapse.³⁹

Our group at Cleveland Clinic has never used laser surgery alone without dilation on the subglottic stenosis caused by GPA. Incidentally, patients treated with laser surgery in other institutions prior to their referral to the Cleveland Clinic have developed complicating secondary stenoses that required more extensive surgical intervention to overcome the severe secondary superimposed damage. In theory, use of the laser may create unnecessary thermal injury that likely worsens local damage. These patients required laryngotracheal reconstructive procedures or had to undergo establishment of permanent tracheotomies.

CONCLUSION

Granulomatosis with polyangiitis is a rare disease that may manifest in multiple areas of the head and neck. Careful attention to diagnosis and management is critical, as these patients tend to have progressive disease with debilitating sequelae. The rheumatologist, otolaryngologist, and internist should identify patients with any constellation of symptoms that may be typical of GPA. A collaborative effort to diagnose, treat, and follow these patients is paramount to successful disease management.

The head and neck are the most common sites of involvement at initial presentation of granulomatosis with polyangiitis (GPA [Wegener’s granulomatosis]). Head and neck manifestations occur initially in 73% of patients, and eventually, up to 92% of patients with GPA are affected.¹ Many of these compromise the upper airway. Although treatment is multidisciplinary, the effects on the airway make it important to understand upper airway presentations and treatments. This article examines upper airway disease presentations, their assessment, and their advocated interventions.

DISEASE COURSE

Because head and neck involvement may be associated with a less aggressive form of GPA, outcomes for patients with predominantly head and neck involvement may be better compared with those who have involvement of other systems.²

The natural course of GPA may be indolent or rapidly progressive. Regardless, left untreated, it progresses to a generalized systemic disease that often leads to significant morbidity and likely mortality. Most patients (96%) achieve remission with immunosuppressive therapy, but nearly half (49%) have at least one relapse.¹ For this reason, systemic immunosuppressive medications play a dominant role in systemic and localized head and neck disease control. Patients often require maintenance medications along with additional therapies during disease exacerbation.³ Therefore, key partnerships between internists, rheumatologists, and otolaryngologists are paramount in the treatment and follow-up of these patients.

DIAGNOSIS: MAINSTAY IS SEROLOGIC EVALUATION

The differential diagnosis of GPA includes infection, lymphoproliferative disease (T-cell lymphoma), systemic lupus erythematosus, rheumatoid arthritis, sarcoidosis, and other granulomatous diseases such as eosinophilic GPA (Churg-Strauss syndrome), polyarteritis nodosa, and microscopic polyangiitis. Appropriate diagnosis is critical because treatment of these entities varies drastically.

The mainstay of GPA diagnosis is serologic evaluation for a cytoplasmic pattern of antineutrophil cytoplasmic antibodies (cANCA), which are reactive toward proteinase-3 (PR3) or myeloperoxidase (MPO). Testing for cANCA yields a pooled sensitivity of 91% and specificity of 99%. Sensitivity falls significantly (63%) when the disease is in nonacute stages, while the specificity remains high.⁴ These cANCA test characteristics allow a high positive predictive value for this rare disease.

Biopsy is typically reserved for cases in which serologic ANCA testing is nondiagnostic. Biopsy tissue may be readily accessible from the head and neck, but these biopsies may bear significant false-negative rates.^4–6 Diagnosis requires demonstration of palisading granulomas as vascular or extravascular lesions within the upper respiratory tract tissues. The specific site biopsied from within the head and neck has been shown to influence diagnostic yield, with sinonasal biopsies producing the highest yield.

SINONASAL MANIFESTATIONS

The nose and paranasal sinuses are the most frequently affected sites in the head and neck, noted in 64% to 80% of patients. Additionally, the nose is the only site of involvement in 30% of patients.⁷ Given the high frequency of sinonasal manifestations, GPA should be considered as a potential diagnosis among patients with persistent sinonasal disease.

Pathophysiology and disease course

The pathophysiologic mechanisms leading to the changes in the sinonasal tract in GPA have not been established. GPA is believed to be an immunologic disease that manifests as a vasculitis of small- and medium-sized vessels. Multiple potential causative factors have been identified, including fibrinoid necrosis of small blood vessels, epithelial granulomas, chronic inflammation, and prior surgical intervention.^8,9 The acute and chronic inflammation, coupled with the epithelioid granuloma formation, damages adjacent small- to medium-sized vessels. The vasculitis leads to diminished blood flow and subsequent avascular necrosis, which may promote tissue necrosis and bone destruction. This destructive process typically starts in the midseptum supplied by Kiesselbach plexus and in the turbinates. The process then eventually spreads to the paranasal sinuses.⁸

Patient evaluation

Examination of the nasal cavities is typically performed by rigid or flexible nasal endoscopy and often reveals nasal crusting, friable erythematous mucosa, granulation, and even signs of sinusitis. All or part of the cartilaginous septum may be involved, leading to significant septal defects. As the degree of cartilage destruction increases, nasal dorsal support decreases, leading to a visible depression of the external nose known as a “saddle-nose” deformity, which is present in 23% of patients with GPA.^7,10

Imaging assessment by computed tomography (CT) is needed to establish disease extent and involvement. Atypical findings may include bony erosion and destruction of the septum and turbinates; erosion of bony partitions within the ethmoid sinuses; neo-osteogenesis of the maxillary, frontal, and sphenoid sinuses; and complete bony obliteration of the maxillary, frontal, and sphenoid sinuses.^9,11

Clinical presentation

Sinonasal disease indicates the degree of disease activity.¹² Clinical findings may vary, but they have a significant impact on quality of life in these patients.¹³ Most patients with active disease present with nasal crusting (69%), chronic rhinosinusitis (CRS) symptoms (61%), nasal obstruction (58%), and serosanguinous nasal discharge (52%).¹⁰ Patients may also complain of foul-smelling rhinorrhea, recurrent epistaxis, hyposmia, anosmia, and epiphora (from granulomatous compression or obstruction of the lacrimal system). In a series of 120 patients with GPA, Cannady et al found that four (3.3%) patients had mucoceles and three (2.5%) had orbital pseudotumor.¹⁰

Any structure in the sinonasal cavity, including mucosa, septum, turbinates, and sinuses proper, may be affected because of the vasculitic involvement of mucosal blood vessels that causes diminished blood flow and subsequent necrosis. The area of the anterior septum supplied by Kiesselbach plexus is the most common site of active nasal disease, which can eventually lead to the common presentation of an anterior nasal septal perforation.

Otologic disease secondary to sinonasal GPA

Otologic involvement is observed in 19% to 38% of patients with GPA.^14,15 Most patients with GPA who exhibit otologic symptoms have middle ear or mastoid disease. It typically appears as chronic otitis media (COM) with conductive hearing loss.¹⁶ In most cases, the otologic involvement is secondary to Eustachian tube dysfunction caused by the presence of extensive disease in the nasopharynx.

Additionally, chronic mastoiditis can result from direct mastoid involvement with GPA. Facial nerve palsy secondary to infective bony destruction is a rare but repeatedly reported complication of GPA.^14,15

Inner ear involvement is a relatively common otologic presentation of GPA. Patients may experience sensorineural hearing loss (SNHL) as well as vertigo, which may mimic Cogan syndrome. Importantly, patients may exhibit inner ear involvement with or without middle ear and mastoid disease. The SNHL observed in patients with GPA may be responsive to steroid or immunosuppressive therapy.

Refractory CRS in GPA is a complex problem for which aggressive surgical intervention is often counterproductive. Unfortunately, traditional medical therapies are also often inadequate to treat progressive sinonasal symptomatology. As the nasal tissue becomes devascularized, loss of normal mucociliary function aggravates the sinus pathology, and clinical symptoms may worsen. Simple antibiotic regimens used to manage uncomplicated sinusitis are often inadequate in these patients. The subsequent progression to frank necrosis in localized regions creates an intranasal foreign body, allowing bacterial colonization, which is often refractory to antibiotics because of the inability of drug tissue penetration into these devascularized nasal structures.^12,17

Medical management must be tailored to be effective in this complex intranasal milieu. Successful treatment requires a multifaceted and often prolonged treatment course. A high index of suspicion should be maintained for Staphylococcus aureus. As a rule, endoscopically obtained cultures should be used to guide antibiotic selection. Several weeks of culture-directed antibiotics followed by topical antibiotic irrigations (eg, mupirocin irrigations) can be useful to reduce the frequency of sinonasal exacerbations.

Frequent saline irrigations using high-volume, high-flow irrigation devices (as opposed to low-volume, low-flow applicators such as nasal spray bottles) can be an excellent adjunct to maintenance therapy and are effective in clearing debris and augmenting mucociliary clearance in affected nasal cavities and those with septal perforations. Occasional in-office endoscopic debridement of large crusts adherent to intranasal structures or the edges of a septal perforation can also help to improve obstructive symptoms.

Surgery for refractory cases. Surgery should be reserved for refractory cases unresponsive to maximal medical efforts or those cases with impending complications (ie, mucoceles). Overall, only 16% of patients with sinonasal GPA required surgical intervention in a large series of 120 patients at our institution. In this series, one-third of all patients had undergone previous functional nasal surgery at an outside institution without resolution of symptoms. Anecdotal evidence suggests that surgery for GPA can contribute to additional scarring and lead to protracted sinonasal symptoms.^10,18

The decision to perform surgery is individualized and based on severity of the disease process, patient expectations, and surgeon expertise. In our experience at Cleveland Clinic, functional endoscopic sinus surgery in the setting of GPA is a surgical challenge, given extensive alteration of the sinonasal anatomy from previous surgery, prior and ongoing inflammation, chronic crusting, and scarring. Consequently, it has been our practice to employ conservative efforts prior to consideration of surgery. A complete surgical cure is exceedingly rare, and the patient should be counseled about the possible need for revision surgery and ongoing nonsurgical therapies. Meticulous postoperative care with weekly postoperative debridement, saline or antibiotic irrigations, and culture-directed antibiotics, is essential during the early postoperative recovery phase.

Management of epiphora. The most common ophthalmologic findings in patients with GPA include chronic epiphora and orbital pseudotumor. With the advent of advanced endoscopic techniques, the otolaryngologist plays a greater role in the surgical management of these ophthalmologic disease entities. In a series reported by Cannady et al,¹⁰ endoscopic dacrocystorhinostomy was performed successfully in seven patients, including one revision.

Nasal reconstruction for saddle-nose deformity: effective in selected patients. The progressive loss of septal support that occurs with the enlarging anterior septal perforation often results in significant collapse of the cartilaginous midvault of the nose. The tip cartilages in turn also begin to lose projection, resulting in a shortened nose with the characteristic saddle-nose deformity. The psychologic impact of this disfiguring facial abnormality is significant. The loss of midvault support also results in worsening nasal obstruction and increases the incidence of anosmia as the superior nasal vault becomes obstructed. For these reasons, patients often seek referral for potential reconstruction.

Despite the potential benefits, the general consensus in the medical community has been that surgical procedures on the nose should be avoided in GPA patients.¹⁷ Most nasal destruction in these patients is the consequence of poor tissue perfusion from the active vasculitis. Poor wound healing, reconstructive graft resorption, and worsening necrosis have been observed in patients who have undergone ill-advised surgical procedures.

These poor outcomes do not, however, preclude the potential for safe and effective surgical intervention. In three small published series, good surgical outcomes were achieved but the procedures were done in very highly selected patients and were modified to address the specific clinical issues seen in GPA patients.^19–21 The critical step in achieving a good outcome is working closely with the patient’s rheumatologist to identify an appropriate clinical window during which the patient’s disease process is in a period of relative remission. The second major factor is to modify the surgical techniques to take into account the very poor vascular framework of the recipient nasal bed.

Management of COM. Because the COM in patients with GPA is frequently secondary to nasopharyngeal disease, systemic control of GPA is the first priority. Systemic control is also the first-line treatment for patients with mixed or sensorineural hearing loss, or with vertigo. For continued or symptomatic middle ear effusions that do not resolve with systemic therapy, placement of a ventilation tube may be considered. In patients with significant hearing loss, hearing amplification devices may be warranted.^15,22 Cochlear implant devices in GPA patients are experimental and may pose undue risks of meningitis.

SUBGLOTTIC STENOSIS AND TRACHEAL MANIFESTATIONS

Subglottic stenosis affects 10% to 20% of patients with GPA.^1,23,24 Because of its potential life-threatening airway complications, patients should be carefully assessed for this disease manifestation. It may be the only manifestation of GPA or may be part of a spectrum of other disease manifestations. Therefore, the work-up for subglottic stenosis of unknown etiology should always include an evaluation for GPA.

Pathophysiology and disease course

The etiology of subglottic stenosis in GPA is not well understood. Theories primarily involve the vulnerability of the subglottic tissues to damage, chronic inflammation, and scarring.²⁵ The combination of vasculitis in the setting of active inflammation may synergistically produce a hyperactive reparative mechanism in GPA patients that leads to cartilaginous fibrotic scarring and stenosis. Wound healing can be divided into the phases of inflammation, proliferation, and remodeling. An imbalance or exaggerated response of any of these levels (and likely all) produces an abnormal healing response.²⁶ Similarly, each of these phases may be targeted to improve the healing process.

Patient evaluation

The presence of subglottic stenosis must be considered in a GPA patient with respiratory symptoms. As part of the routine initial evaluation, an office-based nasopharyngeal/laryngeal endoscopy using a flexible laryngoscope should be performed to assess the presence and severity of luminal airway narrowing. Flexible laryngoscopy reveals a circumferential narrowing of the subglottis. The stenotic tissue may vary from friable with erythematous and inflamed mucosa to a rigid mature fibrotic band, depending on the inflammatory state of the stenosis.^18,27

Subclinical stenosis may be identified with routine endoscopy. An appropriate baseline is needed to follow the progression of disease and to adjust the timing of any potential intervention. The ability to digitally record a patient’s examination allows further tracking of disease and is commonly used in our practices.

Although flexible fiberoptic examination is critical in diagnosis and follow-up, intraoperative direct laryngoscopy using rigid laryngoscopes and telescopes provides the optimum view of the subglottis. In particular, this view provides greater information on the length and degree of the stenosis and allows evaluation of potential stenotic segments in the inferior trachea.

Spiral CT with 3-dimensional reconstruction of the laryngotracheal lumen and virtual bronchoscopy may provide information that complements laryngoscopy. CT may permit assessment of the entire tracheobronchial pathway. Because 15% to 55% of GPA patients have additional bronchial stenotic segments, assessment of the entire airway is important.^28,29

Diagnosis of GPA in patients younger than 20 years is associated with the development of subglottic stenosis.^23,30 The GPA patient with subglottic stenosis may or may not have other active systemic symptoms. The efficacy of systemic therapy often does not correlate with the degree of subglottic stenosis. Importantly, when systemic disease enters remission, the subglottic stenosis may remain due to residual scarring of the subglottis.³¹

Patients with subglottic stenosis may present with hoarseness, cough, wheeze, stridor, or dyspnea on exertion.^27,32 The stridor and wheeze may be confused with the wheeze of asthma, often leading to misdiagnosis.¹⁷

Subglottic stenosis likely begins at a small degree and increases gradually, allowing the patient to adjust his or her breathing pattern until a critical stenotic airway area is reached. Typically, and dependent on their pulmonary health, patients are asymptomatic until about 75% airway stenosis (60% in children).^33,34 At this point, symptoms may become evident and correlate with the degree of stenosis, ranging from cough and mild shortness of breath to life-threatening stridor and obstruction. Importantly, as the airway caliber narrows, mucous plugging becomes a greater concern, as it can cause acute stridulous exacerbations and airway obstruction.

A significant proportion of patients with GPA who have subclinical asymptomatic stenosis may not receive laryngeal examination. Patients who have suspicious clinical histories should be referred for evaluation of subglottic stenosis prior to symptom worsening.

Patients with significant (approximately 80%) stenosis can present with respiratory symptoms that may be life-threatening. Because airway management in this setting is substantially more difficult, the goal should be to obtain a diagnosis and perform intervention before this advanced presentation develops.

Pauzner et al described a possible association between GPA tracheal stenosis and pregnancy.³⁵ Women of childbearing age who have GPA should be counseled about this possible association and the need for close follow-up during the partum and postpartum periods.

Treatment is controversial

The treatment of subglottic stenosis of GPA requires multidisciplinary management by the rheumatologist, otolaryngologist, and pulmonologist. Systemic manifestations of disease are managed by immunosuppressive therapy, but up to 80% of patients may require surgical management of subglottic stenosis, and the remaining 20% will respond to systemic medical therapy.^22,23,36,37 Overall, the treatment of this disease is controversial and varies by center. The therapeutic arsenal consists of conventional immunosuppressive therapy, endoscopic dilation, endoscopic or laser excision, and surgical resection of the stenotic segment followed by reconstruction.

Tracheotomy. Historically, tracheotomies were performed in approximately one-half of patients with airway manifestations of GPA when the patient had active disease or when airway patency could not be adequately maintained. Most of these patients were eventually decannulated.^23,25 At present, tracheotomy is performed infrequently and is reserved for patients who have either a severely tenuous airway (with tracheotomy the only safe option available to obtain a secure airway) or who express a preference for tracheotomy. In a recent study by Hoffman et al,³⁸ tracheotomy was avoided in 21 patients through the use of stenosis dilation procedures.

Dilation. Endoscopic subglottic dilation is the currently advocated method of treatment, and has shown promising results. In two studies with a total of 41 GPA patients who were able to avoid tracheotomy and open surgical procedures, 24% underwent decannulation of previously placed tracheotomies and 24% required only one procedure at an average follow-up of 3.4 and 5 years per study. In these studies, the technique of intralesional corticosteroid with mechanical dilation (ILCD) was performed.^31,36,38

Preferred: Dilation plus medical therapy

Because of the inflammatory etiology of this condition, surgical intervention has the risk of potentially worsening the stenosis. However, combining dilation of the stenosis with aggressive local medical treatment to prevent scar formation and cellular proliferation has been shown to be effective and safe. This treatment modality was recently recommended as the preferred therapy based on a number of relatively small clinical trials for subglottic stenosis, without the benefit of large controlled trials.

Our patient population consists of two subsets: (1) those who respond well to ILCD and systemic medical therapy, requiring a minimal number of dilations before no longer needing procedures because of a possible “burn out” of the subglottic disease, and (2) those who continue to have recurrence of stenosis, requiring repeat ILCD. The latter group requires close long-term observation.

To counter the effects of the exaggerated healing reaction of inflammation (early) and proliferation (late) following injury, two medications are applied to the area of repaired stenosis. The stenotic lesion is first injected submucosally with a long-acting corticosteroid suspension such as methylprednisolone. The solution is injected along the submucosal-perichondrial plane. Incisions are made in a star-like fashion, employing sharp metal microlaryngeal blades or, less commonly, the carbon dioxide laser. These incisions release the constricting stenotic ring and break it up, widening the diameter of the airway and simultaneously preserving islands of intact mucous membrane between the incisions. This epithelium is intended to regenerate and resurface the expanded lumen. Progressive serial dilations are performed using semirigid, flexible, smooth dilators or high-pressure balloon dilation. The next stage involves repeated topical applications of mitomycin-C to further inhibit fibrosis and restenosis by inhibiting cellular proliferation of the vigorous injury cycles of these lesions. Application of mitomycin-C to the dilated area of a laryngotracheal stenosis has been associated with a decreased rate of stenosis relapse.³⁹

Our group at Cleveland Clinic has never used laser surgery alone without dilation on the subglottic stenosis caused by GPA. Incidentally, patients treated with laser surgery in other institutions prior to their referral to the Cleveland Clinic have developed complicating secondary stenoses that required more extensive surgical intervention to overcome the severe secondary superimposed damage. In theory, use of the laser may create unnecessary thermal injury that likely worsens local damage. These patients required laryngotracheal reconstructive procedures or had to undergo establishment of permanent tracheotomies.

CONCLUSION

Granulomatosis with polyangiitis is a rare disease that may manifest in multiple areas of the head and neck. Careful attention to diagnosis and management is critical, as these patients tend to have progressive disease with debilitating sequelae. The rheumatologist, otolaryngologist, and internist should identify patients with any constellation of symptoms that may be typical of GPA. A collaborative effort to diagnose, treat, and follow these patients is paramount to successful disease management.

Necrotizing glomerulonephritis (GN) is the classical renal manifestation of the small-vessel vasculitides, which include granulomatosis with polyangiitis (GPA [Wegener’s granulomatosis]), microscopic polyangiitis (MPA), and eosinophilic GPA (Churg-Strauss syndrome). MPA is pauci-immune (lacks antibody depositions) and causes focal segmental necrotizing GN. Other small-vessel vasculitides are Henoch-SchÖnlein purpura, which features nephritis from immunoglobulin A–dominant immune deposits, and essential cryoglobulinemic vasculitis, in which cryoglobulin immune deposits lead to membranoproliferative GN.¹

Renal involvement occurs in 25% to 75% of patients with antineutrophil cytoplasmic antibody (ANCA)–associated systemic vasculitis (AASV), with the higher percentage reflecting patients who first present to a nephrologist rather than a rheumatologist. Roughly 35% are dialysis-dependent, mainly those who are elderly or proteinase-3– or myeloperoxidase-ANCA–positive. In duc tion of remission through immunosuppression allows 50% to 60% of dialysis-dependent patients to recover independent renal function.^2,3

PROGNOSTIC SIGNIFICANCE OF RENAL INVOLVEMENT

Patients should be assessed at the earliest opportunity for renal involvement as it is highly predictive of survival. Diagnosis allows immunosuppressive treatment to be started early, when kidney function may still be preserved.

Reinhold-Keller et al³ examined survival by level of renal involvement at diagnosis in 155 patients with GPA who were followed for a median of 7 years. Survival in those with normal renal function, but with nephritic urinary sediment at diagnosis, declined over time compared with patients who had no renal involvement at diagnosis, with a more than twofold greater risk of death (hazard ratio [HR], 2.41; 95% confidence interval [CI] 0.53–11.06). Patients who had impaired renal function at diagnosis had a fivefold greater risk of death (HR, 5.42; 95% CI 1.76–16.68).

Maximum serum creatinine in the first month of treatment is also highly predictive of survival. An outcome analysis followed 80 patients with AASV and renal involvement for a median of 46.7 months.⁴ Patients were divided equally into groups by maximum serum creatinine levels after the first month of treatment: less than 299 μmol/L, 299 to 582 μmol/L, and greater than 582 μmol/L. All patients were treated for induction of remission with cyclophosphamide and oral corticosteroids. Survival was significantly worse in patients who had the highest maximum serum creatinine in the first month (P = .025).

Pooled prospective data from four European Vasculitis Study Group (EUVAS) trials of 535 patients with AASV and follow-up of 5.2 years found a mortality ratio of 2.6 (95% CI, 2.2–3.1) compared with matched subjects from the general population.⁵ Stage 5 chronic kidney disease (glomerular filtration rate < 15 mL/min) was a significant negative prognostic determinant of survival in these trials.

A DISEASE OF AGING

Renal vasculitis is most prevalent in people aged 50 years and older and often occurs in those aged 70 years and older.⁶ Because the very old may not have extrarenal symptoms, it is necessary to maintain a high index of suspicion for AASV and measure urinary sediment and renal function in this age group.

Older patients also present with more severe renal disease and have a poorer prognosis. Harper and Savage compared presentation and outcomes of patients aged 65 years and older with renal AASV with those of patients younger than 65 years.⁷ Older patients had more severe renal failure than did younger patients (serum creatinine 657 vs 470 μmol/L, respectively; P < .001), and this did not appear to be associated with delayed diagnosis. Survival was worse in those with serum creatinine levels greater than 400 μmol/L irrespective of age; however, when comparing younger and older groups with similar renal insufficiency, older patients were more likely to progress to end-stage renal failure (P = .039), survival was worse (P = .016), and death occurred earlier.⁷

HISTOPATHOLOGIC CLASSIFICATION

An international working group of renal pathologists⁸ developed pathologic classifications for rapidly progressive GN caused by AASV: focal (≥ 50% normal glomeruli), crescentic (≥ 50% glomeruli with cellular crescents), mixed (no predominant glomerular feature), and sclerotic (≥ 50% globally sclerotic glomeruli). These correspond to the order of severity of renal-function impairment. A study of 100 biopsies from patients with ANCA-associated GN found that the classifications at presentation closely correlated with outcomes.⁸

Patients with sclerotic GN had the worst renal function initially, with little improvement at 5 years; hence, immunosuppression is of little value if the kidney is more than 50% sclerotic. Patients with focal disease who had good renal function initially were found to retain good function after 5 years of treatment. Patients in the crescentic class present with rapidly progressive GN and very poor renal function. However, they were found to improve considerably after 5 years and had good recovery (P = .001). Presenting disease manifestations within the kidney are of diagnostic as well as prognostic value.

TREATMENT OF AASV

Lower dosage of cyclophosphamide

Standard immunosuppressive treatment for vasculitis is oral cyclophosphamide, 2 mg/kg per day. To reduce toxic effects and amount of the drug used, we tested whether a pulse dose could induce remission. In the EUVAS randomized trial of oral versus pulse cyclophosphamide (the CYCLOPS study),⁹ 149 AASV patients with renal involvement received either pulse cyclophosphamide, 15 mg/kg every 2 to 3 weeks, or daily oral cyclophosphamide, 2 mg/kg per day, plus prednisone. The groups did not differ in time to remission (HR, 1.098) or in proportion of patients who had achieved remission at 9 months (88.1% vs 87.7%). The pulse-dose group needed half the amount of drug to achieve remission compared with the oral-dose group. Pulse dosing is currently the preferred method in Europe, where doses are administered in the clinic rather than at home.

In a 4.3-year follow-up, twice as many patients relapsed in the pulse-dose group compared with the oral group (HR, 0.50; P = .029), but there was no difference between groups in renal function (P = .82), end-stage renal disease (ESRD), or death.¹⁰ It should be borne in mind that there is a tendency to overtreat. An analysis of four EUVAS trials found a risk of mortality of 11% in the first year; 59% of these were due to treatment-related adverse events.¹¹

Despite being prone to renal failure and infectious complications, elderly patients with ANCA-associated GN who do not have ESRD fare better with immunosuppressive therapy than without in terms of progression and survival. Cyclophosphamide dosage should be reduced in these patients.

Plasma exchange

In crescentic disease and rapidly progressing renal failure, plasma exchange (PE) with albumin reduces circulating antibodies by up to 60% and promotes renal recovery. The MEPEX trial compared the addition of either PE or intravenous methylprednisolone (MEP) to oral cyclophosphamide and prednisolone in 137 newly diagnosed AASV patients with severe crescentic GN (serum creatinine > 500 μmol/L).¹² Two-thirds of the group were oliguric. After 3 months, 69% of PE-treated compared with 49% of MEP-treated patients were alive and had achieved independent renal function (P = .02). There was also a reduction in risk for ESRD of 24% at 12 months in the PE versus MEP group. Mortality was similarly high in both groups, however; roughly one-third had died by 12 months, reflecting the higher rates of complications in this older-aged group (median, 66 years).

For patients undergoing PE who have a sudden drop in hemoglobin, gastrointestinal bleeding is only one possible underlying condition. The patient may have bleeding into the pulmonary parenchyma, and computed tomography of the lung should be performed. This is more likely to occur when plasma is exchanged with albumin rather than fresh frozen plasma.

Renal replacement therapy

End-stage renal disease occurs in approximately 25% of patients 3 to 4 years after they present with AASV. Renal-limited disease occurs most often in those with MPA. When there is active rather than sclerotic disease but irreversible renal failure is suspected, immunosuppression can be tried for 3 months. If there is no response, improvement in renal function is unlikely and immunosuppressive treatment is continued only for extrarenal disease. Patients with ESRD can be treated with hemodialysis, peritoneal dialysis at home, or kidney transplant.

Lionaki et al¹³ described the rate of relapse in AASV patients before and after kidney dialysis compared with that in AASV patients with preserved renal function. Over a median of 40 months, 136 of 523 patients progressed to ESRD. Rate of relapse of vasculitis was significantly lower for the patients on chronic dialysis (0.08 episodes per person-year) than for the same patients before dialysis (0.2 episodes) and for the patients with preserved renal function (0.15 episodes). Infections, an important cause of death, were twice as frequent for patients on dialysis and maintenance immunosuppression.

Weidanz et al¹⁴ reported on a retrospective case series that examined whether immunosuppressive therapy with its risk of infection is beneficial for vasculitis patients on dialysis. They retrospectively examined 46 cases of AASV over 30 years and found that the patients with ESRD received less immunosuppression, but their rate of infection was twice that of pre-ESRD patients, and mortality quadrupled while on dialysis. The mode of dialysis did not affect survival, however. These results may support early discontinuation of immunosuppressive treatment in patients with ESRD and suggest that it be used only in those with active disease.

Renal transplant

At the time of transplantation, patients receive a massive immunosupressive induction regimen consisting of anti-CD25 antibody and triple conventional immunosuppressive drugs, usually a calcineurin inhibitor, antimetabolite, and prednisolone. Survival in transplant patients with vasculitis is not significantly different from that of other kidney transplant patients.¹⁵

Patients should not receive transplants until at least 12 months after induction of remission; patients who underwent transplant less than 12 months after remission had a mortality HR of 2.3 (P < .05).¹⁶ Vasculopathy occurs more frequently in ANCA-positive patients, which leads to graft loss.

Graft loss due to recurrent vasculitis is also possible. Nachman et al¹⁷ found double the rate of infection for transplant compared with nontransplant AASV patients, but the rate of relapse was lower than the rate before transplant or for patients on dialysis. There was no significant difference in rates of relapse between patients with or without circulating ANCA at the time of transplant or between those having GPA, MPA, or renal-limited disease.¹⁸

Cardiovascular risk

Renal involvement in vasculitis increases cardiovascular morbidity. Vasculitis patients with renal involvement (n =113) were matched with patients with chronic kidney disease and other contributing cardiovascular risk factors.¹⁸ After approximately 4 years of follow-up, the vasculitis patients had an HR of 2.23 (P = .017) for cardiovascular events. AASV patients with the highest excess risk had histories of cardiovascular events (HR, 4), dialysis dependency (HR, 4.3), poor renal function at admission (HR, 0.977), and history of smoking (HR, 3.9).

CONCLUSION

Level of renal function at diagnosis is an important predictor of survival. Poor renal function correlates with mortality, especially in the elderly. Pathologic classification of renal vasculitis based on histopathology obtained from the kidney biopsy correlates closely with prognosis. About 60% of initially dialysis-dependent patients with active GN can regain independent renal function. Those on dialysis have a lower rate of relapse of active vasculitis than do those with independent renal function; patients with kidney transplants have the lowest rate of relapse. There is a doubling of infection rate in patients who have ESRD and who receive any form of renal replacement therapy. Lastly, renal involvement in AASV is an independent and serious contributor to risk for cardiovascular disease.

Necrotizing glomerulonephritis (GN) is the classical renal manifestation of the small-vessel vasculitides, which include granulomatosis with polyangiitis (GPA [Wegener’s granulomatosis]), microscopic polyangiitis (MPA), and eosinophilic GPA (Churg-Strauss syndrome). MPA is pauci-immune (lacks antibody depositions) and causes focal segmental necrotizing GN. Other small-vessel vasculitides are Henoch-SchÖnlein purpura, which features nephritis from immunoglobulin A–dominant immune deposits, and essential cryoglobulinemic vasculitis, in which cryoglobulin immune deposits lead to membranoproliferative GN.¹

Renal involvement occurs in 25% to 75% of patients with antineutrophil cytoplasmic antibody (ANCA)–associated systemic vasculitis (AASV), with the higher percentage reflecting patients who first present to a nephrologist rather than a rheumatologist. Roughly 35% are dialysis-dependent, mainly those who are elderly or proteinase-3– or myeloperoxidase-ANCA–positive. In duc tion of remission through immunosuppression allows 50% to 60% of dialysis-dependent patients to recover independent renal function.^2,3

PROGNOSTIC SIGNIFICANCE OF RENAL INVOLVEMENT

Patients should be assessed at the earliest opportunity for renal involvement as it is highly predictive of survival. Diagnosis allows immunosuppressive treatment to be started early, when kidney function may still be preserved.

Reinhold-Keller et al³ examined survival by level of renal involvement at diagnosis in 155 patients with GPA who were followed for a median of 7 years. Survival in those with normal renal function, but with nephritic urinary sediment at diagnosis, declined over time compared with patients who had no renal involvement at diagnosis, with a more than twofold greater risk of death (hazard ratio [HR], 2.41; 95% confidence interval [CI] 0.53–11.06). Patients who had impaired renal function at diagnosis had a fivefold greater risk of death (HR, 5.42; 95% CI 1.76–16.68).

Maximum serum creatinine in the first month of treatment is also highly predictive of survival. An outcome analysis followed 80 patients with AASV and renal involvement for a median of 46.7 months.⁴ Patients were divided equally into groups by maximum serum creatinine levels after the first month of treatment: less than 299 μmol/L, 299 to 582 μmol/L, and greater than 582 μmol/L. All patients were treated for induction of remission with cyclophosphamide and oral corticosteroids. Survival was significantly worse in patients who had the highest maximum serum creatinine in the first month (P = .025).

Pooled prospective data from four European Vasculitis Study Group (EUVAS) trials of 535 patients with AASV and follow-up of 5.2 years found a mortality ratio of 2.6 (95% CI, 2.2–3.1) compared with matched subjects from the general population.⁵ Stage 5 chronic kidney disease (glomerular filtration rate < 15 mL/min) was a significant negative prognostic determinant of survival in these trials.

A DISEASE OF AGING

Renal vasculitis is most prevalent in people aged 50 years and older and often occurs in those aged 70 years and older.⁶ Because the very old may not have extrarenal symptoms, it is necessary to maintain a high index of suspicion for AASV and measure urinary sediment and renal function in this age group.

Older patients also present with more severe renal disease and have a poorer prognosis. Harper and Savage compared presentation and outcomes of patients aged 65 years and older with renal AASV with those of patients younger than 65 years.⁷ Older patients had more severe renal failure than did younger patients (serum creatinine 657 vs 470 μmol/L, respectively; P < .001), and this did not appear to be associated with delayed diagnosis. Survival was worse in those with serum creatinine levels greater than 400 μmol/L irrespective of age; however, when comparing younger and older groups with similar renal insufficiency, older patients were more likely to progress to end-stage renal failure (P = .039), survival was worse (P = .016), and death occurred earlier.⁷

HISTOPATHOLOGIC CLASSIFICATION

An international working group of renal pathologists⁸ developed pathologic classifications for rapidly progressive GN caused by AASV: focal (≥ 50% normal glomeruli), crescentic (≥ 50% glomeruli with cellular crescents), mixed (no predominant glomerular feature), and sclerotic (≥ 50% globally sclerotic glomeruli). These correspond to the order of severity of renal-function impairment. A study of 100 biopsies from patients with ANCA-associated GN found that the classifications at presentation closely correlated with outcomes.⁸

Patients with sclerotic GN had the worst renal function initially, with little improvement at 5 years; hence, immunosuppression is of little value if the kidney is more than 50% sclerotic. Patients with focal disease who had good renal function initially were found to retain good function after 5 years of treatment. Patients in the crescentic class present with rapidly progressive GN and very poor renal function. However, they were found to improve considerably after 5 years and had good recovery (P = .001). Presenting disease manifestations within the kidney are of diagnostic as well as prognostic value.

TREATMENT OF AASV

Lower dosage of cyclophosphamide

Standard immunosuppressive treatment for vasculitis is oral cyclophosphamide, 2 mg/kg per day. To reduce toxic effects and amount of the drug used, we tested whether a pulse dose could induce remission. In the EUVAS randomized trial of oral versus pulse cyclophosphamide (the CYCLOPS study),⁹ 149 AASV patients with renal involvement received either pulse cyclophosphamide, 15 mg/kg every 2 to 3 weeks, or daily oral cyclophosphamide, 2 mg/kg per day, plus prednisone. The groups did not differ in time to remission (HR, 1.098) or in proportion of patients who had achieved remission at 9 months (88.1% vs 87.7%). The pulse-dose group needed half the amount of drug to achieve remission compared with the oral-dose group. Pulse dosing is currently the preferred method in Europe, where doses are administered in the clinic rather than at home.

In a 4.3-year follow-up, twice as many patients relapsed in the pulse-dose group compared with the oral group (HR, 0.50; P = .029), but there was no difference between groups in renal function (P = .82), end-stage renal disease (ESRD), or death.¹⁰ It should be borne in mind that there is a tendency to overtreat. An analysis of four EUVAS trials found a risk of mortality of 11% in the first year; 59% of these were due to treatment-related adverse events.¹¹

Despite being prone to renal failure and infectious complications, elderly patients with ANCA-associated GN who do not have ESRD fare better with immunosuppressive therapy than without in terms of progression and survival. Cyclophosphamide dosage should be reduced in these patients.

Plasma exchange

In crescentic disease and rapidly progressing renal failure, plasma exchange (PE) with albumin reduces circulating antibodies by up to 60% and promotes renal recovery. The MEPEX trial compared the addition of either PE or intravenous methylprednisolone (MEP) to oral cyclophosphamide and prednisolone in 137 newly diagnosed AASV patients with severe crescentic GN (serum creatinine > 500 μmol/L).¹² Two-thirds of the group were oliguric. After 3 months, 69% of PE-treated compared with 49% of MEP-treated patients were alive and had achieved independent renal function (P = .02). There was also a reduction in risk for ESRD of 24% at 12 months in the PE versus MEP group. Mortality was similarly high in both groups, however; roughly one-third had died by 12 months, reflecting the higher rates of complications in this older-aged group (median, 66 years).

For patients undergoing PE who have a sudden drop in hemoglobin, gastrointestinal bleeding is only one possible underlying condition. The patient may have bleeding into the pulmonary parenchyma, and computed tomography of the lung should be performed. This is more likely to occur when plasma is exchanged with albumin rather than fresh frozen plasma.

Renal replacement therapy

End-stage renal disease occurs in approximately 25% of patients 3 to 4 years after they present with AASV. Renal-limited disease occurs most often in those with MPA. When there is active rather than sclerotic disease but irreversible renal failure is suspected, immunosuppression can be tried for 3 months. If there is no response, improvement in renal function is unlikely and immunosuppressive treatment is continued only for extrarenal disease. Patients with ESRD can be treated with hemodialysis, peritoneal dialysis at home, or kidney transplant.

Lionaki et al¹³ described the rate of relapse in AASV patients before and after kidney dialysis compared with that in AASV patients with preserved renal function. Over a median of 40 months, 136 of 523 patients progressed to ESRD. Rate of relapse of vasculitis was significantly lower for the patients on chronic dialysis (0.08 episodes per person-year) than for the same patients before dialysis (0.2 episodes) and for the patients with preserved renal function (0.15 episodes). Infections, an important cause of death, were twice as frequent for patients on dialysis and maintenance immunosuppression.

Weidanz et al¹⁴ reported on a retrospective case series that examined whether immunosuppressive therapy with its risk of infection is beneficial for vasculitis patients on dialysis. They retrospectively examined 46 cases of AASV over 30 years and found that the patients with ESRD received less immunosuppression, but their rate of infection was twice that of pre-ESRD patients, and mortality quadrupled while on dialysis. The mode of dialysis did not affect survival, however. These results may support early discontinuation of immunosuppressive treatment in patients with ESRD and suggest that it be used only in those with active disease.

Renal transplant

At the time of transplantation, patients receive a massive immunosupressive induction regimen consisting of anti-CD25 antibody and triple conventional immunosuppressive drugs, usually a calcineurin inhibitor, antimetabolite, and prednisolone. Survival in transplant patients with vasculitis is not significantly different from that of other kidney transplant patients.¹⁵

Patients should not receive transplants until at least 12 months after induction of remission; patients who underwent transplant less than 12 months after remission had a mortality HR of 2.3 (P < .05).¹⁶ Vasculopathy occurs more frequently in ANCA-positive patients, which leads to graft loss.

Graft loss due to recurrent vasculitis is also possible. Nachman et al¹⁷ found double the rate of infection for transplant compared with nontransplant AASV patients, but the rate of relapse was lower than the rate before transplant or for patients on dialysis. There was no significant difference in rates of relapse between patients with or without circulating ANCA at the time of transplant or between those having GPA, MPA, or renal-limited disease.¹⁸

Cardiovascular risk

Renal involvement in vasculitis increases cardiovascular morbidity. Vasculitis patients with renal involvement (n =113) were matched with patients with chronic kidney disease and other contributing cardiovascular risk factors.¹⁸ After approximately 4 years of follow-up, the vasculitis patients had an HR of 2.23 (P = .017) for cardiovascular events. AASV patients with the highest excess risk had histories of cardiovascular events (HR, 4), dialysis dependency (HR, 4.3), poor renal function at admission (HR, 0.977), and history of smoking (HR, 3.9).

CONCLUSION

Level of renal function at diagnosis is an important predictor of survival. Poor renal function correlates with mortality, especially in the elderly. Pathologic classification of renal vasculitis based on histopathology obtained from the kidney biopsy correlates closely with prognosis. About 60% of initially dialysis-dependent patients with active GN can regain independent renal function. Those on dialysis have a lower rate of relapse of active vasculitis than do those with independent renal function; patients with kidney transplants have the lowest rate of relapse. There is a doubling of infection rate in patients who have ESRD and who receive any form of renal replacement therapy. Lastly, renal involvement in AASV is an independent and serious contributor to risk for cardiovascular disease.

Necrotizing glomerulonephritis (GN) is the classical renal manifestation of the small-vessel vasculitides, which include granulomatosis with polyangiitis (GPA [Wegener’s granulomatosis]), microscopic polyangiitis (MPA), and eosinophilic GPA (Churg-Strauss syndrome). MPA is pauci-immune (lacks antibody depositions) and causes focal segmental necrotizing GN. Other small-vessel vasculitides are Henoch-SchÖnlein purpura, which features nephritis from immunoglobulin A–dominant immune deposits, and essential cryoglobulinemic vasculitis, in which cryoglobulin immune deposits lead to membranoproliferative GN.¹

Renal involvement occurs in 25% to 75% of patients with antineutrophil cytoplasmic antibody (ANCA)–associated systemic vasculitis (AASV), with the higher percentage reflecting patients who first present to a nephrologist rather than a rheumatologist. Roughly 35% are dialysis-dependent, mainly those who are elderly or proteinase-3– or myeloperoxidase-ANCA–positive. In duc tion of remission through immunosuppression allows 50% to 60% of dialysis-dependent patients to recover independent renal function.^2,3

PROGNOSTIC SIGNIFICANCE OF RENAL INVOLVEMENT

Patients should be assessed at the earliest opportunity for renal involvement as it is highly predictive of survival. Diagnosis allows immunosuppressive treatment to be started early, when kidney function may still be preserved.

Reinhold-Keller et al³ examined survival by level of renal involvement at diagnosis in 155 patients with GPA who were followed for a median of 7 years. Survival in those with normal renal function, but with nephritic urinary sediment at diagnosis, declined over time compared with patients who had no renal involvement at diagnosis, with a more than twofold greater risk of death (hazard ratio [HR], 2.41; 95% confidence interval [CI] 0.53–11.06). Patients who had impaired renal function at diagnosis had a fivefold greater risk of death (HR, 5.42; 95% CI 1.76–16.68).

Maximum serum creatinine in the first month of treatment is also highly predictive of survival. An outcome analysis followed 80 patients with AASV and renal involvement for a median of 46.7 months.⁴ Patients were divided equally into groups by maximum serum creatinine levels after the first month of treatment: less than 299 μmol/L, 299 to 582 μmol/L, and greater than 582 μmol/L. All patients were treated for induction of remission with cyclophosphamide and oral corticosteroids. Survival was significantly worse in patients who had the highest maximum serum creatinine in the first month (P = .025).

Pooled prospective data from four European Vasculitis Study Group (EUVAS) trials of 535 patients with AASV and follow-up of 5.2 years found a mortality ratio of 2.6 (95% CI, 2.2–3.1) compared with matched subjects from the general population.⁵ Stage 5 chronic kidney disease (glomerular filtration rate < 15 mL/min) was a significant negative prognostic determinant of survival in these trials.

A DISEASE OF AGING

Renal vasculitis is most prevalent in people aged 50 years and older and often occurs in those aged 70 years and older.⁶ Because the very old may not have extrarenal symptoms, it is necessary to maintain a high index of suspicion for AASV and measure urinary sediment and renal function in this age group.

Older patients also present with more severe renal disease and have a poorer prognosis. Harper and Savage compared presentation and outcomes of patients aged 65 years and older with renal AASV with those of patients younger than 65 years.⁷ Older patients had more severe renal failure than did younger patients (serum creatinine 657 vs 470 μmol/L, respectively; P < .001), and this did not appear to be associated with delayed diagnosis. Survival was worse in those with serum creatinine levels greater than 400 μmol/L irrespective of age; however, when comparing younger and older groups with similar renal insufficiency, older patients were more likely to progress to end-stage renal failure (P = .039), survival was worse (P = .016), and death occurred earlier.⁷

HISTOPATHOLOGIC CLASSIFICATION

An international working group of renal pathologists⁸ developed pathologic classifications for rapidly progressive GN caused by AASV: focal (≥ 50% normal glomeruli), crescentic (≥ 50% glomeruli with cellular crescents), mixed (no predominant glomerular feature), and sclerotic (≥ 50% globally sclerotic glomeruli). These correspond to the order of severity of renal-function impairment. A study of 100 biopsies from patients with ANCA-associated GN found that the classifications at presentation closely correlated with outcomes.⁸

Patients with sclerotic GN had the worst renal function initially, with little improvement at 5 years; hence, immunosuppression is of little value if the kidney is more than 50% sclerotic. Patients with focal disease who had good renal function initially were found to retain good function after 5 years of treatment. Patients in the crescentic class present with rapidly progressive GN and very poor renal function. However, they were found to improve considerably after 5 years and had good recovery (P = .001). Presenting disease manifestations within the kidney are of diagnostic as well as prognostic value.

TREATMENT OF AASV

Lower dosage of cyclophosphamide

Standard immunosuppressive treatment for vasculitis is oral cyclophosphamide, 2 mg/kg per day. To reduce toxic effects and amount of the drug used, we tested whether a pulse dose could induce remission. In the EUVAS randomized trial of oral versus pulse cyclophosphamide (the CYCLOPS study),⁹ 149 AASV patients with renal involvement received either pulse cyclophosphamide, 15 mg/kg every 2 to 3 weeks, or daily oral cyclophosphamide, 2 mg/kg per day, plus prednisone. The groups did not differ in time to remission (HR, 1.098) or in proportion of patients who had achieved remission at 9 months (88.1% vs 87.7%). The pulse-dose group needed half the amount of drug to achieve remission compared with the oral-dose group. Pulse dosing is currently the preferred method in Europe, where doses are administered in the clinic rather than at home.

In a 4.3-year follow-up, twice as many patients relapsed in the pulse-dose group compared with the oral group (HR, 0.50; P = .029), but there was no difference between groups in renal function (P = .82), end-stage renal disease (ESRD), or death.¹⁰ It should be borne in mind that there is a tendency to overtreat. An analysis of four EUVAS trials found a risk of mortality of 11% in the first year; 59% of these were due to treatment-related adverse events.¹¹

Despite being prone to renal failure and infectious complications, elderly patients with ANCA-associated GN who do not have ESRD fare better with immunosuppressive therapy than without in terms of progression and survival. Cyclophosphamide dosage should be reduced in these patients.

Plasma exchange

In crescentic disease and rapidly progressing renal failure, plasma exchange (PE) with albumin reduces circulating antibodies by up to 60% and promotes renal recovery. The MEPEX trial compared the addition of either PE or intravenous methylprednisolone (MEP) to oral cyclophosphamide and prednisolone in 137 newly diagnosed AASV patients with severe crescentic GN (serum creatinine > 500 μmol/L).¹² Two-thirds of the group were oliguric. After 3 months, 69% of PE-treated compared with 49% of MEP-treated patients were alive and had achieved independent renal function (P = .02). There was also a reduction in risk for ESRD of 24% at 12 months in the PE versus MEP group. Mortality was similarly high in both groups, however; roughly one-third had died by 12 months, reflecting the higher rates of complications in this older-aged group (median, 66 years).

For patients undergoing PE who have a sudden drop in hemoglobin, gastrointestinal bleeding is only one possible underlying condition. The patient may have bleeding into the pulmonary parenchyma, and computed tomography of the lung should be performed. This is more likely to occur when plasma is exchanged with albumin rather than fresh frozen plasma.

Renal replacement therapy

End-stage renal disease occurs in approximately 25% of patients 3 to 4 years after they present with AASV. Renal-limited disease occurs most often in those with MPA. When there is active rather than sclerotic disease but irreversible renal failure is suspected, immunosuppression can be tried for 3 months. If there is no response, improvement in renal function is unlikely and immunosuppressive treatment is continued only for extrarenal disease. Patients with ESRD can be treated with hemodialysis, peritoneal dialysis at home, or kidney transplant.

Lionaki et al¹³ described the rate of relapse in AASV patients before and after kidney dialysis compared with that in AASV patients with preserved renal function. Over a median of 40 months, 136 of 523 patients progressed to ESRD. Rate of relapse of vasculitis was significantly lower for the patients on chronic dialysis (0.08 episodes per person-year) than for the same patients before dialysis (0.2 episodes) and for the patients with preserved renal function (0.15 episodes). Infections, an important cause of death, were twice as frequent for patients on dialysis and maintenance immunosuppression.

Weidanz et al¹⁴ reported on a retrospective case series that examined whether immunosuppressive therapy with its risk of infection is beneficial for vasculitis patients on dialysis. They retrospectively examined 46 cases of AASV over 30 years and found that the patients with ESRD received less immunosuppression, but their rate of infection was twice that of pre-ESRD patients, and mortality quadrupled while on dialysis. The mode of dialysis did not affect survival, however. These results may support early discontinuation of immunosuppressive treatment in patients with ESRD and suggest that it be used only in those with active disease.

Renal transplant

At the time of transplantation, patients receive a massive immunosupressive induction regimen consisting of anti-CD25 antibody and triple conventional immunosuppressive drugs, usually a calcineurin inhibitor, antimetabolite, and prednisolone. Survival in transplant patients with vasculitis is not significantly different from that of other kidney transplant patients.¹⁵

Patients should not receive transplants until at least 12 months after induction of remission; patients who underwent transplant less than 12 months after remission had a mortality HR of 2.3 (P < .05).¹⁶ Vasculopathy occurs more frequently in ANCA-positive patients, which leads to graft loss.

Graft loss due to recurrent vasculitis is also possible. Nachman et al¹⁷ found double the rate of infection for transplant compared with nontransplant AASV patients, but the rate of relapse was lower than the rate before transplant or for patients on dialysis. There was no significant difference in rates of relapse between patients with or without circulating ANCA at the time of transplant or between those having GPA, MPA, or renal-limited disease.¹⁸

Cardiovascular risk

Renal involvement in vasculitis increases cardiovascular morbidity. Vasculitis patients with renal involvement (n =113) were matched with patients with chronic kidney disease and other contributing cardiovascular risk factors.¹⁸ After approximately 4 years of follow-up, the vasculitis patients had an HR of 2.23 (P = .017) for cardiovascular events. AASV patients with the highest excess risk had histories of cardiovascular events (HR, 4), dialysis dependency (HR, 4.3), poor renal function at admission (HR, 0.977), and history of smoking (HR, 3.9).

CONCLUSION

Level of renal function at diagnosis is an important predictor of survival. Poor renal function correlates with mortality, especially in the elderly. Pathologic classification of renal vasculitis based on histopathology obtained from the kidney biopsy correlates closely with prognosis. About 60% of initially dialysis-dependent patients with active GN can regain independent renal function. Those on dialysis have a lower rate of relapse of active vasculitis than do those with independent renal function; patients with kidney transplants have the lowest rate of relapse. There is a doubling of infection rate in patients who have ESRD and who receive any form of renal replacement therapy. Lastly, renal involvement in AASV is an independent and serious contributor to risk for cardiovascular disease.

The pulmonary manifestations of small-vessel vasculitis are nonspecific and often overlap with other conditions. Consequently, the diagnosis and management of pulmonary vasculitis are complex and require special attention to detail. This article reviews clinical experience with vasculitis as it manifests in the pulmonary setting, with the goal of providing a sound clinical approach to diagnosis and management.

DIAGNOSTIC CONSIDERATIONS

Accurate diagnosis is enhanced with imaging technology, judicious use of bronchoscopy, and awareness of disorders that mimic or masquerade as pulmonary vasculitis. The diagnosis can be approached on the basis of pattern recognition. For example, microscopic polyangiitis (MPA) is characterized solely by alveolar hemorrhage syndrome. However, other diagnostic possibilities must be considered, such as infection, acute respiratory distress syndrome, and complications of medicines. The hallmark manifestation of granulomatosis with polyangiitis (GPA [Wegener’s granulomatosis]) is necrotizing granulomatous inflammations, but the pulmonary manifestations can include nodules, cavitary masses, airway stenosis, and alveolar hemorrhage. Asthma with eosinophilia is the distinguishing feature of eosinophilic GPA (Churg-Strauss syndrome, EGPA), and Goodpasture syndrome involves deposition of complement and immunoglobulins.

The use of imaging

The best imaging tool for suspected pulmonary vasculitides is high-resolution computed tomography (CT). As a general rule, CT for patients with suspected vasculitis should be ordered without contrast medium as contrast is not needed to assess the lung parenchyma. Vasculitis patients often have renal insufficiency, and contrast-free CT will help protect the kidneys. Another option, which will enhance evaluation of the distribution and location of pulmonary disease, is multiplanar reconstructions of images with virtual bronchoscopy or airway reconstruction. Certain findings on imaging will help to differentiate the vasculitides from one another as well as from mimicking diagnoses.

Eosinophilic GPA. Chest images of patients with EGPA appear as patchy, nonsegmental, often peripheral consolidations of ground-glass opacity. These tend to reside in all lobes of the lungs, close to the surface and occasionally accompanied by septal markings.

Microscopic polyangiitis. Although classically a disease of alveolar hemorrhage, MPA often does not manifest with hemoptysis. Approximately one-third of patients with MPA do not cough up blood, even after a large amount of hemorrhage directly into the parenchyma. Patients may present with nonspecific symptoms such as fatigue and shortness of breath. Chest imaging will enhance diagnostic accuracy, particularly when considered in conjunction with laboratory test results. MPA patients usually have low hematocrit levels and may actually have an increased diffusing capacity of the lung for carbon monoxide (Dlco).

Granulomatosis with polyangiitis. This form of vasculitis has characteristic nodules, cavitary lesions, and, in the worst cases, multifocal masses in the lungs. These can be identified with contrast-free CT, with examination for possible airway involvement.

Multiple lung cavity nodules and pronounced airway narrowing are significant diagnostic clues for GPA. Nodules up to 10 cm in diameter tend to be near sub-pleural and peripheral areas. Microbes and fungus may complicate the nodules’ primary presentation. While bronchoscopy may be helpful with imaging, surgical biopsy remains the gold standard to rule out infections.

The disease may be multifocal, occurring outside the lungs from the larynx to bronchi and anywhere in the lung. Subglottic stenosis caused by inflammation and scarring affects 16% of patients with GPA, but it also often develops independently of other features of GPA and may have its own course independent of systemic symptoms.¹

Bronchoscopy

Bronchoscopy is a relatively low-risk way to assess airways and nodules, but it has had a limited role in the diagnosis of nonfocal interstitial lung disease and rheumatologic lung disease in general. New technologies that augment traditional bronchoscopy and enhance its utility for diagnosis for focal entities are described below.

Electromagnetic navigation bronchoscopy (ENB) uses electromagnetic technology to localize and guide a catheter through the bronchial pathways. With the help of a virtual, 3-dimensional bronchial map reconstructed from a chest CT, the clinician can navigate to a desired location within the lung for biopsy and diagnosis of pulmonary nodules. The result is a diagnostic yield per nodule of nearly 80%.² Seijo et al showed that diagnostic yields by ENB increase with the presence of the bronchus sign, or a bronchus leading directly to a peripheral lung lesion, as viewed on CT imaging.² If nodules are bronchocentric, or surround airways, there is greater likelihood of reaching a diagnosis without resorting to surgery.

In peripheral radial ultrasound, a catheter is threaded through another catheter sheath in order to visualize the lesion. This technology can precisely localize lung lesions and often give some clues about the final pathology.

Bronchoscopic confocal fluorescence microscopy³ is a new form of microscopy that uses a fiberoptic miniprobe instead of an objective lens. High-quality images are achieved by the use of autofluorescence. Researchers have used the technology to detect changes in the respiratory bronchioles and other structures, but a clear atlas of many disease states does not yet exist. Oddly, endobronchial GPA images have been catalogued.³

Virtual bronchoscopy is a 3-dimensional image reconstruction and display technique that converts standard CT images into multiplanar images, which can be stacked. Virtual bronchoscopy augments conventional CT because of its ability to enhance detection in the subglottic region and more accurately measure stenosis.⁴ The technique cannot replace traditional bronchoscopy, however, because mucus and secretions can appear as abnormalities and cause false-positive results.

Detecting mimics

Diagnoses that masquerade as EGPA include chronic eosinophilic pneumonia, bronchiolitis obliterans with organizing pneumonia, and other interstitial lung diseases. Allergic bronchopulmonary aspergillosis—an asthma syndrome sometimes associated with eosinophilia and high immunoglobulin-E levels—also mimics EGPA. This diagnostic possibility is particularly relevant if the patient is taking immunosuppressive agents or corticosteroids.

Although alveolar hemorrhage is the sole pulmonary manifestation of MPA, the diagnosis is not limited to MPA alone. Alveolar hemorrhage may have other causes, including infection or acute respiratory distress syndrome. Bronchial lavage is recommended for accurate diagnosis, with the introduction of successive volumes of saline into the lungs and examination for increasing amounts of heme in each of the aliquots of alveolar lavage fluid.

Several diagnoses can mimic GPA. Many infections, including those caused by mycobacteria and Cryptococcus, can mimic endobronchial GPA. Biopsy of all new ulcers is recommended to minimize the possibility of missing these diagnoses. Tuberculosis in its latent form can closely resemble scarred GPA. Other mimickers of cavitary lung lesions can include metastatic melanoma, metastatic renal and thyroid cancers, squamous cell carcinoma, and rheumatoid arthritis with necrobiotic nodules that open in the lungs.

TREATMENT STRATEGIES

Medications

Although many patients with GPA are surgical candidates because of dyspnea related to fixed endobronchial or endotracheal obstructions, any surgical treatment carries the risk of inciting further flares. Treatment should focus first on mitigating the systemic inflammatory disorder with pharmacologic intervention. Standard pharmacologic therapy includes corticosteroids, azathioprine, cyclophosphamide, and rituximab. Patients with subglottic stenosis are frequently unresponsive to standard immunosuppressive therapy (glucocorticoids in combination with a cytotoxic agent).¹

Surgical reconstruction

When medication falls short and surgery is needed to reverse strictures, a number of tools are at our disposal. Some involve heat, such as laser, cauterization, and argon plasma coagulation. In argon plasma coagulation, a jet of ionized argon gas (plasma) is directed through a probe passed through an endoscope. Other techniques rely on cold: cryoprobes, microdebriders, and rigid scissors. In general, freeze therapies cause less scarring than heat therapy. With any surgical technique, there is risk of scars that will contract and cause structural collapse, resulting in restenosis.

Dilation

The high rate of stenosis relapse has spurred interest in alternatives to surgical treatment. One of these, dilation via endoscopy, also may mitigate the wound healing process. Other techniques for clearing the obstructed area include rigid bronchoscopy, the use of bougies (increasingly larger dilators), and balloon dilation. Balloon dilation has some advantages over the other techniques. It permits maximal radial direction and pressure, causes less damage to trachea wall mucosa, and achieves better overall results; however, the procedure usually needs to be repeated.⁵ It must be done quickly, and it requires flawless communication between the otolaryngologist or pulmonologist and anesthesiologist in order to stabilize the airway below the vocal cords.

Intratracheal dilation-injection therapy

Dilation can be augmented with glucocorticoid injections. In 1991, researchers at the National Institutes of Health utilized a combination dilation-injection therapy for 20 patients who had GPA and subglottic stenosis.¹ Patients were first treated with mercury-filled dilators coated with 1% triamcinolone cream. Methylprednisolone acetate was then injected into the stenotic area. None of the patients treated with intratracheal dilation-injection therapy required a tracheostomy and six who already had tracheostomies were decannulated. In contrast, 56% of patients who received standard immunosuppressive therapy and no intratracheal dilation-injection therapy required tracheostomy. Intratracheal dilation-injection therapy is considered a safe and effective treatment of GPA-associated subglottic stenosis and, in the absence of major organ disease activity, could be used without systemic immunosuppressive agents.

Mitomycin-C is a controversial alternative to corticosteroids during dilation. Mitomycin-C is an alkylating agent that inhibits fibroblast proliferation and extracellular matrix protein synthesis, with the potential for reduced scarring. In a recent trial of 26 patients, two doses given 3 to 4 weeks apart reduced the rate of stenosis for 2 to 3 years compared with a single dose.⁶ Restenosis occurred in both groups, however, and after 5 years, the relapse rates were the same.

Nd:YAG laser photoresection versus endobronchial electrosurgery

One of the most effective therapies for treating obstructive lesions is Nd:YAG laser photoresection (LPR) in which a laser that utilizes the crystal neodymium-doped yttrium aluminum garnet (Nd:Y₃Al₅O₁₂) is paired with a flexible bronchoscope. The procedure can produce favorable outcomes,⁷ but it has not gained favor because of perceptions that the lasers require rigid bronchoscopy, expensive equipment, and special training. There are also concerns about complications.

The lower-cost endobronchial electrosurgery (EBES) also failed to gain acceptance because of cumbersome delivery systems and complications associated with power units. Recently, engineers have spawned a new generation of electrosurgical devices, prompting renewed interest in EBES.

A recent study compared LPR and EBES in patients who represented 118 evaluations for LPR.⁸ Forty percent were considered amenable to EBES and so did not go on to receive the more costly LPR. Of those, 89% achieved success in alleviating the obstruction. The authors concluded that EBES can potentially eliminate the need for LPR in 36% of procedures, and that it could achieve significant savings in cost and time. We use these ablative therapies only in dire circumstances; we use non–heat-based therapies, including repeated dilation, prior to considering use of other therapies.

Cryotherapy

Cryotherapy spray was initially thought to have great therapeutic potential, but the high pressures of the spray caused complications. This modality remains under investigation, however. Some probe-based cryotherapy techniques have been effective anecdotally. These use a metal-tipped probe attached to a cryogen; the Joule-Thompson effect causes delayed tissue destruction.

Stents

A small number of case reports note patient improvement after stenting.^9,10 We use stents in rare circumstances, but because complications are frequent and sometimes severe, we consider stenting a last-resort option. In 2005, the US Food and Drug Administration mandated a Black Box warning against the use of metallic stents in patients who have benign tracheal strictures.

Multimodality therapies

In general, when intervention is required to salvage airways, a combination of dilation and steroid injection with or without topical mitomycin-C is standard. We try to avoid use of thermal therapy with laser or electrocautery because of the risk of exuberant inflammation and restenosis from thermal injury. No specific standard of care exists in these cases; reliance on clinical judgment is critical because of the presentation and variety of airway lesions. Further, no large-scale randomized trials exist to guide therapy, so it is best to work with a multidisciplinary team whose members have experience in managing these complex patients.

CONCLUSION

The differential diagnosis of pulmonary manifestations of small-vessel vasculitis is complex. Several diagnoses can mimic various forms of pulmonary vasculitis, and the manifestations and symptoms often overlap with other organ systems.

Imaging is useful for analysis of common patterns of small and midsize vasculitis, although the results may be confounded by disorders that mimic pulmonary vasculitis. To enhance diagnostic accuracy, laboratory and clinical findings should be considered along with images. Ideally, treatment will be minimally destructive and mucosa-sparing. Dilation therapies can be augmented with corticosteroid injections or, possibly, mitomycin-C.

The pulmonary manifestations of small-vessel vasculitis are nonspecific and often overlap with other conditions. Consequently, the diagnosis and management of pulmonary vasculitis are complex and require special attention to detail. This article reviews clinical experience with vasculitis as it manifests in the pulmonary setting, with the goal of providing a sound clinical approach to diagnosis and management.

DIAGNOSTIC CONSIDERATIONS

Accurate diagnosis is enhanced with imaging technology, judicious use of bronchoscopy, and awareness of disorders that mimic or masquerade as pulmonary vasculitis. The diagnosis can be approached on the basis of pattern recognition. For example, microscopic polyangiitis (MPA) is characterized solely by alveolar hemorrhage syndrome. However, other diagnostic possibilities must be considered, such as infection, acute respiratory distress syndrome, and complications of medicines. The hallmark manifestation of granulomatosis with polyangiitis (GPA [Wegener’s granulomatosis]) is necrotizing granulomatous inflammations, but the pulmonary manifestations can include nodules, cavitary masses, airway stenosis, and alveolar hemorrhage. Asthma with eosinophilia is the distinguishing feature of eosinophilic GPA (Churg-Strauss syndrome, EGPA), and Goodpasture syndrome involves deposition of complement and immunoglobulins.

The use of imaging

The best imaging tool for suspected pulmonary vasculitides is high-resolution computed tomography (CT). As a general rule, CT for patients with suspected vasculitis should be ordered without contrast medium as contrast is not needed to assess the lung parenchyma. Vasculitis patients often have renal insufficiency, and contrast-free CT will help protect the kidneys. Another option, which will enhance evaluation of the distribution and location of pulmonary disease, is multiplanar reconstructions of images with virtual bronchoscopy or airway reconstruction. Certain findings on imaging will help to differentiate the vasculitides from one another as well as from mimicking diagnoses.

Eosinophilic GPA. Chest images of patients with EGPA appear as patchy, nonsegmental, often peripheral consolidations of ground-glass opacity. These tend to reside in all lobes of the lungs, close to the surface and occasionally accompanied by septal markings.

Microscopic polyangiitis. Although classically a disease of alveolar hemorrhage, MPA often does not manifest with hemoptysis. Approximately one-third of patients with MPA do not cough up blood, even after a large amount of hemorrhage directly into the parenchyma. Patients may present with nonspecific symptoms such as fatigue and shortness of breath. Chest imaging will enhance diagnostic accuracy, particularly when considered in conjunction with laboratory test results. MPA patients usually have low hematocrit levels and may actually have an increased diffusing capacity of the lung for carbon monoxide (Dlco).

Granulomatosis with polyangiitis. This form of vasculitis has characteristic nodules, cavitary lesions, and, in the worst cases, multifocal masses in the lungs. These can be identified with contrast-free CT, with examination for possible airway involvement.

Multiple lung cavity nodules and pronounced airway narrowing are significant diagnostic clues for GPA. Nodules up to 10 cm in diameter tend to be near sub-pleural and peripheral areas. Microbes and fungus may complicate the nodules’ primary presentation. While bronchoscopy may be helpful with imaging, surgical biopsy remains the gold standard to rule out infections.

The disease may be multifocal, occurring outside the lungs from the larynx to bronchi and anywhere in the lung. Subglottic stenosis caused by inflammation and scarring affects 16% of patients with GPA, but it also often develops independently of other features of GPA and may have its own course independent of systemic symptoms.¹

Bronchoscopy

Bronchoscopy is a relatively low-risk way to assess airways and nodules, but it has had a limited role in the diagnosis of nonfocal interstitial lung disease and rheumatologic lung disease in general. New technologies that augment traditional bronchoscopy and enhance its utility for diagnosis for focal entities are described below.

Electromagnetic navigation bronchoscopy (ENB) uses electromagnetic technology to localize and guide a catheter through the bronchial pathways. With the help of a virtual, 3-dimensional bronchial map reconstructed from a chest CT, the clinician can navigate to a desired location within the lung for biopsy and diagnosis of pulmonary nodules. The result is a diagnostic yield per nodule of nearly 80%.² Seijo et al showed that diagnostic yields by ENB increase with the presence of the bronchus sign, or a bronchus leading directly to a peripheral lung lesion, as viewed on CT imaging.² If nodules are bronchocentric, or surround airways, there is greater likelihood of reaching a diagnosis without resorting to surgery.

In peripheral radial ultrasound, a catheter is threaded through another catheter sheath in order to visualize the lesion. This technology can precisely localize lung lesions and often give some clues about the final pathology.

Bronchoscopic confocal fluorescence microscopy³ is a new form of microscopy that uses a fiberoptic miniprobe instead of an objective lens. High-quality images are achieved by the use of autofluorescence. Researchers have used the technology to detect changes in the respiratory bronchioles and other structures, but a clear atlas of many disease states does not yet exist. Oddly, endobronchial GPA images have been catalogued.³

Virtual bronchoscopy is a 3-dimensional image reconstruction and display technique that converts standard CT images into multiplanar images, which can be stacked. Virtual bronchoscopy augments conventional CT because of its ability to enhance detection in the subglottic region and more accurately measure stenosis.⁴ The technique cannot replace traditional bronchoscopy, however, because mucus and secretions can appear as abnormalities and cause false-positive results.

Detecting mimics

Diagnoses that masquerade as EGPA include chronic eosinophilic pneumonia, bronchiolitis obliterans with organizing pneumonia, and other interstitial lung diseases. Allergic bronchopulmonary aspergillosis—an asthma syndrome sometimes associated with eosinophilia and high immunoglobulin-E levels—also mimics EGPA. This diagnostic possibility is particularly relevant if the patient is taking immunosuppressive agents or corticosteroids.

Although alveolar hemorrhage is the sole pulmonary manifestation of MPA, the diagnosis is not limited to MPA alone. Alveolar hemorrhage may have other causes, including infection or acute respiratory distress syndrome. Bronchial lavage is recommended for accurate diagnosis, with the introduction of successive volumes of saline into the lungs and examination for increasing amounts of heme in each of the aliquots of alveolar lavage fluid.

Several diagnoses can mimic GPA. Many infections, including those caused by mycobacteria and Cryptococcus, can mimic endobronchial GPA. Biopsy of all new ulcers is recommended to minimize the possibility of missing these diagnoses. Tuberculosis in its latent form can closely resemble scarred GPA. Other mimickers of cavitary lung lesions can include metastatic melanoma, metastatic renal and thyroid cancers, squamous cell carcinoma, and rheumatoid arthritis with necrobiotic nodules that open in the lungs.

TREATMENT STRATEGIES

Medications

Although many patients with GPA are surgical candidates because of dyspnea related to fixed endobronchial or endotracheal obstructions, any surgical treatment carries the risk of inciting further flares. Treatment should focus first on mitigating the systemic inflammatory disorder with pharmacologic intervention. Standard pharmacologic therapy includes corticosteroids, azathioprine, cyclophosphamide, and rituximab. Patients with subglottic stenosis are frequently unresponsive to standard immunosuppressive therapy (glucocorticoids in combination with a cytotoxic agent).¹

Surgical reconstruction

When medication falls short and surgery is needed to reverse strictures, a number of tools are at our disposal. Some involve heat, such as laser, cauterization, and argon plasma coagulation. In argon plasma coagulation, a jet of ionized argon gas (plasma) is directed through a probe passed through an endoscope. Other techniques rely on cold: cryoprobes, microdebriders, and rigid scissors. In general, freeze therapies cause less scarring than heat therapy. With any surgical technique, there is risk of scars that will contract and cause structural collapse, resulting in restenosis.

Dilation

The high rate of stenosis relapse has spurred interest in alternatives to surgical treatment. One of these, dilation via endoscopy, also may mitigate the wound healing process. Other techniques for clearing the obstructed area include rigid bronchoscopy, the use of bougies (increasingly larger dilators), and balloon dilation. Balloon dilation has some advantages over the other techniques. It permits maximal radial direction and pressure, causes less damage to trachea wall mucosa, and achieves better overall results; however, the procedure usually needs to be repeated.⁵ It must be done quickly, and it requires flawless communication between the otolaryngologist or pulmonologist and anesthesiologist in order to stabilize the airway below the vocal cords.

Intratracheal dilation-injection therapy

Dilation can be augmented with glucocorticoid injections. In 1991, researchers at the National Institutes of Health utilized a combination dilation-injection therapy for 20 patients who had GPA and subglottic stenosis.¹ Patients were first treated with mercury-filled dilators coated with 1% triamcinolone cream. Methylprednisolone acetate was then injected into the stenotic area. None of the patients treated with intratracheal dilation-injection therapy required a tracheostomy and six who already had tracheostomies were decannulated. In contrast, 56% of patients who received standard immunosuppressive therapy and no intratracheal dilation-injection therapy required tracheostomy. Intratracheal dilation-injection therapy is considered a safe and effective treatment of GPA-associated subglottic stenosis and, in the absence of major organ disease activity, could be used without systemic immunosuppressive agents.

Mitomycin-C is a controversial alternative to corticosteroids during dilation. Mitomycin-C is an alkylating agent that inhibits fibroblast proliferation and extracellular matrix protein synthesis, with the potential for reduced scarring. In a recent trial of 26 patients, two doses given 3 to 4 weeks apart reduced the rate of stenosis for 2 to 3 years compared with a single dose.⁶ Restenosis occurred in both groups, however, and after 5 years, the relapse rates were the same.

Nd:YAG laser photoresection versus endobronchial electrosurgery

One of the most effective therapies for treating obstructive lesions is Nd:YAG laser photoresection (LPR) in which a laser that utilizes the crystal neodymium-doped yttrium aluminum garnet (Nd:Y₃Al₅O₁₂) is paired with a flexible bronchoscope. The procedure can produce favorable outcomes,⁷ but it has not gained favor because of perceptions that the lasers require rigid bronchoscopy, expensive equipment, and special training. There are also concerns about complications.

The lower-cost endobronchial electrosurgery (EBES) also failed to gain acceptance because of cumbersome delivery systems and complications associated with power units. Recently, engineers have spawned a new generation of electrosurgical devices, prompting renewed interest in EBES.

A recent study compared LPR and EBES in patients who represented 118 evaluations for LPR.⁸ Forty percent were considered amenable to EBES and so did not go on to receive the more costly LPR. Of those, 89% achieved success in alleviating the obstruction. The authors concluded that EBES can potentially eliminate the need for LPR in 36% of procedures, and that it could achieve significant savings in cost and time. We use these ablative therapies only in dire circumstances; we use non–heat-based therapies, including repeated dilation, prior to considering use of other therapies.

Cryotherapy

Cryotherapy spray was initially thought to have great therapeutic potential, but the high pressures of the spray caused complications. This modality remains under investigation, however. Some probe-based cryotherapy techniques have been effective anecdotally. These use a metal-tipped probe attached to a cryogen; the Joule-Thompson effect causes delayed tissue destruction.

Stents

A small number of case reports note patient improvement after stenting.^9,10 We use stents in rare circumstances, but because complications are frequent and sometimes severe, we consider stenting a last-resort option. In 2005, the US Food and Drug Administration mandated a Black Box warning against the use of metallic stents in patients who have benign tracheal strictures.

Multimodality therapies

In general, when intervention is required to salvage airways, a combination of dilation and steroid injection with or without topical mitomycin-C is standard. We try to avoid use of thermal therapy with laser or electrocautery because of the risk of exuberant inflammation and restenosis from thermal injury. No specific standard of care exists in these cases; reliance on clinical judgment is critical because of the presentation and variety of airway lesions. Further, no large-scale randomized trials exist to guide therapy, so it is best to work with a multidisciplinary team whose members have experience in managing these complex patients.

CONCLUSION

The differential diagnosis of pulmonary manifestations of small-vessel vasculitis is complex. Several diagnoses can mimic various forms of pulmonary vasculitis, and the manifestations and symptoms often overlap with other organ systems.

Imaging is useful for analysis of common patterns of small and midsize vasculitis, although the results may be confounded by disorders that mimic pulmonary vasculitis. To enhance diagnostic accuracy, laboratory and clinical findings should be considered along with images. Ideally, treatment will be minimally destructive and mucosa-sparing. Dilation therapies can be augmented with corticosteroid injections or, possibly, mitomycin-C.

The pulmonary manifestations of small-vessel vasculitis are nonspecific and often overlap with other conditions. Consequently, the diagnosis and management of pulmonary vasculitis are complex and require special attention to detail. This article reviews clinical experience with vasculitis as it manifests in the pulmonary setting, with the goal of providing a sound clinical approach to diagnosis and management.

DIAGNOSTIC CONSIDERATIONS

Accurate diagnosis is enhanced with imaging technology, judicious use of bronchoscopy, and awareness of disorders that mimic or masquerade as pulmonary vasculitis. The diagnosis can be approached on the basis of pattern recognition. For example, microscopic polyangiitis (MPA) is characterized solely by alveolar hemorrhage syndrome. However, other diagnostic possibilities must be considered, such as infection, acute respiratory distress syndrome, and complications of medicines. The hallmark manifestation of granulomatosis with polyangiitis (GPA [Wegener’s granulomatosis]) is necrotizing granulomatous inflammations, but the pulmonary manifestations can include nodules, cavitary masses, airway stenosis, and alveolar hemorrhage. Asthma with eosinophilia is the distinguishing feature of eosinophilic GPA (Churg-Strauss syndrome, EGPA), and Goodpasture syndrome involves deposition of complement and immunoglobulins.

The use of imaging

The best imaging tool for suspected pulmonary vasculitides is high-resolution computed tomography (CT). As a general rule, CT for patients with suspected vasculitis should be ordered without contrast medium as contrast is not needed to assess the lung parenchyma. Vasculitis patients often have renal insufficiency, and contrast-free CT will help protect the kidneys. Another option, which will enhance evaluation of the distribution and location of pulmonary disease, is multiplanar reconstructions of images with virtual bronchoscopy or airway reconstruction. Certain findings on imaging will help to differentiate the vasculitides from one another as well as from mimicking diagnoses.

Eosinophilic GPA. Chest images of patients with EGPA appear as patchy, nonsegmental, often peripheral consolidations of ground-glass opacity. These tend to reside in all lobes of the lungs, close to the surface and occasionally accompanied by septal markings.

Microscopic polyangiitis. Although classically a disease of alveolar hemorrhage, MPA often does not manifest with hemoptysis. Approximately one-third of patients with MPA do not cough up blood, even after a large amount of hemorrhage directly into the parenchyma. Patients may present with nonspecific symptoms such as fatigue and shortness of breath. Chest imaging will enhance diagnostic accuracy, particularly when considered in conjunction with laboratory test results. MPA patients usually have low hematocrit levels and may actually have an increased diffusing capacity of the lung for carbon monoxide (Dlco).

Granulomatosis with polyangiitis. This form of vasculitis has characteristic nodules, cavitary lesions, and, in the worst cases, multifocal masses in the lungs. These can be identified with contrast-free CT, with examination for possible airway involvement.

Multiple lung cavity nodules and pronounced airway narrowing are significant diagnostic clues for GPA. Nodules up to 10 cm in diameter tend to be near sub-pleural and peripheral areas. Microbes and fungus may complicate the nodules’ primary presentation. While bronchoscopy may be helpful with imaging, surgical biopsy remains the gold standard to rule out infections.

The disease may be multifocal, occurring outside the lungs from the larynx to bronchi and anywhere in the lung. Subglottic stenosis caused by inflammation and scarring affects 16% of patients with GPA, but it also often develops independently of other features of GPA and may have its own course independent of systemic symptoms.¹

Bronchoscopy

Bronchoscopy is a relatively low-risk way to assess airways and nodules, but it has had a limited role in the diagnosis of nonfocal interstitial lung disease and rheumatologic lung disease in general. New technologies that augment traditional bronchoscopy and enhance its utility for diagnosis for focal entities are described below.

Electromagnetic navigation bronchoscopy (ENB) uses electromagnetic technology to localize and guide a catheter through the bronchial pathways. With the help of a virtual, 3-dimensional bronchial map reconstructed from a chest CT, the clinician can navigate to a desired location within the lung for biopsy and diagnosis of pulmonary nodules. The result is a diagnostic yield per nodule of nearly 80%.² Seijo et al showed that diagnostic yields by ENB increase with the presence of the bronchus sign, or a bronchus leading directly to a peripheral lung lesion, as viewed on CT imaging.² If nodules are bronchocentric, or surround airways, there is greater likelihood of reaching a diagnosis without resorting to surgery.

In peripheral radial ultrasound, a catheter is threaded through another catheter sheath in order to visualize the lesion. This technology can precisely localize lung lesions and often give some clues about the final pathology.

Bronchoscopic confocal fluorescence microscopy³ is a new form of microscopy that uses a fiberoptic miniprobe instead of an objective lens. High-quality images are achieved by the use of autofluorescence. Researchers have used the technology to detect changes in the respiratory bronchioles and other structures, but a clear atlas of many disease states does not yet exist. Oddly, endobronchial GPA images have been catalogued.³

Virtual bronchoscopy is a 3-dimensional image reconstruction and display technique that converts standard CT images into multiplanar images, which can be stacked. Virtual bronchoscopy augments conventional CT because of its ability to enhance detection in the subglottic region and more accurately measure stenosis.⁴ The technique cannot replace traditional bronchoscopy, however, because mucus and secretions can appear as abnormalities and cause false-positive results.

Detecting mimics

Diagnoses that masquerade as EGPA include chronic eosinophilic pneumonia, bronchiolitis obliterans with organizing pneumonia, and other interstitial lung diseases. Allergic bronchopulmonary aspergillosis—an asthma syndrome sometimes associated with eosinophilia and high immunoglobulin-E levels—also mimics EGPA. This diagnostic possibility is particularly relevant if the patient is taking immunosuppressive agents or corticosteroids.

Although alveolar hemorrhage is the sole pulmonary manifestation of MPA, the diagnosis is not limited to MPA alone. Alveolar hemorrhage may have other causes, including infection or acute respiratory distress syndrome. Bronchial lavage is recommended for accurate diagnosis, with the introduction of successive volumes of saline into the lungs and examination for increasing amounts of heme in each of the aliquots of alveolar lavage fluid.

Several diagnoses can mimic GPA. Many infections, including those caused by mycobacteria and Cryptococcus, can mimic endobronchial GPA. Biopsy of all new ulcers is recommended to minimize the possibility of missing these diagnoses. Tuberculosis in its latent form can closely resemble scarred GPA. Other mimickers of cavitary lung lesions can include metastatic melanoma, metastatic renal and thyroid cancers, squamous cell carcinoma, and rheumatoid arthritis with necrobiotic nodules that open in the lungs.

TREATMENT STRATEGIES

Medications

Although many patients with GPA are surgical candidates because of dyspnea related to fixed endobronchial or endotracheal obstructions, any surgical treatment carries the risk of inciting further flares. Treatment should focus first on mitigating the systemic inflammatory disorder with pharmacologic intervention. Standard pharmacologic therapy includes corticosteroids, azathioprine, cyclophosphamide, and rituximab. Patients with subglottic stenosis are frequently unresponsive to standard immunosuppressive therapy (glucocorticoids in combination with a cytotoxic agent).¹

Surgical reconstruction

When medication falls short and surgery is needed to reverse strictures, a number of tools are at our disposal. Some involve heat, such as laser, cauterization, and argon plasma coagulation. In argon plasma coagulation, a jet of ionized argon gas (plasma) is directed through a probe passed through an endoscope. Other techniques rely on cold: cryoprobes, microdebriders, and rigid scissors. In general, freeze therapies cause less scarring than heat therapy. With any surgical technique, there is risk of scars that will contract and cause structural collapse, resulting in restenosis.

Dilation

The high rate of stenosis relapse has spurred interest in alternatives to surgical treatment. One of these, dilation via endoscopy, also may mitigate the wound healing process. Other techniques for clearing the obstructed area include rigid bronchoscopy, the use of bougies (increasingly larger dilators), and balloon dilation. Balloon dilation has some advantages over the other techniques. It permits maximal radial direction and pressure, causes less damage to trachea wall mucosa, and achieves better overall results; however, the procedure usually needs to be repeated.⁵ It must be done quickly, and it requires flawless communication between the otolaryngologist or pulmonologist and anesthesiologist in order to stabilize the airway below the vocal cords.

Intratracheal dilation-injection therapy

Dilation can be augmented with glucocorticoid injections. In 1991, researchers at the National Institutes of Health utilized a combination dilation-injection therapy for 20 patients who had GPA and subglottic stenosis.¹ Patients were first treated with mercury-filled dilators coated with 1% triamcinolone cream. Methylprednisolone acetate was then injected into the stenotic area. None of the patients treated with intratracheal dilation-injection therapy required a tracheostomy and six who already had tracheostomies were decannulated. In contrast, 56% of patients who received standard immunosuppressive therapy and no intratracheal dilation-injection therapy required tracheostomy. Intratracheal dilation-injection therapy is considered a safe and effective treatment of GPA-associated subglottic stenosis and, in the absence of major organ disease activity, could be used without systemic immunosuppressive agents.

Mitomycin-C is a controversial alternative to corticosteroids during dilation. Mitomycin-C is an alkylating agent that inhibits fibroblast proliferation and extracellular matrix protein synthesis, with the potential for reduced scarring. In a recent trial of 26 patients, two doses given 3 to 4 weeks apart reduced the rate of stenosis for 2 to 3 years compared with a single dose.⁶ Restenosis occurred in both groups, however, and after 5 years, the relapse rates were the same.

Nd:YAG laser photoresection versus endobronchial electrosurgery

One of the most effective therapies for treating obstructive lesions is Nd:YAG laser photoresection (LPR) in which a laser that utilizes the crystal neodymium-doped yttrium aluminum garnet (Nd:Y₃Al₅O₁₂) is paired with a flexible bronchoscope. The procedure can produce favorable outcomes,⁷ but it has not gained favor because of perceptions that the lasers require rigid bronchoscopy, expensive equipment, and special training. There are also concerns about complications.

The lower-cost endobronchial electrosurgery (EBES) also failed to gain acceptance because of cumbersome delivery systems and complications associated with power units. Recently, engineers have spawned a new generation of electrosurgical devices, prompting renewed interest in EBES.

A recent study compared LPR and EBES in patients who represented 118 evaluations for LPR.⁸ Forty percent were considered amenable to EBES and so did not go on to receive the more costly LPR. Of those, 89% achieved success in alleviating the obstruction. The authors concluded that EBES can potentially eliminate the need for LPR in 36% of procedures, and that it could achieve significant savings in cost and time. We use these ablative therapies only in dire circumstances; we use non–heat-based therapies, including repeated dilation, prior to considering use of other therapies.

Cryotherapy

Cryotherapy spray was initially thought to have great therapeutic potential, but the high pressures of the spray caused complications. This modality remains under investigation, however. Some probe-based cryotherapy techniques have been effective anecdotally. These use a metal-tipped probe attached to a cryogen; the Joule-Thompson effect causes delayed tissue destruction.

Stents

A small number of case reports note patient improvement after stenting.^9,10 We use stents in rare circumstances, but because complications are frequent and sometimes severe, we consider stenting a last-resort option. In 2005, the US Food and Drug Administration mandated a Black Box warning against the use of metallic stents in patients who have benign tracheal strictures.

Multimodality therapies

In general, when intervention is required to salvage airways, a combination of dilation and steroid injection with or without topical mitomycin-C is standard. We try to avoid use of thermal therapy with laser or electrocautery because of the risk of exuberant inflammation and restenosis from thermal injury. No specific standard of care exists in these cases; reliance on clinical judgment is critical because of the presentation and variety of airway lesions. Further, no large-scale randomized trials exist to guide therapy, so it is best to work with a multidisciplinary team whose members have experience in managing these complex patients.

CONCLUSION

The differential diagnosis of pulmonary manifestations of small-vessel vasculitis is complex. Several diagnoses can mimic various forms of pulmonary vasculitis, and the manifestations and symptoms often overlap with other organ systems.

Imaging is useful for analysis of common patterns of small and midsize vasculitis, although the results may be confounded by disorders that mimic pulmonary vasculitis. To enhance diagnostic accuracy, laboratory and clinical findings should be considered along with images. Ideally, treatment will be minimally destructive and mucosa-sparing. Dilation therapies can be augmented with corticosteroid injections or, possibly, mitomycin-C.

We have long understood that vasculitic conditions have various clinical manifestations. The Chapel Hill Consensus Conference classification of systemic vasculitis in 1994¹ contributed significantly to our understanding of the spectrum of vasculitides and their manifestations, enhancing our diagnostic ability and the likelihood of appropriate treatment.

The ophthalmic manifestations of vasculitis are protean and nonspecific, and should be considered in the overall context of the disease. Patients should be evaluated with the following questions in mind:

• Are the manifestations related to the vasculitis itself?
• Are the manifestations a result or complication of therapy?
• Are the manifestations signs of a completely unrelated and superimposed condition?

This article reviews the three areas of ocular inflammation related to vasculitis and comments on the role of tissue biopsy in the management of these patients.

THREE AREAS OF OCULAR INFLAMMATION

Orbital inflammation

Orbital disease can affect the lacrimal gland (inflammatory dacryoadenitis), extraocular muscles (orbital myositis), and the orbital soft tissues (inflammatory orbital pseudotumor). Orbital inflammation is characterized by relatively sudden onset (within days) of pain, erythema, and proptosis. Diplopia and visual loss from either compression or inflammation of the optic nerve or nerve sheath may be present. Depending upon the structures involved and the degree of involvement, orbital inflammation can be sight-threatening.

Either computed tomography or magnetic resonance imaging should be performed to assess orbital or extraorbital involvement. The orbital structures are particularly amenable to biopsy, which, in this author’s opinion, should be performed whenever possible. The biopsy may need to be interpreted within the context of previous or concurrent immunosuppressive therapy, which can alter the histologic picture, minimize inflammation, and make detection of vasculitis difficult. In addition to identifying inflammation, biopsy helps to identify fungal infection or lymphoma that can follow prolonged immunosuppressive therapy.

Treatment of orbital inflammation requires corticosteroid therapy or some other type of systemic immunosuppression.

Ocular, or globe, inflammation

Episcleritis: observation or topical therapy. Episcleritis usually manifests as an otherwise asymptomatic red eye with typical sector-shaped inflammation. Pain is generally not an issue, although patients often report that the eye does not feel normal. Vision is unaffected and there is no potential threat to sight.

The slit-lamp examination shows dilated vessels in the episcleral tissues that blanch after instillation of a drop of 10% phenylephrine. Simple observation may be the best management course, but topical nonsteroidal anti-inflammatory drugs (NSAIDs) or topical corticosteroids may help some patients who have discomfort. There is probably a spectrum of disease in that some patients may have either severe episcleritis or mild scleritis (Figure 1B). At times it can be difficult to differentiate between severe episcleritis and mild scleritis. Although scleritis generally requires systemic therapy, topical therapy is justified for mild scleritis. Episcleritis is associated with systemic disease in approximately 36% of patients.^2–4

Scleritis: may be sight-threatening; requires systemic therapy. Scleritis characteristically presents with intense pain and a red eye.^3,5–7 Patients may be sensitive to light and their vision may be compromised. Cataracts and glaucoma can complicate the course of scleritis.

With slit-lamp examination, the redness does not blanch upon instillation of topical 10% phenylephrine as it does with episcleritis. The adjacent cornea may also be affected (Figure 1C). Healed scleritis leaves an area of thinned sclera that appears as a visible blue spot, so if the patient’s history includes red eye with pain and a blue area is visible, the clinician can be confident that a prior episode of scleritis occurred.

Scleritis can be anterior or posterior, and the implications are slightly different for each type. Anterior scleritis can be subclassified as diffuse, nodular, or necrotizing. The necrotizing type can be characterized by painful inflammation or, in the case of scleromalacia perforans, no inflammation and no pain. Posterior scleritis may have minimal pain.

Akpek et al⁵ reported on a group of 243 patients with scleritis (average age, 52 years; range, 5 to 93 years) who were followed for an average of 1.7 years (range, 0 to 16.6 years). An associated medical condition was present in 107 (44%) patients. Rheumatologic conditions accounted for 37%, with rheumatoid arthritis being most common; infectious disease, with herpes zoster ophthalmicus being most common, accounted for 7%. Of those with an associated medical condition, 78% had been diagnosed previously; the remaining 22% were diagnosed at presentation or the condition developed during follow-up.

Treatment typically requires systemic therapy with NSAIDs, but more often oral or intravenous corticosteroids or even methotrexate, mycophenolate mofetil, cyclophosphamide, or rituximab may be required. Patients with antineutrophil cytoplasmic antibody (ANCA)–positive disease may require more intensive therapy than those with ANCA-negative disease.

Keratitis: may be sight-threatening. Patients with keratitis should be evaluated in the same spirit as patients with scleritis (Figure 1C). Although many patients may have superficial keratitis, which is often related to a dry eye and has no prognostic significance, deep or peripheral ulcerative keratitis is not only consistent with systemic vasculitis but also sight-threatening. Symptoms similar to those observed with scleritis typically include severe pain and photophobia and, as with scleritis, treatment usually involves systemic therapy.

There is no specific treatment for the eye other than treating the underlying condition. Vascular occlusions can sometimes give rise to neovascularization and patients should be followed for this possibility. As with a central nervous system ischemic event, recovery can be variable.

Uveitis. The term “uvea,” derived from the Greek word for grape, describes the shape of the iris, ciliary body, and choroid. Uveitis is a generic term for intraocular inflammation affecting any or all of these structures.

Iritis, or anterior uveitis, is a frequent accompaniment of keratitis or scleritis. Primarily uveitic involvement with retinal vessel vasculitis involving both arteries and veins is uncommon in general but typical of Behçet disease, especially if a hypopyon uveitis is present.

Anterior uveitis can be treated with topical corticosteroids and cycloplegic drugs, but middle and posterior uveitis almost always requires systemic therapy. Most recently, use of anti–tumor necrosis factor-α drugs has been effective in treating Behçet uveitis.⁸ The visual prognosis with Behçet disease remains guarded.

GRANULOMATOSIS WITH POLYANGIITIS: EYE INVOLVEMENT IS COMMON

In terms of specific small-vessel vasculitic diseases that affect the eye, granulomatosis with polyangiitis (GPA [Wegener’s granulomatosis]) is the quintessential condition. In data obtained from the Wegener Granulomatosis Support Group,⁹ eye involvement was noted at presentation in 211 of 701 patients (30%), and during the course of their disease an additional 147 patients developed eye involvement. From the time of initial presentation through the course of follow-up, 359 of the 701 patients (51%) eventually had some type of eye involvement.

In a series of patients seen at the Mayo Clinic,¹⁰ orbital inflammatory disease and scleritis were the two most frequent manifestations of eye involvement with GPA. Orbital involvement typically presents with pain, erythema, swelling, and proptosis. Varying degrees of ptosis, diplopia, or visual loss may also be present. Imaging may show an infiltrate that is usually adjacent to the maxillary or ethmoid sinus. This same process can affect the superior temporal orbital quadrant, an area apart from any sinus, and involve the lacrimal gland.

BIOPSY IS ADVISED

Biopsy, either incisional, at times to include debulking, or excisional if possible, is recommended to establish a diagnosis or aid in the selection of therapy. Orbital disease has been observed to progress in patients who are receiving maintenance therapy with methotrexate and have no evidence of systemic disease activity. Acute and chronic inflammation with evidence of active vasculitis is usually seen histologically. Personal observations suggest that intraorbital corticosteroid injection followed by rituximab has been effective therapy for this limited subset of patients. Diagnostic biopsies often must be interpreted in light of partial treatment, making histopathologic diagnosis challenging at times. Biopsy is important for exclusion of lymphoproliferative disease or fungal infection.

CONCLUSION

Underlying vasculitis might play a role in patients with nonspecific ocular presentations. It is essential that the ophthalmologist collaborate with a specialist in vasculitis (and vice versa) for evaluation and subsequent therapy, which often involves some form of immunosuppression.

We have long understood that vasculitic conditions have various clinical manifestations. The Chapel Hill Consensus Conference classification of systemic vasculitis in 1994¹ contributed significantly to our understanding of the spectrum of vasculitides and their manifestations, enhancing our diagnostic ability and the likelihood of appropriate treatment.

The ophthalmic manifestations of vasculitis are protean and nonspecific, and should be considered in the overall context of the disease. Patients should be evaluated with the following questions in mind:

• Are the manifestations related to the vasculitis itself?
• Are the manifestations a result or complication of therapy?
• Are the manifestations signs of a completely unrelated and superimposed condition?

This article reviews the three areas of ocular inflammation related to vasculitis and comments on the role of tissue biopsy in the management of these patients.

THREE AREAS OF OCULAR INFLAMMATION

Orbital inflammation

Orbital disease can affect the lacrimal gland (inflammatory dacryoadenitis), extraocular muscles (orbital myositis), and the orbital soft tissues (inflammatory orbital pseudotumor). Orbital inflammation is characterized by relatively sudden onset (within days) of pain, erythema, and proptosis. Diplopia and visual loss from either compression or inflammation of the optic nerve or nerve sheath may be present. Depending upon the structures involved and the degree of involvement, orbital inflammation can be sight-threatening.

Either computed tomography or magnetic resonance imaging should be performed to assess orbital or extraorbital involvement. The orbital structures are particularly amenable to biopsy, which, in this author’s opinion, should be performed whenever possible. The biopsy may need to be interpreted within the context of previous or concurrent immunosuppressive therapy, which can alter the histologic picture, minimize inflammation, and make detection of vasculitis difficult. In addition to identifying inflammation, biopsy helps to identify fungal infection or lymphoma that can follow prolonged immunosuppressive therapy.

Treatment of orbital inflammation requires corticosteroid therapy or some other type of systemic immunosuppression.

Ocular, or globe, inflammation

Episcleritis: observation or topical therapy. Episcleritis usually manifests as an otherwise asymptomatic red eye with typical sector-shaped inflammation. Pain is generally not an issue, although patients often report that the eye does not feel normal. Vision is unaffected and there is no potential threat to sight.

The slit-lamp examination shows dilated vessels in the episcleral tissues that blanch after instillation of a drop of 10% phenylephrine. Simple observation may be the best management course, but topical nonsteroidal anti-inflammatory drugs (NSAIDs) or topical corticosteroids may help some patients who have discomfort. There is probably a spectrum of disease in that some patients may have either severe episcleritis or mild scleritis (Figure 1B). At times it can be difficult to differentiate between severe episcleritis and mild scleritis. Although scleritis generally requires systemic therapy, topical therapy is justified for mild scleritis. Episcleritis is associated with systemic disease in approximately 36% of patients.^2–4

Scleritis: may be sight-threatening; requires systemic therapy. Scleritis characteristically presents with intense pain and a red eye.^3,5–7 Patients may be sensitive to light and their vision may be compromised. Cataracts and glaucoma can complicate the course of scleritis.

With slit-lamp examination, the redness does not blanch upon instillation of topical 10% phenylephrine as it does with episcleritis. The adjacent cornea may also be affected (Figure 1C). Healed scleritis leaves an area of thinned sclera that appears as a visible blue spot, so if the patient’s history includes red eye with pain and a blue area is visible, the clinician can be confident that a prior episode of scleritis occurred.

Scleritis can be anterior or posterior, and the implications are slightly different for each type. Anterior scleritis can be subclassified as diffuse, nodular, or necrotizing. The necrotizing type can be characterized by painful inflammation or, in the case of scleromalacia perforans, no inflammation and no pain. Posterior scleritis may have minimal pain.

Akpek et al⁵ reported on a group of 243 patients with scleritis (average age, 52 years; range, 5 to 93 years) who were followed for an average of 1.7 years (range, 0 to 16.6 years). An associated medical condition was present in 107 (44%) patients. Rheumatologic conditions accounted for 37%, with rheumatoid arthritis being most common; infectious disease, with herpes zoster ophthalmicus being most common, accounted for 7%. Of those with an associated medical condition, 78% had been diagnosed previously; the remaining 22% were diagnosed at presentation or the condition developed during follow-up.

Treatment typically requires systemic therapy with NSAIDs, but more often oral or intravenous corticosteroids or even methotrexate, mycophenolate mofetil, cyclophosphamide, or rituximab may be required. Patients with antineutrophil cytoplasmic antibody (ANCA)–positive disease may require more intensive therapy than those with ANCA-negative disease.

Keratitis: may be sight-threatening. Patients with keratitis should be evaluated in the same spirit as patients with scleritis (Figure 1C). Although many patients may have superficial keratitis, which is often related to a dry eye and has no prognostic significance, deep or peripheral ulcerative keratitis is not only consistent with systemic vasculitis but also sight-threatening. Symptoms similar to those observed with scleritis typically include severe pain and photophobia and, as with scleritis, treatment usually involves systemic therapy.

There is no specific treatment for the eye other than treating the underlying condition. Vascular occlusions can sometimes give rise to neovascularization and patients should be followed for this possibility. As with a central nervous system ischemic event, recovery can be variable.

Uveitis. The term “uvea,” derived from the Greek word for grape, describes the shape of the iris, ciliary body, and choroid. Uveitis is a generic term for intraocular inflammation affecting any or all of these structures.

Iritis, or anterior uveitis, is a frequent accompaniment of keratitis or scleritis. Primarily uveitic involvement with retinal vessel vasculitis involving both arteries and veins is uncommon in general but typical of Behçet disease, especially if a hypopyon uveitis is present.

Anterior uveitis can be treated with topical corticosteroids and cycloplegic drugs, but middle and posterior uveitis almost always requires systemic therapy. Most recently, use of anti–tumor necrosis factor-α drugs has been effective in treating Behçet uveitis.⁸ The visual prognosis with Behçet disease remains guarded.

GRANULOMATOSIS WITH POLYANGIITIS: EYE INVOLVEMENT IS COMMON

In terms of specific small-vessel vasculitic diseases that affect the eye, granulomatosis with polyangiitis (GPA [Wegener’s granulomatosis]) is the quintessential condition. In data obtained from the Wegener Granulomatosis Support Group,⁹ eye involvement was noted at presentation in 211 of 701 patients (30%), and during the course of their disease an additional 147 patients developed eye involvement. From the time of initial presentation through the course of follow-up, 359 of the 701 patients (51%) eventually had some type of eye involvement.

In a series of patients seen at the Mayo Clinic,¹⁰ orbital inflammatory disease and scleritis were the two most frequent manifestations of eye involvement with GPA. Orbital involvement typically presents with pain, erythema, swelling, and proptosis. Varying degrees of ptosis, diplopia, or visual loss may also be present. Imaging may show an infiltrate that is usually adjacent to the maxillary or ethmoid sinus. This same process can affect the superior temporal orbital quadrant, an area apart from any sinus, and involve the lacrimal gland.

BIOPSY IS ADVISED

Biopsy, either incisional, at times to include debulking, or excisional if possible, is recommended to establish a diagnosis or aid in the selection of therapy. Orbital disease has been observed to progress in patients who are receiving maintenance therapy with methotrexate and have no evidence of systemic disease activity. Acute and chronic inflammation with evidence of active vasculitis is usually seen histologically. Personal observations suggest that intraorbital corticosteroid injection followed by rituximab has been effective therapy for this limited subset of patients. Diagnostic biopsies often must be interpreted in light of partial treatment, making histopathologic diagnosis challenging at times. Biopsy is important for exclusion of lymphoproliferative disease or fungal infection.

CONCLUSION

Underlying vasculitis might play a role in patients with nonspecific ocular presentations. It is essential that the ophthalmologist collaborate with a specialist in vasculitis (and vice versa) for evaluation and subsequent therapy, which often involves some form of immunosuppression.

We have long understood that vasculitic conditions have various clinical manifestations. The Chapel Hill Consensus Conference classification of systemic vasculitis in 1994¹ contributed significantly to our understanding of the spectrum of vasculitides and their manifestations, enhancing our diagnostic ability and the likelihood of appropriate treatment.

The ophthalmic manifestations of vasculitis are protean and nonspecific, and should be considered in the overall context of the disease. Patients should be evaluated with the following questions in mind:

• Are the manifestations related to the vasculitis itself?
• Are the manifestations a result or complication of therapy?
• Are the manifestations signs of a completely unrelated and superimposed condition?

This article reviews the three areas of ocular inflammation related to vasculitis and comments on the role of tissue biopsy in the management of these patients.

THREE AREAS OF OCULAR INFLAMMATION

Orbital inflammation

Orbital disease can affect the lacrimal gland (inflammatory dacryoadenitis), extraocular muscles (orbital myositis), and the orbital soft tissues (inflammatory orbital pseudotumor). Orbital inflammation is characterized by relatively sudden onset (within days) of pain, erythema, and proptosis. Diplopia and visual loss from either compression or inflammation of the optic nerve or nerve sheath may be present. Depending upon the structures involved and the degree of involvement, orbital inflammation can be sight-threatening.

Either computed tomography or magnetic resonance imaging should be performed to assess orbital or extraorbital involvement. The orbital structures are particularly amenable to biopsy, which, in this author’s opinion, should be performed whenever possible. The biopsy may need to be interpreted within the context of previous or concurrent immunosuppressive therapy, which can alter the histologic picture, minimize inflammation, and make detection of vasculitis difficult. In addition to identifying inflammation, biopsy helps to identify fungal infection or lymphoma that can follow prolonged immunosuppressive therapy.

Treatment of orbital inflammation requires corticosteroid therapy or some other type of systemic immunosuppression.

Ocular, or globe, inflammation

Episcleritis: observation or topical therapy. Episcleritis usually manifests as an otherwise asymptomatic red eye with typical sector-shaped inflammation. Pain is generally not an issue, although patients often report that the eye does not feel normal. Vision is unaffected and there is no potential threat to sight.

The slit-lamp examination shows dilated vessels in the episcleral tissues that blanch after instillation of a drop of 10% phenylephrine. Simple observation may be the best management course, but topical nonsteroidal anti-inflammatory drugs (NSAIDs) or topical corticosteroids may help some patients who have discomfort. There is probably a spectrum of disease in that some patients may have either severe episcleritis or mild scleritis (Figure 1B). At times it can be difficult to differentiate between severe episcleritis and mild scleritis. Although scleritis generally requires systemic therapy, topical therapy is justified for mild scleritis. Episcleritis is associated with systemic disease in approximately 36% of patients.^2–4

Scleritis: may be sight-threatening; requires systemic therapy. Scleritis characteristically presents with intense pain and a red eye.^3,5–7 Patients may be sensitive to light and their vision may be compromised. Cataracts and glaucoma can complicate the course of scleritis.

With slit-lamp examination, the redness does not blanch upon instillation of topical 10% phenylephrine as it does with episcleritis. The adjacent cornea may also be affected (Figure 1C). Healed scleritis leaves an area of thinned sclera that appears as a visible blue spot, so if the patient’s history includes red eye with pain and a blue area is visible, the clinician can be confident that a prior episode of scleritis occurred.

Scleritis can be anterior or posterior, and the implications are slightly different for each type. Anterior scleritis can be subclassified as diffuse, nodular, or necrotizing. The necrotizing type can be characterized by painful inflammation or, in the case of scleromalacia perforans, no inflammation and no pain. Posterior scleritis may have minimal pain.

Akpek et al⁵ reported on a group of 243 patients with scleritis (average age, 52 years; range, 5 to 93 years) who were followed for an average of 1.7 years (range, 0 to 16.6 years). An associated medical condition was present in 107 (44%) patients. Rheumatologic conditions accounted for 37%, with rheumatoid arthritis being most common; infectious disease, with herpes zoster ophthalmicus being most common, accounted for 7%. Of those with an associated medical condition, 78% had been diagnosed previously; the remaining 22% were diagnosed at presentation or the condition developed during follow-up.

Treatment typically requires systemic therapy with NSAIDs, but more often oral or intravenous corticosteroids or even methotrexate, mycophenolate mofetil, cyclophosphamide, or rituximab may be required. Patients with antineutrophil cytoplasmic antibody (ANCA)–positive disease may require more intensive therapy than those with ANCA-negative disease.

Keratitis: may be sight-threatening. Patients with keratitis should be evaluated in the same spirit as patients with scleritis (Figure 1C). Although many patients may have superficial keratitis, which is often related to a dry eye and has no prognostic significance, deep or peripheral ulcerative keratitis is not only consistent with systemic vasculitis but also sight-threatening. Symptoms similar to those observed with scleritis typically include severe pain and photophobia and, as with scleritis, treatment usually involves systemic therapy.

There is no specific treatment for the eye other than treating the underlying condition. Vascular occlusions can sometimes give rise to neovascularization and patients should be followed for this possibility. As with a central nervous system ischemic event, recovery can be variable.

Uveitis. The term “uvea,” derived from the Greek word for grape, describes the shape of the iris, ciliary body, and choroid. Uveitis is a generic term for intraocular inflammation affecting any or all of these structures.

Iritis, or anterior uveitis, is a frequent accompaniment of keratitis or scleritis. Primarily uveitic involvement with retinal vessel vasculitis involving both arteries and veins is uncommon in general but typical of Behçet disease, especially if a hypopyon uveitis is present.

Anterior uveitis can be treated with topical corticosteroids and cycloplegic drugs, but middle and posterior uveitis almost always requires systemic therapy. Most recently, use of anti–tumor necrosis factor-α drugs has been effective in treating Behçet uveitis.⁸ The visual prognosis with Behçet disease remains guarded.

GRANULOMATOSIS WITH POLYANGIITIS: EYE INVOLVEMENT IS COMMON

In terms of specific small-vessel vasculitic diseases that affect the eye, granulomatosis with polyangiitis (GPA [Wegener’s granulomatosis]) is the quintessential condition. In data obtained from the Wegener Granulomatosis Support Group,⁹ eye involvement was noted at presentation in 211 of 701 patients (30%), and during the course of their disease an additional 147 patients developed eye involvement. From the time of initial presentation through the course of follow-up, 359 of the 701 patients (51%) eventually had some type of eye involvement.

In a series of patients seen at the Mayo Clinic,¹⁰ orbital inflammatory disease and scleritis were the two most frequent manifestations of eye involvement with GPA. Orbital involvement typically presents with pain, erythema, swelling, and proptosis. Varying degrees of ptosis, diplopia, or visual loss may also be present. Imaging may show an infiltrate that is usually adjacent to the maxillary or ethmoid sinus. This same process can affect the superior temporal orbital quadrant, an area apart from any sinus, and involve the lacrimal gland.

BIOPSY IS ADVISED

Biopsy, either incisional, at times to include debulking, or excisional if possible, is recommended to establish a diagnosis or aid in the selection of therapy. Orbital disease has been observed to progress in patients who are receiving maintenance therapy with methotrexate and have no evidence of systemic disease activity. Acute and chronic inflammation with evidence of active vasculitis is usually seen histologically. Personal observations suggest that intraorbital corticosteroid injection followed by rituximab has been effective therapy for this limited subset of patients. Diagnostic biopsies often must be interpreted in light of partial treatment, making histopathologic diagnosis challenging at times. Biopsy is important for exclusion of lymphoproliferative disease or fungal infection.

CONCLUSION

Underlying vasculitis might play a role in patients with nonspecific ocular presentations. It is essential that the ophthalmologist collaborate with a specialist in vasculitis (and vice versa) for evaluation and subsequent therapy, which often involves some form of immunosuppression.

Granulomatosis with polyangiitis (GPA), is one of the most common types of small-vessel vasculitis, with an estimated prevalence in the United States of 3 per 100,000 people. It is distinguished from other necrotizing vasculitides by its tendency to affect the upper and lower respiratory system and the kidneys. Despite the success of induction and maintenance treatments with cyclophosphamide (CYC), glucocorticoids, and less toxic immunosuppressive alternative therapies in improving the disease course, significant treatment-related toxicities and frequent disease relapses demand stringent patient-specific monitoring in order to provide early treatment of relapses and prevent or decrease morbidity.

SMALL-VESSEL VASCULITIS MANAGEMENT OVERVIEW

Granulomatosis with polyangiitis (formerly Wegener’s granulomatosis, or WG) is an antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis that often affects the respiratory system and kidneys across a broad spectrum of clinical presentations, from mild through life-threatening disease. Patients with severe disease present with significant multisystem manifestations, which, in addition to the respiratory system and kidneys, may involve the joints, eyes, and other organs.

Managing patients diagnosed with systemic small-vessel vasculitides such as GPA and microscopic polyangiitis (MPA) is an inexact science. The goals of treatment are to increase survival, induce and maintain remission, reduce relapses, and minimize treatment-related toxicity. Inducing and maintaining remission have become realistic goals because of the availability of medications that prolong life. On the other hand, extended periods of treatment associated with prolonged life increase the risk of treatment-related toxicity in patients who are inadequately monitored.

MONITORING CONSIDERATIONS

Achieving treatment goals requires long-term monitoring of both disease activity and treatment-related toxicities, with constant adjustments to meet the needs of the individual patient and address the often rapidly changing disease and treatment course. The monitoring protocol consists of regularly scheduled follow-up office visits, urine sediment analyses at every office visit whether or not the patient has relapse symptoms, laboratory tests at regular intervals as indicated by the patient’s medication plan and disease presentation, additional tests such as lung computed tomography (CT), and patient education regarding new symptoms and the frequency of office visits. A consistent monitoring strategy will help detect a relapse before it can produce more severe morbidity, identify treatment-related complications, and—equally important—identify the achievement of remission. An example of the consequences of inconsistent monitoring is presented in “Relapse in a nonadherent patient.”

Because there is no definitive cure for small-vessel vasculitis, relapse is always a possibility. The early diagnosis and treatment of relapse may prevent or decrease morbidity from disease, but strict monitoring is needed to identify relapse and initiate treatment before morbidity occurs (see “Relapse in a patient with new symptoms”). Repeat induction therapy following a relapse introduces risk of drug toxicity and requires careful monitoring, as does long-term maintenance therapy.

In addition to induction and maintenance therapy, several other situations, including prior therapeutic complications, serum creatinine levels, and risk of cardiovascular disease, require special monitoring attention.

Induction therapy: monitor response

Response to treatment during induction must be monitored to identify whether remission is achieved. Induction monitoring requires complete assessment of organ-system involvement at every visit with tools such as the Birmingham Vasculitis Activity Score (BVAS) and, when appropriate, the BVAS/WG. If new or worsening symptoms develop during induction therapy, then the patient needs assessment for continued disease activity as well as treatment complications such as infections related to immunosuppressive therapy.

During induction therapy with daily oral CYC, monitoring should include weekly complete blood cell counts to ensure early identification of leukopenia and other cytopenias. The risk of morbidities increases with the cumulative dose, so a stable blood count for 2 months does not obviate the risk of leukopenia. If persistent hematuria is present without cellular casts, cystoscopy is indicated to look for signs of hemorrhagic cystitis. Prophylaxis against Pneumocystis jirovecii is recommended in all patients who receive immunosuppressive therapy. Finally, bone density measurements should be done at baseline.

Monitoring during maintenance therapy is similar to induction monitoring; however, when the dosage of methotrexate or azathioprine is stabilized, the frequency of some tests can be extended to monthly rather than weekly. For example, a complete blood cell count, comprehensive metabolic panel, sedimentation rate, C-reactive protein measurement, and urinalysis should be performed monthly. Follow-up visits should include urine sediment analyses and monitoring for cardiovascular disease risk factors. Medication monitoring should include cystoscopy for persistent hematuria without cellular casts, bone density measurements, and ophthalmologic examinations as frequently as indicated for each individual’s needs. P jirovecii prophylaxis should continue as long as the patient receives immunosuppressive medication.

Therapy-related complications

Bladder complications. In a retrospective analysis of 145 patients with GPA treated with CYC and followed for 0.5 to 27 years (median 8.5 years), nonglomerular hematuria developed in 50% of the patients and bladder carcinoma in 5%.² The cumulative CYC dose (19 to 251 g) in this group was much higher than what is currently used. Cytologic examination of the urine showed 43% sensitivity for dysplasia (specificity 100%) and 29% sensitivity for atypia (specificity 89%). In contrast, in a retrospective outcomes analysis involving newly diagnosed patients with GPA treated with CYC or methotrexate, 82 patients followed for up to 12 years had no incidents of cystitis or bladder cancer.³ Patients in this study were treated with CYC for only 3 to 6 months and therefore received a lower cumulative dose.

To prevent cystitis during treatment with CYC, the patient should be well hydrated, especially in the morning when CYC should be taken. The bladder should be emptied frequently. The addition of mesna when administering intravenous CYC decreases the risk of cystitis. Serial cystoscopy and urine cytology should be used only in patients with nonglomerular hematuria.

Infertility. Preservation of ovarian function is a concern with CYC therapy in women of childbearing age. The cumulative dose threshold for gonadal failure is unknown, because data from cancer studies⁴ demonstrating gonadal failure involve higher cumulative CYC doses than are typical for vasculitis treatment. It is also unknown whether duration of amenorrhea predicts the recovery of menses or fertility. The primary option for preservation of ovarian function is the use of gonadotropin-releasing hormone agonists. Oral contraceptives also may be used, but the best prevention is to avoid CYC in these patients if possible.

Osteoporosis. At glucocorticoid dosages of 5 mg/day or greater, bone mineral density begins a rapid decline within the first 3 months and peaks at 6 months.⁵ The American College of Rheumatology has provided recommendations for the prevention and treatment of glucocorticoid-induced osteoporosis.⁵ Table 2 presents recommendations for postmenopausal women and men aged 50 years and older who will use glucocorticoids for 3 months or more.⁵ Recommendations are also available for premenopausal women and men younger than 50 years of age who have a history of fragility fracture.

Leukopenia. Leukopenia should be avoided during CYC treatment. The target white blood cell count should be within the normal range. During treatment with daily oral CYC, the patient should be monitored with a weekly complete blood cell count and medication should be adjusted to maintain the target white blood cell count.

Upon completion of induction therapy, after 3 to 6 months, the patient is switched to maintenance therapy with an alternative immunosuppressive agent such as azathioprine or methotrexate, depending on the serum creatinine concentration and other factors. This transition, characterized by full-dose immunosuppressive therapy when the bone marrow has been previously suppressed by CYC treatment, may induce pancytopenia. Monitoring with weekly complete blood counts for at least 4 weeks after initiating maintenance therapy can help ensure stability during the transition period.

Monitor serum creatinine and adjust dosages

The serum creatinine concentration may increase as CYC treatment progresses; in some cases, the serum creatinine concentration increases before a response to treatment is seen. The CYC dosages should be adjusted as necessary in response to serum creatinine changes. Careful monitoring of serum creatinine is necessary during methotrexate therapy, as methotrexate treatment in the setting of renal insufficiency increases the risk of bone marrow suppression.

Cardiovascular disease in GPA and MPA

Premature atherosclerosis has been well described in patients with GPA.⁶ Within 5 years of diagnosis of GPA or MPA, a cardiovascular event will occur in 14% of patients.⁷ In the absence of specific guidelines for prevention of cardiovascular disease in patients with vasculitis, it is essential to monitor patients and treat modifiable traditional risk factors aggressively, especially in younger patients. Suppiah et al found that independent determinants of cardiovascular outcome included older age, diastolic hypertension, and positive proteinase-3–ANCA status in patients without prior cardiovascular disease.⁷

In the Wegener’s Clinical Occurrence of Thrombosis (WeCLOT) study, Merkel et al showed an increased incidence of thrombosis in patients with active GPA⁸ (see “Relapse presenting as thrombosis,” left). As with cardiovascular disease, there are no specific guidelines for monitoring asymptomatic patients for thrombosis or for duration of anticoagulation in patients with GPA. It is recommended that patients be evaluated for active GPA or relapse in the setting of acute thrombosis whether or not symptoms of active GPA are present.

Granulomatosis with polyangiitis (GPA), is one of the most common types of small-vessel vasculitis, with an estimated prevalence in the United States of 3 per 100,000 people. It is distinguished from other necrotizing vasculitides by its tendency to affect the upper and lower respiratory system and the kidneys. Despite the success of induction and maintenance treatments with cyclophosphamide (CYC), glucocorticoids, and less toxic immunosuppressive alternative therapies in improving the disease course, significant treatment-related toxicities and frequent disease relapses demand stringent patient-specific monitoring in order to provide early treatment of relapses and prevent or decrease morbidity.

SMALL-VESSEL VASCULITIS MANAGEMENT OVERVIEW

Granulomatosis with polyangiitis (formerly Wegener’s granulomatosis, or WG) is an antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis that often affects the respiratory system and kidneys across a broad spectrum of clinical presentations, from mild through life-threatening disease. Patients with severe disease present with significant multisystem manifestations, which, in addition to the respiratory system and kidneys, may involve the joints, eyes, and other organs.

Managing patients diagnosed with systemic small-vessel vasculitides such as GPA and microscopic polyangiitis (MPA) is an inexact science. The goals of treatment are to increase survival, induce and maintain remission, reduce relapses, and minimize treatment-related toxicity. Inducing and maintaining remission have become realistic goals because of the availability of medications that prolong life. On the other hand, extended periods of treatment associated with prolonged life increase the risk of treatment-related toxicity in patients who are inadequately monitored.

MONITORING CONSIDERATIONS

Achieving treatment goals requires long-term monitoring of both disease activity and treatment-related toxicities, with constant adjustments to meet the needs of the individual patient and address the often rapidly changing disease and treatment course. The monitoring protocol consists of regularly scheduled follow-up office visits, urine sediment analyses at every office visit whether or not the patient has relapse symptoms, laboratory tests at regular intervals as indicated by the patient’s medication plan and disease presentation, additional tests such as lung computed tomography (CT), and patient education regarding new symptoms and the frequency of office visits. A consistent monitoring strategy will help detect a relapse before it can produce more severe morbidity, identify treatment-related complications, and—equally important—identify the achievement of remission. An example of the consequences of inconsistent monitoring is presented in “Relapse in a nonadherent patient.”

Because there is no definitive cure for small-vessel vasculitis, relapse is always a possibility. The early diagnosis and treatment of relapse may prevent or decrease morbidity from disease, but strict monitoring is needed to identify relapse and initiate treatment before morbidity occurs (see “Relapse in a patient with new symptoms”). Repeat induction therapy following a relapse introduces risk of drug toxicity and requires careful monitoring, as does long-term maintenance therapy.

In addition to induction and maintenance therapy, several other situations, including prior therapeutic complications, serum creatinine levels, and risk of cardiovascular disease, require special monitoring attention.

Induction therapy: monitor response

Response to treatment during induction must be monitored to identify whether remission is achieved. Induction monitoring requires complete assessment of organ-system involvement at every visit with tools such as the Birmingham Vasculitis Activity Score (BVAS) and, when appropriate, the BVAS/WG. If new or worsening symptoms develop during induction therapy, then the patient needs assessment for continued disease activity as well as treatment complications such as infections related to immunosuppressive therapy.

During induction therapy with daily oral CYC, monitoring should include weekly complete blood cell counts to ensure early identification of leukopenia and other cytopenias. The risk of morbidities increases with the cumulative dose, so a stable blood count for 2 months does not obviate the risk of leukopenia. If persistent hematuria is present without cellular casts, cystoscopy is indicated to look for signs of hemorrhagic cystitis. Prophylaxis against Pneumocystis jirovecii is recommended in all patients who receive immunosuppressive therapy. Finally, bone density measurements should be done at baseline.

Monitoring during maintenance therapy is similar to induction monitoring; however, when the dosage of methotrexate or azathioprine is stabilized, the frequency of some tests can be extended to monthly rather than weekly. For example, a complete blood cell count, comprehensive metabolic panel, sedimentation rate, C-reactive protein measurement, and urinalysis should be performed monthly. Follow-up visits should include urine sediment analyses and monitoring for cardiovascular disease risk factors. Medication monitoring should include cystoscopy for persistent hematuria without cellular casts, bone density measurements, and ophthalmologic examinations as frequently as indicated for each individual’s needs. P jirovecii prophylaxis should continue as long as the patient receives immunosuppressive medication.

Therapy-related complications

Bladder complications. In a retrospective analysis of 145 patients with GPA treated with CYC and followed for 0.5 to 27 years (median 8.5 years), nonglomerular hematuria developed in 50% of the patients and bladder carcinoma in 5%.² The cumulative CYC dose (19 to 251 g) in this group was much higher than what is currently used. Cytologic examination of the urine showed 43% sensitivity for dysplasia (specificity 100%) and 29% sensitivity for atypia (specificity 89%). In contrast, in a retrospective outcomes analysis involving newly diagnosed patients with GPA treated with CYC or methotrexate, 82 patients followed for up to 12 years had no incidents of cystitis or bladder cancer.³ Patients in this study were treated with CYC for only 3 to 6 months and therefore received a lower cumulative dose.

To prevent cystitis during treatment with CYC, the patient should be well hydrated, especially in the morning when CYC should be taken. The bladder should be emptied frequently. The addition of mesna when administering intravenous CYC decreases the risk of cystitis. Serial cystoscopy and urine cytology should be used only in patients with nonglomerular hematuria.

Infertility. Preservation of ovarian function is a concern with CYC therapy in women of childbearing age. The cumulative dose threshold for gonadal failure is unknown, because data from cancer studies⁴ demonstrating gonadal failure involve higher cumulative CYC doses than are typical for vasculitis treatment. It is also unknown whether duration of amenorrhea predicts the recovery of menses or fertility. The primary option for preservation of ovarian function is the use of gonadotropin-releasing hormone agonists. Oral contraceptives also may be used, but the best prevention is to avoid CYC in these patients if possible.

Osteoporosis. At glucocorticoid dosages of 5 mg/day or greater, bone mineral density begins a rapid decline within the first 3 months and peaks at 6 months.⁵ The American College of Rheumatology has provided recommendations for the prevention and treatment of glucocorticoid-induced osteoporosis.⁵ Table 2 presents recommendations for postmenopausal women and men aged 50 years and older who will use glucocorticoids for 3 months or more.⁵ Recommendations are also available for premenopausal women and men younger than 50 years of age who have a history of fragility fracture.

Leukopenia. Leukopenia should be avoided during CYC treatment. The target white blood cell count should be within the normal range. During treatment with daily oral CYC, the patient should be monitored with a weekly complete blood cell count and medication should be adjusted to maintain the target white blood cell count.

Upon completion of induction therapy, after 3 to 6 months, the patient is switched to maintenance therapy with an alternative immunosuppressive agent such as azathioprine or methotrexate, depending on the serum creatinine concentration and other factors. This transition, characterized by full-dose immunosuppressive therapy when the bone marrow has been previously suppressed by CYC treatment, may induce pancytopenia. Monitoring with weekly complete blood counts for at least 4 weeks after initiating maintenance therapy can help ensure stability during the transition period.

Monitor serum creatinine and adjust dosages

The serum creatinine concentration may increase as CYC treatment progresses; in some cases, the serum creatinine concentration increases before a response to treatment is seen. The CYC dosages should be adjusted as necessary in response to serum creatinine changes. Careful monitoring of serum creatinine is necessary during methotrexate therapy, as methotrexate treatment in the setting of renal insufficiency increases the risk of bone marrow suppression.

Cardiovascular disease in GPA and MPA

Premature atherosclerosis has been well described in patients with GPA.⁶ Within 5 years of diagnosis of GPA or MPA, a cardiovascular event will occur in 14% of patients.⁷ In the absence of specific guidelines for prevention of cardiovascular disease in patients with vasculitis, it is essential to monitor patients and treat modifiable traditional risk factors aggressively, especially in younger patients. Suppiah et al found that independent determinants of cardiovascular outcome included older age, diastolic hypertension, and positive proteinase-3–ANCA status in patients without prior cardiovascular disease.⁷

In the Wegener’s Clinical Occurrence of Thrombosis (WeCLOT) study, Merkel et al showed an increased incidence of thrombosis in patients with active GPA⁸ (see “Relapse presenting as thrombosis,” left). As with cardiovascular disease, there are no specific guidelines for monitoring asymptomatic patients for thrombosis or for duration of anticoagulation in patients with GPA. It is recommended that patients be evaluated for active GPA or relapse in the setting of acute thrombosis whether or not symptoms of active GPA are present.

Granulomatosis with polyangiitis (GPA), is one of the most common types of small-vessel vasculitis, with an estimated prevalence in the United States of 3 per 100,000 people. It is distinguished from other necrotizing vasculitides by its tendency to affect the upper and lower respiratory system and the kidneys. Despite the success of induction and maintenance treatments with cyclophosphamide (CYC), glucocorticoids, and less toxic immunosuppressive alternative therapies in improving the disease course, significant treatment-related toxicities and frequent disease relapses demand stringent patient-specific monitoring in order to provide early treatment of relapses and prevent or decrease morbidity.

SMALL-VESSEL VASCULITIS MANAGEMENT OVERVIEW

Granulomatosis with polyangiitis (formerly Wegener’s granulomatosis, or WG) is an antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis that often affects the respiratory system and kidneys across a broad spectrum of clinical presentations, from mild through life-threatening disease. Patients with severe disease present with significant multisystem manifestations, which, in addition to the respiratory system and kidneys, may involve the joints, eyes, and other organs.

Managing patients diagnosed with systemic small-vessel vasculitides such as GPA and microscopic polyangiitis (MPA) is an inexact science. The goals of treatment are to increase survival, induce and maintain remission, reduce relapses, and minimize treatment-related toxicity. Inducing and maintaining remission have become realistic goals because of the availability of medications that prolong life. On the other hand, extended periods of treatment associated with prolonged life increase the risk of treatment-related toxicity in patients who are inadequately monitored.

MONITORING CONSIDERATIONS

Achieving treatment goals requires long-term monitoring of both disease activity and treatment-related toxicities, with constant adjustments to meet the needs of the individual patient and address the often rapidly changing disease and treatment course. The monitoring protocol consists of regularly scheduled follow-up office visits, urine sediment analyses at every office visit whether or not the patient has relapse symptoms, laboratory tests at regular intervals as indicated by the patient’s medication plan and disease presentation, additional tests such as lung computed tomography (CT), and patient education regarding new symptoms and the frequency of office visits. A consistent monitoring strategy will help detect a relapse before it can produce more severe morbidity, identify treatment-related complications, and—equally important—identify the achievement of remission. An example of the consequences of inconsistent monitoring is presented in “Relapse in a nonadherent patient.”

Because there is no definitive cure for small-vessel vasculitis, relapse is always a possibility. The early diagnosis and treatment of relapse may prevent or decrease morbidity from disease, but strict monitoring is needed to identify relapse and initiate treatment before morbidity occurs (see “Relapse in a patient with new symptoms”). Repeat induction therapy following a relapse introduces risk of drug toxicity and requires careful monitoring, as does long-term maintenance therapy.

In addition to induction and maintenance therapy, several other situations, including prior therapeutic complications, serum creatinine levels, and risk of cardiovascular disease, require special monitoring attention.

Induction therapy: monitor response

Response to treatment during induction must be monitored to identify whether remission is achieved. Induction monitoring requires complete assessment of organ-system involvement at every visit with tools such as the Birmingham Vasculitis Activity Score (BVAS) and, when appropriate, the BVAS/WG. If new or worsening symptoms develop during induction therapy, then the patient needs assessment for continued disease activity as well as treatment complications such as infections related to immunosuppressive therapy.

During induction therapy with daily oral CYC, monitoring should include weekly complete blood cell counts to ensure early identification of leukopenia and other cytopenias. The risk of morbidities increases with the cumulative dose, so a stable blood count for 2 months does not obviate the risk of leukopenia. If persistent hematuria is present without cellular casts, cystoscopy is indicated to look for signs of hemorrhagic cystitis. Prophylaxis against Pneumocystis jirovecii is recommended in all patients who receive immunosuppressive therapy. Finally, bone density measurements should be done at baseline.

Monitoring during maintenance therapy is similar to induction monitoring; however, when the dosage of methotrexate or azathioprine is stabilized, the frequency of some tests can be extended to monthly rather than weekly. For example, a complete blood cell count, comprehensive metabolic panel, sedimentation rate, C-reactive protein measurement, and urinalysis should be performed monthly. Follow-up visits should include urine sediment analyses and monitoring for cardiovascular disease risk factors. Medication monitoring should include cystoscopy for persistent hematuria without cellular casts, bone density measurements, and ophthalmologic examinations as frequently as indicated for each individual’s needs. P jirovecii prophylaxis should continue as long as the patient receives immunosuppressive medication.

Therapy-related complications

Bladder complications. In a retrospective analysis of 145 patients with GPA treated with CYC and followed for 0.5 to 27 years (median 8.5 years), nonglomerular hematuria developed in 50% of the patients and bladder carcinoma in 5%.² The cumulative CYC dose (19 to 251 g) in this group was much higher than what is currently used. Cytologic examination of the urine showed 43% sensitivity for dysplasia (specificity 100%) and 29% sensitivity for atypia (specificity 89%). In contrast, in a retrospective outcomes analysis involving newly diagnosed patients with GPA treated with CYC or methotrexate, 82 patients followed for up to 12 years had no incidents of cystitis or bladder cancer.³ Patients in this study were treated with CYC for only 3 to 6 months and therefore received a lower cumulative dose.

To prevent cystitis during treatment with CYC, the patient should be well hydrated, especially in the morning when CYC should be taken. The bladder should be emptied frequently. The addition of mesna when administering intravenous CYC decreases the risk of cystitis. Serial cystoscopy and urine cytology should be used only in patients with nonglomerular hematuria.

Infertility. Preservation of ovarian function is a concern with CYC therapy in women of childbearing age. The cumulative dose threshold for gonadal failure is unknown, because data from cancer studies⁴ demonstrating gonadal failure involve higher cumulative CYC doses than are typical for vasculitis treatment. It is also unknown whether duration of amenorrhea predicts the recovery of menses or fertility. The primary option for preservation of ovarian function is the use of gonadotropin-releasing hormone agonists. Oral contraceptives also may be used, but the best prevention is to avoid CYC in these patients if possible.

Osteoporosis. At glucocorticoid dosages of 5 mg/day or greater, bone mineral density begins a rapid decline within the first 3 months and peaks at 6 months.⁵ The American College of Rheumatology has provided recommendations for the prevention and treatment of glucocorticoid-induced osteoporosis.⁵ Table 2 presents recommendations for postmenopausal women and men aged 50 years and older who will use glucocorticoids for 3 months or more.⁵ Recommendations are also available for premenopausal women and men younger than 50 years of age who have a history of fragility fracture.

Leukopenia. Leukopenia should be avoided during CYC treatment. The target white blood cell count should be within the normal range. During treatment with daily oral CYC, the patient should be monitored with a weekly complete blood cell count and medication should be adjusted to maintain the target white blood cell count.

Upon completion of induction therapy, after 3 to 6 months, the patient is switched to maintenance therapy with an alternative immunosuppressive agent such as azathioprine or methotrexate, depending on the serum creatinine concentration and other factors. This transition, characterized by full-dose immunosuppressive therapy when the bone marrow has been previously suppressed by CYC treatment, may induce pancytopenia. Monitoring with weekly complete blood counts for at least 4 weeks after initiating maintenance therapy can help ensure stability during the transition period.

Monitor serum creatinine and adjust dosages

The serum creatinine concentration may increase as CYC treatment progresses; in some cases, the serum creatinine concentration increases before a response to treatment is seen. The CYC dosages should be adjusted as necessary in response to serum creatinine changes. Careful monitoring of serum creatinine is necessary during methotrexate therapy, as methotrexate treatment in the setting of renal insufficiency increases the risk of bone marrow suppression.

Cardiovascular disease in GPA and MPA

Premature atherosclerosis has been well described in patients with GPA.⁶ Within 5 years of diagnosis of GPA or MPA, a cardiovascular event will occur in 14% of patients.⁷ In the absence of specific guidelines for prevention of cardiovascular disease in patients with vasculitis, it is essential to monitor patients and treat modifiable traditional risk factors aggressively, especially in younger patients. Suppiah et al found that independent determinants of cardiovascular outcome included older age, diastolic hypertension, and positive proteinase-3–ANCA status in patients without prior cardiovascular disease.⁷

In the Wegener’s Clinical Occurrence of Thrombosis (WeCLOT) study, Merkel et al showed an increased incidence of thrombosis in patients with active GPA⁸ (see “Relapse presenting as thrombosis,” left). As with cardiovascular disease, there are no specific guidelines for monitoring asymptomatic patients for thrombosis or for duration of anticoagulation in patients with GPA. It is recommended that patients be evaluated for active GPA or relapse in the setting of acute thrombosis whether or not symptoms of active GPA are present.

In 2007, Falagas et al¹ provided a systematic review of studies focusing on infection-related morbidity and mortality in patients with connective tissue diseases. Many of the studies reviewed were published prior to the introduction of biologic agents for the treatment of rheumatologic disorders. In 39 studies focusing on infection incidence, patient outcomes, or both in patients with systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), polymyositis/dermatomyositis, granulomatosis with polyangiitis (GPA, [Wegener’s granulomatosis]), and systemic sclerosis, serious infection developed in 29% of patients and 24% of these died due to the infection with a median attributable mortality of 5.2%. Most of the reported infections were common bacterial syndromes such as pneumonia or bacteremia, and opportunistic fungal (Pneumocystis) infections.

Similarly, in 2006 Alarcón² reported that 25% to 50% of patients with SLE had significant morbidity primarily from common bacterial infections, with viral, fungal, and parasitic infection less common. Staphylococcus aureus was a common cause of soft tissue infection, septic arthritis, and bacteremia. Streptococcus pneumoniae typically caused respiratory infections, although meningitis and sepsis were reported with SLE. Gram-negative bacteria such as Escherichia coli, Klebsiella species, and Pseudomonas species usually caused urinary tract infections and nosocomial pneumonia. Other bacterial infections included Nocardia species, Mycobacterium tuberculosis, and, rarely, Listeria monocytogenes. The most common viral infection was herpes zoster. Fungal infections included Pneumocystis jirovecii (formerly known as Pneumocystis carinii) and Candida species.

In scleroderma, another connective tissue disease evaluated in the literature by Alarcón,² reports of bacterial, viral, and fungal infections are limited to case reports. In scleroderma patients, viral infections with cytomegalovirus (CMV), parvovirus B19, and P jirovecii were similar to pathogens observed with SLE.

In polymyositis/dermatomyositis, gram-positive pneumonia affected 15% to 20% of patients and S aureus occurred frequently in the juvenile form of the disease. Herpes zoster was commonly observed, but CMV was relatively rare. Other viral infections included Coxsackie virus, parvovirus B19, and hepatitis C in polymyositis/dermatomyositis. Infection with P jirovecii is frequently fatal in these patients. Other fungal infections seen in polymyositis/dermatomyositis include candidiasis and histoplasmosis.²

Since the approval of antitumor necrosis factor (anti-TNF) agents for RA in the late 1990s, as well as other more recent biologic agents, there has been heightened awareness of infectious complications in rheumatologic patients. A major concern with the anti-TNF agents is the risk of granulomatous infection, particularly mycobacterial disease and dimorphic fungal infections such as histoplasmosis and coccidioidomycosis. Formation of granulomas is the major host defense against mycobacterial infection and is mediated in large part by TNF-alpha. The precise risk of infection associated with each of the various biologic agents is still under study, and rates from randomized trials have differed from postmarketing surveillance studies. Important pathogens associated with biologic agents include Nocardia, CMV, Listeria, Aspergillus, and JC virus (JCV).^3,4 Delays in the diagnosis of these infections in immunocompromised patients have led to poor outcomes.

KEY PATHOGENS IN INFECTIONS OF IMMUNOCOMPROMISED HOSTS

Pneumocystis jirovecii

For many decades, P jirovecii was classified as a protozoan but, based on gene sequencing, the organism has been reclassified as a fungus. P jirovecii is a low-virulence, unicellular organism that is the causative agent of Pneumocystis pneumonia (PCP). Epidemiologically, primary infection most likely occurs in infants and children. Colonization may be transient, entering the airways and then resolving over a period of weeks or months. Alternatively, the organism may enter a latent state similar to tuberculosis with reactivation occurring during times of intense immunosuppression. However, molecular epidemiology studies show that new cases of PCP are likely environmentally acquired through multiple exposures rather than reactivation of latent infection.^5,6 Transmission is thought to be airborne from person to person. Pathogenically, the trophic form of the organism attaches to type 1 alveolar cells and remains in the extracellular compartment of the alveoli. This colonization evokes an influx of inflammatory cells (CD8 cells, neutrophils, and macrophages). However, not all colonizations result in pneumonia—even in advanced human immunodeficiency virus (HIV) infection. While there is an innate immunity through alveolar macrophages and pulmonary surfactant, alveolar macrophage response is impaired in HIV when the CD4 count is low. Cell-mediated immunity is the main defense against progression to pneumonia with assistance from costimulatory molecules (such as CD28 and CD2) as well as B cells.

Laboratory diagnosis. P jirovecii cannot be grown in culture for clinical purposes, and it is extremely difficult to culture even in the research setting. Cytologic stains such as the Wright-Giemsa and methamine silver stains are the mainstay of laboratory diagnosis. The yield for P jirovecii from routine expectorated sputum is very low and some laboratories discourage this approach. The sensitivity of nebulized sputum using hypertonic saline ranges from 50% to 90%.⁹

In patients with acquired immune deficiency syndrome (AIDS), bronchoscopy provides 90% to 98% sensitivity by BAL. Transbronchial biopsy may provide some additional yield over BAL in a few situations, such as patients who have been receiving partial P jirovecii prophylaxis. Immunofluorescence techniques using monoclonal antibodies to P jirovecii are commercially available and are first-line diagnostic tools in some laboratories. Recently, polymerase chain reaction (PCR) assay has been introduced into clinical practice as a reproducible test with high sensitivity.

Primary therapy. Primary therapy for PCP consists of trimethoprim-sulfamethoxazole (TMP-SMX) or pentamidine. TMP-SMX is considered the drug of choice and is usually administered intravenously for 21 days in HIV patients and 14 days for non-HIV patients. The oral form may be used in patients with less severe PCP with a functioning gastrointestinal tract. Common adverse reactions to TMP-SMX include rash, Stevens-Johnson syndrome, neutropenia, changes in pulmonary function, and nausea/vomiting/diarrhea.¹⁰ Pentamidine is as effective as TMP-SMX, but is associated with renal toxicity, hypotension, severe hypoglycemia, cardiac arrhythmias, and diabetes.¹¹ It is generally reserved for severe cases of PCP in patients who are allergic to or otherwise intolerant of sulfa. Other treatments include atovaquone and trimethoprim-dapsone. Adjunctive corticosteroids have been shown to be beneficial in moderate to severe PCP in HIV patients to reduce the local host inflammatory response to dead or dying organisms. Recent guidelines have recommended corticosteroids for HIV patients with PCP who have an arterial oxygen pressure of 70 mm Hg or less on room air, or an alveolar-arterial (A-a) gradient of oxygen 35 mm Hg or greater.¹² Little is known about the role of adjunctive corticosteroids in non-HIV patients, given a lack of clinical studies.

Prevention. Recent estimates of disease burden from a meta-analysis of 11,900 patients with connective tissue diseases found PCP in 12% of patients with GPA, in 6% of those with polydermatomyositis, in 5% of those with SLE, and in 1% of those with RA.¹ Mortality due to PCP is higher in patients with rheumatic diseases, ranging from 30% in RA to 63% in GPA, than in those with HIV (10% to 20%).¹³ One key risk factor predisposing patients with connective tissue diseases to infection with P jirovecii is recent corticosteroid use. Among patients with connective tissue disease, more than 90% of those infected with P jirovecii have recently received steroid therapy.¹⁴ Additionally, in almost all patients with P jirovecii, lymphopenia with absolute lymphocyte counts less than 1,000/mm³ is present.¹⁵

In patients with HIV, prophylaxis is initiated at a CD4 level of 200/mm³.¹³ However, the cutoff is less clear for non-HIV rheumatic patients. A cutoff of less than 300 cells/mm³ has been proposed for prophylaxis of PCP. However, at that range, approximately 50% of patients with connective tissue disease would remain above the threshold.¹³ One possible solution is to screen by PCR and treat colonization. Other algorithms have been proposed, but there is no general consensus on treatment of non-HIV rheumatic patients.^13,16 Generally, prophylaxis should be considered in patients at the highest risk for PCP. These include patients taking prednisone at doses greater than 20 mg/day for 1 month plus a cytotoxic agent, a TNF inhibitor plus glucocorticoids, and methotrexate plus glucocorticoids in GPA.¹³

Nocardia asteroides and Nocardia species

Classically, Nocardia infection results in abscess formation with infiltrates of polymorphonuclear cells, debris, and thin-walled abscesses. The most frequent site of primary infection is pulmonary. Characteristically, multiple pulmonary nodules or cavities are seen, and Nocardia should be considered in the differential diagnosis of an immunocompromised patient with nodular pneumonia. The nodules can also be masslike in appearance (greater than 2 cm). The presentation of new cavitary lung opacities with systemic symptoms may be mistaken for GPA.²²Nocardia may disseminate to the central nervous system (CNS), skin, joints, and spine, usually causing suppurative infection at these sites. Nocardia has a very strong tropism for neural tissue. In the CNS, Nocardia can cause single or multiple brain abscesses that may be asymptomatic; patients with pulmonary nocardiosis require imaging to rule out occult CNS involvement.

Nocardia species are resistant to several antibiotics. The treatment of choice for Nocardia species is TMPSMX, but imipenem, amikacin, third-generation cephalosporins, and other options such as minocycline and linezolid may be considered depending on the species and the antimicrobial susceptibility pattern.

Histoplasma capsulatum

Histoplasma capsulatum is a dimorphic fungus that causes disease in both healthy and immunocompromised hosts. The organism differs from other pathogenic fungi in that it is an intracellular organism, mainly involving the reticuloendothelial system, and is rarely in the extracellular space. In the United States, infections are clustered endemically in areas such as the Mississippi and Ohio River Valleys, but infections are common worldwide. The fungus is found in soil, mulch, bird excrement, and bat guano. Asymptomatic or mild infections are common in healthy persons residing in endemic areas and occur on a sporadic basis. Epidemics can occur when contaminated material is aerosolized. Histoplasmosis is also an opportunistic infection in patients with impaired T-cell immunity such as persons with AIDS, organ transplant recipients, hematologic malignancies, and corticosteroid use. Clinically significant cases of histoplasmosis have been described in patients with RA while receiving methotrexate alone, corticosteroids alone, and combinations of disease-modifying agents.²³ Histoplasmosis was recently identified in 240 patients in association with TNF inhibitors, translating to 17 per 100,000 patients treated with infliximab.^21,24

Pathogenesis. Infection initially occurs through inhalation of contaminated material from the environment, primarily causing pulmonary infection. The organism converts from a mold form in the environment to a pathogenic yeast form in the host. Once inhaled, the mediastinal lymph nodes provide the first line of defense. Following draining of the lymph nodes, the organism enters the bloodstream in both immunocompetent and immunosuppressed patients. It is spread hematogenously into the spleen, liver, and reticulo-endothelial system, where it is eventually cleared. In immunocompetent patients, cellular immunity limits infection within 7 to 14 days and humoral immunity is not protective.²⁵ Granuloma formation is the hallmark of host defense.

Spectrum of illness. Histoplasmosis is associated with a wide spectrum of illness, with presentation ranging from asymptomatic to mild pulmonary illness to overwhelming pneumonia. Symptomatic pulmonary histoplasmosis typically presents with fever, flulike symptoms, and cough, often with retrosternal chest pain. X-rays show patchy or nodular infiltrates, with hilar or mediastinal lymphadenopathy. In some cases the lung parenchyma is clear and the main feature is fever and bilateral hilar adenopathy. Pulmonary histoplasmosis may be difficult to distinguish from sarcoidosis and tuberculosis. Extrapulmonary disease can present as hepatitis, infective endocarditis, and chronic meningitis. In immunocompromised patients, histoplasmosis can present as a progressive disseminated disease which can be acute, subacute, or chronic. Chronic disseminated histoplasmosis is characterized by cough, persistent fever, wasting, hepatosplenomegaly, oral ulcerations, and progressive cytopenias. Acute disseminated histoplasmosis has a much more fulminant course characterized by respiratory insufficiency, hypotension, multisystem organ failure, coagulopathies, and encephalopathy. Histoplasmosis is primarily a pulmonary disease, but in disseminated disease more than 50% of patients have no pulmonary symptoms and 30% may have normal chest x-rays.²⁶ In one series of infliximab-related cases (n = 10), all came from an endemic area 1 week to 6 months after the first dose of infliximab. Patients presented with cough, fever, and shortness of breath.²⁷ The pathogenesis of histoplasmosis in patients receiving TNF inhibitors is not entirely clear; such patients may be suffering a new primary infection, a reinfection, or, least likely, reactivation of latent infection.

Definitive diagnosis requires culture confirmation from appropriate body fluids or identification of characteristic yeast forms from histopathologic sections of tissue biopsies. Serologic tests may also be used to confirm the diagnosis. Detection of H and M precipitins or bands by immunodiffusion is a routine test in many laboratories. M bands are present in 50% of acute cases but their presence does not distinguish acute from remote infection. H bands are present in only 10% of all acute cases, but their presence is very specific for acute histoplasmosis.²⁸

When looking at complement fixation antibodies to yeast (HY) and mycelial (HMy) forms in pulmonary histoplasmosis, a fourfold rise in titer establishes the diagnosis retrospectively, and a single titer greater than 1:32 is strongly suggestive of active infection. However, in progressive disseminated histoplasmosis, the complement fixation antibodies are frequently negative.²⁹ Detection of antigen in urine and serum by enzyme immunoassay has become a mainstay of diagnosis, with a sensitivity of approximately 90% in progressive disseminated disease.³⁰ Of note, most cases of histoplasmosis associated with biologic agents have detectable urinary antigen tests.

Treatment. Acute pulmonary histoplasmosis is usually self-limited, requiring no treatment. The 2007 Infective Diseases Society of America (IDSA) guidelines recommend observation alone in most cases of mild to moderate pulmonary histoplasmosis unless symptoms persist longer than 1 month. For moderately severe or severe acute pulmonary histoplasmosis, the IDSA recommends lipid formulations of amphotericin B (3.0 to 5.0 mg/kg/day) or deosycholate amphotericin B (0.7 to 1.0 mg/kg/day) for 1 to 2 weeks followed by itraconazole 200 mg twice daily for a total of 12 weeks. Methylprednisolone at a dose of 0.5 to 1.0 mg/kg/day intravenously for 1 to 2 weeks is also recommended. For moderately severe to severe disseminated histoplasmosis, the IDSA recommends lipid formulations of amphotericin B (3.0 mg/kg/day) for 1 to 2 weeks followed by oral itraconazole 200 mg three times daily for 3 days and then 200 mg twice daily for a total of at least 12 months.³¹ Commonly, the immunosuppressive agent is held during treatment.

Another emerging pathogen is Aspergillus species—a ubiquitous mold spread by aerosols of spores. There are many different species of Aspergillus, but the most common human pathogens include A fumigates, A niger, and A flavus. To date, 39 cases of Aspergillus infection associated with infliximab and etanercept have been reported in the Adverse Event Reporting System, translating to 9 to 12 cases per 100,000 patients.²¹

Varicella zoster

JC virus

More than 80% of adults are seropositive for JCV, a DNA virus of the genus Polyomavirus that causes lytic infection of oligodendrocytes.³⁴ In immunocompromised hosts, JCV causes progressive multifocal leukoencephalopathy (PML), a rare but devastating demyelinating disease. PML was first described in malignancy, leukemia, and various other immunocompromised states, prior to its strong association with AIDS in the 1980s. More recently, JCV has been associated with natalizumab for multiple sclerosis and Crohn disease, rituximab for oncology patients, efalizumab for psoriasis,³⁵ and mycophenolate mofetil for transplant recipients.³⁶

In 2006 the US Food and Drug Administration issued a safety alert regarding PML in two patients with SLE treated with rituximab and other immunosuppressives.³⁷ In a review of PML in rheumatic disease, 36 cases were identified in patients who had not previously received a biologic agent. Most of these patients (60%) had SLE.³⁸ Of these, many had little or no immunosuppression over the 6 months prior to the diagnosis of PML, suggesting that SLE itself may predispose to PML. Interestingly, PML is rarely associated with TNF inhibitors.

Classic presentation of PML includes motor weakness, aphasia, dysarthria, vision loss, and cognitive loss. Atypical presentation includes seizures, headaches, and brainstem involvement. PML usually spares the optic nerves, spinal cord, peripheral nerves, and muscles. In persons with underlying rheumatic diseases, PML can be difficult to distinguish from neuropsychiatric SLE or CNS vasculitis.

Treatment. In clinical trials no antiviral agent has been effective in the treatment of PML. In HIV patients who develop PML, highly active antiretroviral therapy should be initiated (if antiretroviral-naïve) or existing antiviral regimens optimized. Antiretroviral therapy in this situation may stabilize disease and possibly increase survival.⁴² For HIV-negative patients who develop PML, the cornerstone of management is immediate decrease or discontinuation of immunosuppression.⁴³ Several adjunctive measures have been reported mainly in natalizumab-associated PML, including corticosteroids, mirtazapine, plasma exchange, and others.

VACCINES

Vaccination is important in the prevention of infectious disease in immunocompromised patients with connective tissue diseases. Because live vaccines are contraindicated in immunocompromised patients, inactivated or component vaccines should be used. It is recommended that patients who will start immunosuppressive therapy be vaccinated 2 to 4 weeks before beginning therapy. If this is not possible, vaccination should be administered during disease remission, 3 months after immunosuppression and 1 to 3 months after administration of high-dose corticosteroids.

• Short-term (less than 14 days)
• At a dose of less than 20 mg/day of prednisone or equivalent
• Long-term on alternate days with short-acting preparations
• At a physiologic dose of prednisone
• Topical, inhaled, intra-articular, bursal, or via tendon.⁴⁴

Until definitive guidelines are developed, practitioners must evaluate and treat each patient individually to maximize the efficacy of disease treatments while preventing infection morbidity and mortality in their patients with connective tissue diseases.

In 2007, Falagas et al¹ provided a systematic review of studies focusing on infection-related morbidity and mortality in patients with connective tissue diseases. Many of the studies reviewed were published prior to the introduction of biologic agents for the treatment of rheumatologic disorders. In 39 studies focusing on infection incidence, patient outcomes, or both in patients with systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), polymyositis/dermatomyositis, granulomatosis with polyangiitis (GPA, [Wegener’s granulomatosis]), and systemic sclerosis, serious infection developed in 29% of patients and 24% of these died due to the infection with a median attributable mortality of 5.2%. Most of the reported infections were common bacterial syndromes such as pneumonia or bacteremia, and opportunistic fungal (Pneumocystis) infections.

Similarly, in 2006 Alarcón² reported that 25% to 50% of patients with SLE had significant morbidity primarily from common bacterial infections, with viral, fungal, and parasitic infection less common. Staphylococcus aureus was a common cause of soft tissue infection, septic arthritis, and bacteremia. Streptococcus pneumoniae typically caused respiratory infections, although meningitis and sepsis were reported with SLE. Gram-negative bacteria such as Escherichia coli, Klebsiella species, and Pseudomonas species usually caused urinary tract infections and nosocomial pneumonia. Other bacterial infections included Nocardia species, Mycobacterium tuberculosis, and, rarely, Listeria monocytogenes. The most common viral infection was herpes zoster. Fungal infections included Pneumocystis jirovecii (formerly known as Pneumocystis carinii) and Candida species.

In scleroderma, another connective tissue disease evaluated in the literature by Alarcón,² reports of bacterial, viral, and fungal infections are limited to case reports. In scleroderma patients, viral infections with cytomegalovirus (CMV), parvovirus B19, and P jirovecii were similar to pathogens observed with SLE.

In polymyositis/dermatomyositis, gram-positive pneumonia affected 15% to 20% of patients and S aureus occurred frequently in the juvenile form of the disease. Herpes zoster was commonly observed, but CMV was relatively rare. Other viral infections included Coxsackie virus, parvovirus B19, and hepatitis C in polymyositis/dermatomyositis. Infection with P jirovecii is frequently fatal in these patients. Other fungal infections seen in polymyositis/dermatomyositis include candidiasis and histoplasmosis.²

Since the approval of antitumor necrosis factor (anti-TNF) agents for RA in the late 1990s, as well as other more recent biologic agents, there has been heightened awareness of infectious complications in rheumatologic patients. A major concern with the anti-TNF agents is the risk of granulomatous infection, particularly mycobacterial disease and dimorphic fungal infections such as histoplasmosis and coccidioidomycosis. Formation of granulomas is the major host defense against mycobacterial infection and is mediated in large part by TNF-alpha. The precise risk of infection associated with each of the various biologic agents is still under study, and rates from randomized trials have differed from postmarketing surveillance studies. Important pathogens associated with biologic agents include Nocardia, CMV, Listeria, Aspergillus, and JC virus (JCV).^3,4 Delays in the diagnosis of these infections in immunocompromised patients have led to poor outcomes.

KEY PATHOGENS IN INFECTIONS OF IMMUNOCOMPROMISED HOSTS

Pneumocystis jirovecii

For many decades, P jirovecii was classified as a protozoan but, based on gene sequencing, the organism has been reclassified as a fungus. P jirovecii is a low-virulence, unicellular organism that is the causative agent of Pneumocystis pneumonia (PCP). Epidemiologically, primary infection most likely occurs in infants and children. Colonization may be transient, entering the airways and then resolving over a period of weeks or months. Alternatively, the organism may enter a latent state similar to tuberculosis with reactivation occurring during times of intense immunosuppression. However, molecular epidemiology studies show that new cases of PCP are likely environmentally acquired through multiple exposures rather than reactivation of latent infection.^5,6 Transmission is thought to be airborne from person to person. Pathogenically, the trophic form of the organism attaches to type 1 alveolar cells and remains in the extracellular compartment of the alveoli. This colonization evokes an influx of inflammatory cells (CD8 cells, neutrophils, and macrophages). However, not all colonizations result in pneumonia—even in advanced human immunodeficiency virus (HIV) infection. While there is an innate immunity through alveolar macrophages and pulmonary surfactant, alveolar macrophage response is impaired in HIV when the CD4 count is low. Cell-mediated immunity is the main defense against progression to pneumonia with assistance from costimulatory molecules (such as CD28 and CD2) as well as B cells.

Laboratory diagnosis. P jirovecii cannot be grown in culture for clinical purposes, and it is extremely difficult to culture even in the research setting. Cytologic stains such as the Wright-Giemsa and methamine silver stains are the mainstay of laboratory diagnosis. The yield for P jirovecii from routine expectorated sputum is very low and some laboratories discourage this approach. The sensitivity of nebulized sputum using hypertonic saline ranges from 50% to 90%.⁹

In patients with acquired immune deficiency syndrome (AIDS), bronchoscopy provides 90% to 98% sensitivity by BAL. Transbronchial biopsy may provide some additional yield over BAL in a few situations, such as patients who have been receiving partial P jirovecii prophylaxis. Immunofluorescence techniques using monoclonal antibodies to P jirovecii are commercially available and are first-line diagnostic tools in some laboratories. Recently, polymerase chain reaction (PCR) assay has been introduced into clinical practice as a reproducible test with high sensitivity.

Primary therapy. Primary therapy for PCP consists of trimethoprim-sulfamethoxazole (TMP-SMX) or pentamidine. TMP-SMX is considered the drug of choice and is usually administered intravenously for 21 days in HIV patients and 14 days for non-HIV patients. The oral form may be used in patients with less severe PCP with a functioning gastrointestinal tract. Common adverse reactions to TMP-SMX include rash, Stevens-Johnson syndrome, neutropenia, changes in pulmonary function, and nausea/vomiting/diarrhea.¹⁰ Pentamidine is as effective as TMP-SMX, but is associated with renal toxicity, hypotension, severe hypoglycemia, cardiac arrhythmias, and diabetes.¹¹ It is generally reserved for severe cases of PCP in patients who are allergic to or otherwise intolerant of sulfa. Other treatments include atovaquone and trimethoprim-dapsone. Adjunctive corticosteroids have been shown to be beneficial in moderate to severe PCP in HIV patients to reduce the local host inflammatory response to dead or dying organisms. Recent guidelines have recommended corticosteroids for HIV patients with PCP who have an arterial oxygen pressure of 70 mm Hg or less on room air, or an alveolar-arterial (A-a) gradient of oxygen 35 mm Hg or greater.¹² Little is known about the role of adjunctive corticosteroids in non-HIV patients, given a lack of clinical studies.

Prevention. Recent estimates of disease burden from a meta-analysis of 11,900 patients with connective tissue diseases found PCP in 12% of patients with GPA, in 6% of those with polydermatomyositis, in 5% of those with SLE, and in 1% of those with RA.¹ Mortality due to PCP is higher in patients with rheumatic diseases, ranging from 30% in RA to 63% in GPA, than in those with HIV (10% to 20%).¹³ One key risk factor predisposing patients with connective tissue diseases to infection with P jirovecii is recent corticosteroid use. Among patients with connective tissue disease, more than 90% of those infected with P jirovecii have recently received steroid therapy.¹⁴ Additionally, in almost all patients with P jirovecii, lymphopenia with absolute lymphocyte counts less than 1,000/mm³ is present.¹⁵

In patients with HIV, prophylaxis is initiated at a CD4 level of 200/mm³.¹³ However, the cutoff is less clear for non-HIV rheumatic patients. A cutoff of less than 300 cells/mm³ has been proposed for prophylaxis of PCP. However, at that range, approximately 50% of patients with connective tissue disease would remain above the threshold.¹³ One possible solution is to screen by PCR and treat colonization. Other algorithms have been proposed, but there is no general consensus on treatment of non-HIV rheumatic patients.^13,16 Generally, prophylaxis should be considered in patients at the highest risk for PCP. These include patients taking prednisone at doses greater than 20 mg/day for 1 month plus a cytotoxic agent, a TNF inhibitor plus glucocorticoids, and methotrexate plus glucocorticoids in GPA.¹³

Nocardia asteroides and Nocardia species

Classically, Nocardia infection results in abscess formation with infiltrates of polymorphonuclear cells, debris, and thin-walled abscesses. The most frequent site of primary infection is pulmonary. Characteristically, multiple pulmonary nodules or cavities are seen, and Nocardia should be considered in the differential diagnosis of an immunocompromised patient with nodular pneumonia. The nodules can also be masslike in appearance (greater than 2 cm). The presentation of new cavitary lung opacities with systemic symptoms may be mistaken for GPA.²²Nocardia may disseminate to the central nervous system (CNS), skin, joints, and spine, usually causing suppurative infection at these sites. Nocardia has a very strong tropism for neural tissue. In the CNS, Nocardia can cause single or multiple brain abscesses that may be asymptomatic; patients with pulmonary nocardiosis require imaging to rule out occult CNS involvement.

Nocardia species are resistant to several antibiotics. The treatment of choice for Nocardia species is TMPSMX, but imipenem, amikacin, third-generation cephalosporins, and other options such as minocycline and linezolid may be considered depending on the species and the antimicrobial susceptibility pattern.

Histoplasma capsulatum

Histoplasma capsulatum is a dimorphic fungus that causes disease in both healthy and immunocompromised hosts. The organism differs from other pathogenic fungi in that it is an intracellular organism, mainly involving the reticuloendothelial system, and is rarely in the extracellular space. In the United States, infections are clustered endemically in areas such as the Mississippi and Ohio River Valleys, but infections are common worldwide. The fungus is found in soil, mulch, bird excrement, and bat guano. Asymptomatic or mild infections are common in healthy persons residing in endemic areas and occur on a sporadic basis. Epidemics can occur when contaminated material is aerosolized. Histoplasmosis is also an opportunistic infection in patients with impaired T-cell immunity such as persons with AIDS, organ transplant recipients, hematologic malignancies, and corticosteroid use. Clinically significant cases of histoplasmosis have been described in patients with RA while receiving methotrexate alone, corticosteroids alone, and combinations of disease-modifying agents.²³ Histoplasmosis was recently identified in 240 patients in association with TNF inhibitors, translating to 17 per 100,000 patients treated with infliximab.^21,24

Pathogenesis. Infection initially occurs through inhalation of contaminated material from the environment, primarily causing pulmonary infection. The organism converts from a mold form in the environment to a pathogenic yeast form in the host. Once inhaled, the mediastinal lymph nodes provide the first line of defense. Following draining of the lymph nodes, the organism enters the bloodstream in both immunocompetent and immunosuppressed patients. It is spread hematogenously into the spleen, liver, and reticulo-endothelial system, where it is eventually cleared. In immunocompetent patients, cellular immunity limits infection within 7 to 14 days and humoral immunity is not protective.²⁵ Granuloma formation is the hallmark of host defense.

Spectrum of illness. Histoplasmosis is associated with a wide spectrum of illness, with presentation ranging from asymptomatic to mild pulmonary illness to overwhelming pneumonia. Symptomatic pulmonary histoplasmosis typically presents with fever, flulike symptoms, and cough, often with retrosternal chest pain. X-rays show patchy or nodular infiltrates, with hilar or mediastinal lymphadenopathy. In some cases the lung parenchyma is clear and the main feature is fever and bilateral hilar adenopathy. Pulmonary histoplasmosis may be difficult to distinguish from sarcoidosis and tuberculosis. Extrapulmonary disease can present as hepatitis, infective endocarditis, and chronic meningitis. In immunocompromised patients, histoplasmosis can present as a progressive disseminated disease which can be acute, subacute, or chronic. Chronic disseminated histoplasmosis is characterized by cough, persistent fever, wasting, hepatosplenomegaly, oral ulcerations, and progressive cytopenias. Acute disseminated histoplasmosis has a much more fulminant course characterized by respiratory insufficiency, hypotension, multisystem organ failure, coagulopathies, and encephalopathy. Histoplasmosis is primarily a pulmonary disease, but in disseminated disease more than 50% of patients have no pulmonary symptoms and 30% may have normal chest x-rays.²⁶ In one series of infliximab-related cases (n = 10), all came from an endemic area 1 week to 6 months after the first dose of infliximab. Patients presented with cough, fever, and shortness of breath.²⁷ The pathogenesis of histoplasmosis in patients receiving TNF inhibitors is not entirely clear; such patients may be suffering a new primary infection, a reinfection, or, least likely, reactivation of latent infection.

Definitive diagnosis requires culture confirmation from appropriate body fluids or identification of characteristic yeast forms from histopathologic sections of tissue biopsies. Serologic tests may also be used to confirm the diagnosis. Detection of H and M precipitins or bands by immunodiffusion is a routine test in many laboratories. M bands are present in 50% of acute cases but their presence does not distinguish acute from remote infection. H bands are present in only 10% of all acute cases, but their presence is very specific for acute histoplasmosis.²⁸

When looking at complement fixation antibodies to yeast (HY) and mycelial (HMy) forms in pulmonary histoplasmosis, a fourfold rise in titer establishes the diagnosis retrospectively, and a single titer greater than 1:32 is strongly suggestive of active infection. However, in progressive disseminated histoplasmosis, the complement fixation antibodies are frequently negative.²⁹ Detection of antigen in urine and serum by enzyme immunoassay has become a mainstay of diagnosis, with a sensitivity of approximately 90% in progressive disseminated disease.³⁰ Of note, most cases of histoplasmosis associated with biologic agents have detectable urinary antigen tests.

Treatment. Acute pulmonary histoplasmosis is usually self-limited, requiring no treatment. The 2007 Infective Diseases Society of America (IDSA) guidelines recommend observation alone in most cases of mild to moderate pulmonary histoplasmosis unless symptoms persist longer than 1 month. For moderately severe or severe acute pulmonary histoplasmosis, the IDSA recommends lipid formulations of amphotericin B (3.0 to 5.0 mg/kg/day) or deosycholate amphotericin B (0.7 to 1.0 mg/kg/day) for 1 to 2 weeks followed by itraconazole 200 mg twice daily for a total of 12 weeks. Methylprednisolone at a dose of 0.5 to 1.0 mg/kg/day intravenously for 1 to 2 weeks is also recommended. For moderately severe to severe disseminated histoplasmosis, the IDSA recommends lipid formulations of amphotericin B (3.0 mg/kg/day) for 1 to 2 weeks followed by oral itraconazole 200 mg three times daily for 3 days and then 200 mg twice daily for a total of at least 12 months.³¹ Commonly, the immunosuppressive agent is held during treatment.

Another emerging pathogen is Aspergillus species—a ubiquitous mold spread by aerosols of spores. There are many different species of Aspergillus, but the most common human pathogens include A fumigates, A niger, and A flavus. To date, 39 cases of Aspergillus infection associated with infliximab and etanercept have been reported in the Adverse Event Reporting System, translating to 9 to 12 cases per 100,000 patients.²¹

Varicella zoster

JC virus

More than 80% of adults are seropositive for JCV, a DNA virus of the genus Polyomavirus that causes lytic infection of oligodendrocytes.³⁴ In immunocompromised hosts, JCV causes progressive multifocal leukoencephalopathy (PML), a rare but devastating demyelinating disease. PML was first described in malignancy, leukemia, and various other immunocompromised states, prior to its strong association with AIDS in the 1980s. More recently, JCV has been associated with natalizumab for multiple sclerosis and Crohn disease, rituximab for oncology patients, efalizumab for psoriasis,³⁵ and mycophenolate mofetil for transplant recipients.³⁶

In 2006 the US Food and Drug Administration issued a safety alert regarding PML in two patients with SLE treated with rituximab and other immunosuppressives.³⁷ In a review of PML in rheumatic disease, 36 cases were identified in patients who had not previously received a biologic agent. Most of these patients (60%) had SLE.³⁸ Of these, many had little or no immunosuppression over the 6 months prior to the diagnosis of PML, suggesting that SLE itself may predispose to PML. Interestingly, PML is rarely associated with TNF inhibitors.

Classic presentation of PML includes motor weakness, aphasia, dysarthria, vision loss, and cognitive loss. Atypical presentation includes seizures, headaches, and brainstem involvement. PML usually spares the optic nerves, spinal cord, peripheral nerves, and muscles. In persons with underlying rheumatic diseases, PML can be difficult to distinguish from neuropsychiatric SLE or CNS vasculitis.

Treatment. In clinical trials no antiviral agent has been effective in the treatment of PML. In HIV patients who develop PML, highly active antiretroviral therapy should be initiated (if antiretroviral-naïve) or existing antiviral regimens optimized. Antiretroviral therapy in this situation may stabilize disease and possibly increase survival.⁴² For HIV-negative patients who develop PML, the cornerstone of management is immediate decrease or discontinuation of immunosuppression.⁴³ Several adjunctive measures have been reported mainly in natalizumab-associated PML, including corticosteroids, mirtazapine, plasma exchange, and others.

VACCINES

Vaccination is important in the prevention of infectious disease in immunocompromised patients with connective tissue diseases. Because live vaccines are contraindicated in immunocompromised patients, inactivated or component vaccines should be used. It is recommended that patients who will start immunosuppressive therapy be vaccinated 2 to 4 weeks before beginning therapy. If this is not possible, vaccination should be administered during disease remission, 3 months after immunosuppression and 1 to 3 months after administration of high-dose corticosteroids.

• Short-term (less than 14 days)
• At a dose of less than 20 mg/day of prednisone or equivalent
• Long-term on alternate days with short-acting preparations
• At a physiologic dose of prednisone
• Topical, inhaled, intra-articular, bursal, or via tendon.⁴⁴

Until definitive guidelines are developed, practitioners must evaluate and treat each patient individually to maximize the efficacy of disease treatments while preventing infection morbidity and mortality in their patients with connective tissue diseases.

In 2007, Falagas et al¹ provided a systematic review of studies focusing on infection-related morbidity and mortality in patients with connective tissue diseases. Many of the studies reviewed were published prior to the introduction of biologic agents for the treatment of rheumatologic disorders. In 39 studies focusing on infection incidence, patient outcomes, or both in patients with systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), polymyositis/dermatomyositis, granulomatosis with polyangiitis (GPA, [Wegener’s granulomatosis]), and systemic sclerosis, serious infection developed in 29% of patients and 24% of these died due to the infection with a median attributable mortality of 5.2%. Most of the reported infections were common bacterial syndromes such as pneumonia or bacteremia, and opportunistic fungal (Pneumocystis) infections.

Similarly, in 2006 Alarcón² reported that 25% to 50% of patients with SLE had significant morbidity primarily from common bacterial infections, with viral, fungal, and parasitic infection less common. Staphylococcus aureus was a common cause of soft tissue infection, septic arthritis, and bacteremia. Streptococcus pneumoniae typically caused respiratory infections, although meningitis and sepsis were reported with SLE. Gram-negative bacteria such as Escherichia coli, Klebsiella species, and Pseudomonas species usually caused urinary tract infections and nosocomial pneumonia. Other bacterial infections included Nocardia species, Mycobacterium tuberculosis, and, rarely, Listeria monocytogenes. The most common viral infection was herpes zoster. Fungal infections included Pneumocystis jirovecii (formerly known as Pneumocystis carinii) and Candida species.

In scleroderma, another connective tissue disease evaluated in the literature by Alarcón,² reports of bacterial, viral, and fungal infections are limited to case reports. In scleroderma patients, viral infections with cytomegalovirus (CMV), parvovirus B19, and P jirovecii were similar to pathogens observed with SLE.

In polymyositis/dermatomyositis, gram-positive pneumonia affected 15% to 20% of patients and S aureus occurred frequently in the juvenile form of the disease. Herpes zoster was commonly observed, but CMV was relatively rare. Other viral infections included Coxsackie virus, parvovirus B19, and hepatitis C in polymyositis/dermatomyositis. Infection with P jirovecii is frequently fatal in these patients. Other fungal infections seen in polymyositis/dermatomyositis include candidiasis and histoplasmosis.²

Since the approval of antitumor necrosis factor (anti-TNF) agents for RA in the late 1990s, as well as other more recent biologic agents, there has been heightened awareness of infectious complications in rheumatologic patients. A major concern with the anti-TNF agents is the risk of granulomatous infection, particularly mycobacterial disease and dimorphic fungal infections such as histoplasmosis and coccidioidomycosis. Formation of granulomas is the major host defense against mycobacterial infection and is mediated in large part by TNF-alpha. The precise risk of infection associated with each of the various biologic agents is still under study, and rates from randomized trials have differed from postmarketing surveillance studies. Important pathogens associated with biologic agents include Nocardia, CMV, Listeria, Aspergillus, and JC virus (JCV).^3,4 Delays in the diagnosis of these infections in immunocompromised patients have led to poor outcomes.

KEY PATHOGENS IN INFECTIONS OF IMMUNOCOMPROMISED HOSTS

Pneumocystis jirovecii

For many decades, P jirovecii was classified as a protozoan but, based on gene sequencing, the organism has been reclassified as a fungus. P jirovecii is a low-virulence, unicellular organism that is the causative agent of Pneumocystis pneumonia (PCP). Epidemiologically, primary infection most likely occurs in infants and children. Colonization may be transient, entering the airways and then resolving over a period of weeks or months. Alternatively, the organism may enter a latent state similar to tuberculosis with reactivation occurring during times of intense immunosuppression. However, molecular epidemiology studies show that new cases of PCP are likely environmentally acquired through multiple exposures rather than reactivation of latent infection.^5,6 Transmission is thought to be airborne from person to person. Pathogenically, the trophic form of the organism attaches to type 1 alveolar cells and remains in the extracellular compartment of the alveoli. This colonization evokes an influx of inflammatory cells (CD8 cells, neutrophils, and macrophages). However, not all colonizations result in pneumonia—even in advanced human immunodeficiency virus (HIV) infection. While there is an innate immunity through alveolar macrophages and pulmonary surfactant, alveolar macrophage response is impaired in HIV when the CD4 count is low. Cell-mediated immunity is the main defense against progression to pneumonia with assistance from costimulatory molecules (such as CD28 and CD2) as well as B cells.

Laboratory diagnosis. P jirovecii cannot be grown in culture for clinical purposes, and it is extremely difficult to culture even in the research setting. Cytologic stains such as the Wright-Giemsa and methamine silver stains are the mainstay of laboratory diagnosis. The yield for P jirovecii from routine expectorated sputum is very low and some laboratories discourage this approach. The sensitivity of nebulized sputum using hypertonic saline ranges from 50% to 90%.⁹

In patients with acquired immune deficiency syndrome (AIDS), bronchoscopy provides 90% to 98% sensitivity by BAL. Transbronchial biopsy may provide some additional yield over BAL in a few situations, such as patients who have been receiving partial P jirovecii prophylaxis. Immunofluorescence techniques using monoclonal antibodies to P jirovecii are commercially available and are first-line diagnostic tools in some laboratories. Recently, polymerase chain reaction (PCR) assay has been introduced into clinical practice as a reproducible test with high sensitivity.

Primary therapy. Primary therapy for PCP consists of trimethoprim-sulfamethoxazole (TMP-SMX) or pentamidine. TMP-SMX is considered the drug of choice and is usually administered intravenously for 21 days in HIV patients and 14 days for non-HIV patients. The oral form may be used in patients with less severe PCP with a functioning gastrointestinal tract. Common adverse reactions to TMP-SMX include rash, Stevens-Johnson syndrome, neutropenia, changes in pulmonary function, and nausea/vomiting/diarrhea.¹⁰ Pentamidine is as effective as TMP-SMX, but is associated with renal toxicity, hypotension, severe hypoglycemia, cardiac arrhythmias, and diabetes.¹¹ It is generally reserved for severe cases of PCP in patients who are allergic to or otherwise intolerant of sulfa. Other treatments include atovaquone and trimethoprim-dapsone. Adjunctive corticosteroids have been shown to be beneficial in moderate to severe PCP in HIV patients to reduce the local host inflammatory response to dead or dying organisms. Recent guidelines have recommended corticosteroids for HIV patients with PCP who have an arterial oxygen pressure of 70 mm Hg or less on room air, or an alveolar-arterial (A-a) gradient of oxygen 35 mm Hg or greater.¹² Little is known about the role of adjunctive corticosteroids in non-HIV patients, given a lack of clinical studies.

Prevention. Recent estimates of disease burden from a meta-analysis of 11,900 patients with connective tissue diseases found PCP in 12% of patients with GPA, in 6% of those with polydermatomyositis, in 5% of those with SLE, and in 1% of those with RA.¹ Mortality due to PCP is higher in patients with rheumatic diseases, ranging from 30% in RA to 63% in GPA, than in those with HIV (10% to 20%).¹³ One key risk factor predisposing patients with connective tissue diseases to infection with P jirovecii is recent corticosteroid use. Among patients with connective tissue disease, more than 90% of those infected with P jirovecii have recently received steroid therapy.¹⁴ Additionally, in almost all patients with P jirovecii, lymphopenia with absolute lymphocyte counts less than 1,000/mm³ is present.¹⁵

In patients with HIV, prophylaxis is initiated at a CD4 level of 200/mm³.¹³ However, the cutoff is less clear for non-HIV rheumatic patients. A cutoff of less than 300 cells/mm³ has been proposed for prophylaxis of PCP. However, at that range, approximately 50% of patients with connective tissue disease would remain above the threshold.¹³ One possible solution is to screen by PCR and treat colonization. Other algorithms have been proposed, but there is no general consensus on treatment of non-HIV rheumatic patients.^13,16 Generally, prophylaxis should be considered in patients at the highest risk for PCP. These include patients taking prednisone at doses greater than 20 mg/day for 1 month plus a cytotoxic agent, a TNF inhibitor plus glucocorticoids, and methotrexate plus glucocorticoids in GPA.¹³

Nocardia asteroides and Nocardia species

Classically, Nocardia infection results in abscess formation with infiltrates of polymorphonuclear cells, debris, and thin-walled abscesses. The most frequent site of primary infection is pulmonary. Characteristically, multiple pulmonary nodules or cavities are seen, and Nocardia should be considered in the differential diagnosis of an immunocompromised patient with nodular pneumonia. The nodules can also be masslike in appearance (greater than 2 cm). The presentation of new cavitary lung opacities with systemic symptoms may be mistaken for GPA.²²Nocardia may disseminate to the central nervous system (CNS), skin, joints, and spine, usually causing suppurative infection at these sites. Nocardia has a very strong tropism for neural tissue. In the CNS, Nocardia can cause single or multiple brain abscesses that may be asymptomatic; patients with pulmonary nocardiosis require imaging to rule out occult CNS involvement.

Nocardia species are resistant to several antibiotics. The treatment of choice for Nocardia species is TMPSMX, but imipenem, amikacin, third-generation cephalosporins, and other options such as minocycline and linezolid may be considered depending on the species and the antimicrobial susceptibility pattern.

Histoplasma capsulatum

Histoplasma capsulatum is a dimorphic fungus that causes disease in both healthy and immunocompromised hosts. The organism differs from other pathogenic fungi in that it is an intracellular organism, mainly involving the reticuloendothelial system, and is rarely in the extracellular space. In the United States, infections are clustered endemically in areas such as the Mississippi and Ohio River Valleys, but infections are common worldwide. The fungus is found in soil, mulch, bird excrement, and bat guano. Asymptomatic or mild infections are common in healthy persons residing in endemic areas and occur on a sporadic basis. Epidemics can occur when contaminated material is aerosolized. Histoplasmosis is also an opportunistic infection in patients with impaired T-cell immunity such as persons with AIDS, organ transplant recipients, hematologic malignancies, and corticosteroid use. Clinically significant cases of histoplasmosis have been described in patients with RA while receiving methotrexate alone, corticosteroids alone, and combinations of disease-modifying agents.²³ Histoplasmosis was recently identified in 240 patients in association with TNF inhibitors, translating to 17 per 100,000 patients treated with infliximab.^21,24

Pathogenesis. Infection initially occurs through inhalation of contaminated material from the environment, primarily causing pulmonary infection. The organism converts from a mold form in the environment to a pathogenic yeast form in the host. Once inhaled, the mediastinal lymph nodes provide the first line of defense. Following draining of the lymph nodes, the organism enters the bloodstream in both immunocompetent and immunosuppressed patients. It is spread hematogenously into the spleen, liver, and reticulo-endothelial system, where it is eventually cleared. In immunocompetent patients, cellular immunity limits infection within 7 to 14 days and humoral immunity is not protective.²⁵ Granuloma formation is the hallmark of host defense.

Spectrum of illness. Histoplasmosis is associated with a wide spectrum of illness, with presentation ranging from asymptomatic to mild pulmonary illness to overwhelming pneumonia. Symptomatic pulmonary histoplasmosis typically presents with fever, flulike symptoms, and cough, often with retrosternal chest pain. X-rays show patchy or nodular infiltrates, with hilar or mediastinal lymphadenopathy. In some cases the lung parenchyma is clear and the main feature is fever and bilateral hilar adenopathy. Pulmonary histoplasmosis may be difficult to distinguish from sarcoidosis and tuberculosis. Extrapulmonary disease can present as hepatitis, infective endocarditis, and chronic meningitis. In immunocompromised patients, histoplasmosis can present as a progressive disseminated disease which can be acute, subacute, or chronic. Chronic disseminated histoplasmosis is characterized by cough, persistent fever, wasting, hepatosplenomegaly, oral ulcerations, and progressive cytopenias. Acute disseminated histoplasmosis has a much more fulminant course characterized by respiratory insufficiency, hypotension, multisystem organ failure, coagulopathies, and encephalopathy. Histoplasmosis is primarily a pulmonary disease, but in disseminated disease more than 50% of patients have no pulmonary symptoms and 30% may have normal chest x-rays.²⁶ In one series of infliximab-related cases (n = 10), all came from an endemic area 1 week to 6 months after the first dose of infliximab. Patients presented with cough, fever, and shortness of breath.²⁷ The pathogenesis of histoplasmosis in patients receiving TNF inhibitors is not entirely clear; such patients may be suffering a new primary infection, a reinfection, or, least likely, reactivation of latent infection.

Definitive diagnosis requires culture confirmation from appropriate body fluids or identification of characteristic yeast forms from histopathologic sections of tissue biopsies. Serologic tests may also be used to confirm the diagnosis. Detection of H and M precipitins or bands by immunodiffusion is a routine test in many laboratories. M bands are present in 50% of acute cases but their presence does not distinguish acute from remote infection. H bands are present in only 10% of all acute cases, but their presence is very specific for acute histoplasmosis.²⁸

When looking at complement fixation antibodies to yeast (HY) and mycelial (HMy) forms in pulmonary histoplasmosis, a fourfold rise in titer establishes the diagnosis retrospectively, and a single titer greater than 1:32 is strongly suggestive of active infection. However, in progressive disseminated histoplasmosis, the complement fixation antibodies are frequently negative.²⁹ Detection of antigen in urine and serum by enzyme immunoassay has become a mainstay of diagnosis, with a sensitivity of approximately 90% in progressive disseminated disease.³⁰ Of note, most cases of histoplasmosis associated with biologic agents have detectable urinary antigen tests.

Treatment. Acute pulmonary histoplasmosis is usually self-limited, requiring no treatment. The 2007 Infective Diseases Society of America (IDSA) guidelines recommend observation alone in most cases of mild to moderate pulmonary histoplasmosis unless symptoms persist longer than 1 month. For moderately severe or severe acute pulmonary histoplasmosis, the IDSA recommends lipid formulations of amphotericin B (3.0 to 5.0 mg/kg/day) or deosycholate amphotericin B (0.7 to 1.0 mg/kg/day) for 1 to 2 weeks followed by itraconazole 200 mg twice daily for a total of 12 weeks. Methylprednisolone at a dose of 0.5 to 1.0 mg/kg/day intravenously for 1 to 2 weeks is also recommended. For moderately severe to severe disseminated histoplasmosis, the IDSA recommends lipid formulations of amphotericin B (3.0 mg/kg/day) for 1 to 2 weeks followed by oral itraconazole 200 mg three times daily for 3 days and then 200 mg twice daily for a total of at least 12 months.³¹ Commonly, the immunosuppressive agent is held during treatment.

Another emerging pathogen is Aspergillus species—a ubiquitous mold spread by aerosols of spores. There are many different species of Aspergillus, but the most common human pathogens include A fumigates, A niger, and A flavus. To date, 39 cases of Aspergillus infection associated with infliximab and etanercept have been reported in the Adverse Event Reporting System, translating to 9 to 12 cases per 100,000 patients.²¹

Varicella zoster

JC virus

More than 80% of adults are seropositive for JCV, a DNA virus of the genus Polyomavirus that causes lytic infection of oligodendrocytes.³⁴ In immunocompromised hosts, JCV causes progressive multifocal leukoencephalopathy (PML), a rare but devastating demyelinating disease. PML was first described in malignancy, leukemia, and various other immunocompromised states, prior to its strong association with AIDS in the 1980s. More recently, JCV has been associated with natalizumab for multiple sclerosis and Crohn disease, rituximab for oncology patients, efalizumab for psoriasis,³⁵ and mycophenolate mofetil for transplant recipients.³⁶

In 2006 the US Food and Drug Administration issued a safety alert regarding PML in two patients with SLE treated with rituximab and other immunosuppressives.³⁷ In a review of PML in rheumatic disease, 36 cases were identified in patients who had not previously received a biologic agent. Most of these patients (60%) had SLE.³⁸ Of these, many had little or no immunosuppression over the 6 months prior to the diagnosis of PML, suggesting that SLE itself may predispose to PML. Interestingly, PML is rarely associated with TNF inhibitors.

Classic presentation of PML includes motor weakness, aphasia, dysarthria, vision loss, and cognitive loss. Atypical presentation includes seizures, headaches, and brainstem involvement. PML usually spares the optic nerves, spinal cord, peripheral nerves, and muscles. In persons with underlying rheumatic diseases, PML can be difficult to distinguish from neuropsychiatric SLE or CNS vasculitis.

Treatment. In clinical trials no antiviral agent has been effective in the treatment of PML. In HIV patients who develop PML, highly active antiretroviral therapy should be initiated (if antiretroviral-naïve) or existing antiviral regimens optimized. Antiretroviral therapy in this situation may stabilize disease and possibly increase survival.⁴² For HIV-negative patients who develop PML, the cornerstone of management is immediate decrease or discontinuation of immunosuppression.⁴³ Several adjunctive measures have been reported mainly in natalizumab-associated PML, including corticosteroids, mirtazapine, plasma exchange, and others.

VACCINES

Vaccination is important in the prevention of infectious disease in immunocompromised patients with connective tissue diseases. Because live vaccines are contraindicated in immunocompromised patients, inactivated or component vaccines should be used. It is recommended that patients who will start immunosuppressive therapy be vaccinated 2 to 4 weeks before beginning therapy. If this is not possible, vaccination should be administered during disease remission, 3 months after immunosuppression and 1 to 3 months after administration of high-dose corticosteroids.

• Short-term (less than 14 days)
• At a dose of less than 20 mg/day of prednisone or equivalent
• Long-term on alternate days with short-acting preparations
• At a physiologic dose of prednisone
• Topical, inhaled, intra-articular, bursal, or via tendon.⁴⁴

Until definitive guidelines are developed, practitioners must evaluate and treat each patient individually to maximize the efficacy of disease treatments while preventing infection morbidity and mortality in their patients with connective tissue diseases.

In 1958, shortly after the first descriptions of granulomatosis with polyangiitis, or GPA (Wegener’s granulomatosis), the 1-year mortality was 18%,¹ mainly due to renal failure. Physicians tried to combat the disease using various immunosuppressive drugs (nitrogen mustard and, in later years, azathioprine and methotrexate), but measurable success came only after investigators introduced cyclophosphamide (CYC) in combination with the glucocorticoid prednisone.²

A key 1992 study showed that the CYC/prednisone combination markedly improved the disease status in 91% of patients,³ with 75% achieving complete remission. The treatment came at a price, however, with almost all patients suffering serious morbidity or side effects. The results also highlighted concerns about potential malignancies caused by prolonged use of CYC and glucocorticoids. Those concerns motivated the European Vasculitis Study Group in the late 1980s and early 1990s to design and validate testing for antineutrophil cytoplasmic antibody (ANCA)–associated vasculitides (AAV) and pursue consensus regarding treatment.⁴

ALTERNATIVES TO STANDARD THERAPY

The accepted therapeutic strategy for GPA is to first induce remission using high doses of CYC and then prevent relapse with longer-term, less toxic therapeutic alternatives. These less toxic therapies include newer agents as well as new methods of delivery, particularly for patients with nonsevere forms of disease.

Methotrexate—effective for early treatment

Methotrexate showed early promise in several nonrandomized trials of patients with nonsevere disease. In one such study, de Groot et al subclassified 100 patients at diagnosis according to the extent and severity of the disease.⁵ Patients were then randomized to receive either standard oral CYC or methotrexate, each combined with prednisolone. Remission rates (90% to 94%) were comparable regardless of whether patients received CYC or methotrexate, although patients with more severe disease who were taking methotrexate took longer to achieve remission. At the same time, relapse rates were higher for methotrexate-taking patients (70%) compared with the CYC group (47%). Thus, while methotrexate could replace CYC for initial treatment of early AAV, CYC had a greater influence on subsequent relapse rates, particularly in patients with more severe forms of disease.

Pulse cyclophosphamide—a new method

Investigators tested pulse delivery of CYC compared with oral daily administration as a means of reducing the CYC dose. An analysis of 14 relatively small studies showed that pulse CYC had the same survival and renal failure rates as continuous therapy.⁶

One such trial, the CYC Daily Oral Versus Pulsed (CYCLOPS) trial, involved 149 patients with generalized disease (nephritis, GPA, and microscopic polyangiitis [MPA]) who were administered either an intravenous (IV) pulse or a daily oral CYC regimen.⁷ The pulse CYC neither shortened patients’ time to remission nor increased the proportion of patients who achieved it. Patients receiving pulse CYC suffered one-third the rate of leukopenia experienced by patients who received the oral regimen. Since infection is a source of mortality in vasculitis, this finding is an important consideration when balancing the benefits of day-to-day control offered by oral administration against the safety of at-risk patients such as the elderly.

This treatment strategy may be relevant for patients with renal impairment. It was once thought that patients with renal failure after receiving CYC had more aggressive disease and therefore needed higher dosages. Investigators who studied the impact of renal insufficiency and hemodialysis on the pharmacokinetics of CYC found that clearance of CYC is impaired in patients with reduced renal function.⁸ Thus, when renal function is suppressed, the CYC dosage should be reduced rather than increased.

Mycophenolate mofetil—efficacy not yet confirmed

Another alternative to CYC, mycophenolate mofetil (MMF), has gained much attention, although its effectiveness is not yet certain. Pilot data show that 13 of 17 patients with MPA achieved remission after 6 months of treatment with MMF.⁹ Meanwhile, the so-called MYCYC trial, in which patients with newly diagnosed AAV receive either the CYCLOPS regimen or MMF, is under way.¹⁰

Deoxyspergualin—remission not sustained

A nonstandard drug that warrants attention is deoxyspergualin (now called gusperimus), licensed in Japan for 15 years. In a prospective, open-label trial of 45 patients with relapsing or refractory GPA, investigators showed that 95% achieved partial remission and 45% full remission, although remission was not sustained when therapy was stopped.¹¹ Because the drug must be administered daily for 21 days by subcutaneous injection, deoxyspergualin is not easy to use. It may represent an alternative, however, because it permitted prednisolone dosage reduction.

EVALUATING RISK AND CHOOSING THERAPIES

CONSIDERATIONS IN CHOOSING REMISSION THERAPY

Overall, when planning remission therapy and its duration, clinicians must balance the efficacy of CYC and glucocorticoids against their toxicity. Close monitoring and the patient’s capacity to adhere to instructions are two critical issues. Other important considerations include the risk and consequences of relapse, which vary in different circumstances, and the association of cancer with CYC therapy.

Relapse risk is variable

Certain patients are at higher risk of relapse than others. Patients with GPA or proteinase-3-ANCA–positive disease are at higher relapse risk than those who have MPA. ANCA-positive disease in remission or rising ANCA markers both increase the risk of relapse. Ear, nose, throat, and lung diseases increase the likelihood of relapse. Patients with GPA who are Staphylococcus aureus carriers have increased risk. Serum creatinine levels of 2.0 to 3.0 mg/dL at the end of induction therapy should arouse concern about renal relapse.

Most relapses affect the ear, nose, and throat system and do not threaten vital organs. Relapse does not increase the risk of end-stage renal disease or death.

Consider mortality and cancer data

Although the strongest predictor of early death is infection, advanced age and renal impairment also predict death. Chronic kidney disease stage at entry and glomerular filtration rate significantly predict mortality.²¹ More than 36 g CYC (equivalent to 9 to 12 months of standard oral therapy) increases the risk of bladder cancer 10-fold and myeloid leukemia 60-fold, but the cancer risk is time-dependent; malignancy requires 12 years on average to emerge.²²

CONCLUSION

Cyclophosphamide in combination with glucocorticoids remains the standard therapy for GPA and related vasculitides, despite the risk of significant treatment-related comorbidities. Several strategies can be employed to reduce exposure, such as sequential withdrawal of CYC and IV administration. The optimization of glucocorticoid dosing will be a major research focus in the next decade. Newer agents may improve the maintenance of remission; for example, azathioprine and methotrexate show equal efficacy and safety, while MMF is less effective. When planning remission maintenance therapy, the relapse risk should be considered carefully because it varies among clinical scenarios. Other factors in the decision include the consequences for the patient, monitoring requirements, and the patient’s ability to understand and adhere to instructions.

In 1958, shortly after the first descriptions of granulomatosis with polyangiitis, or GPA (Wegener’s granulomatosis), the 1-year mortality was 18%,¹ mainly due to renal failure. Physicians tried to combat the disease using various immunosuppressive drugs (nitrogen mustard and, in later years, azathioprine and methotrexate), but measurable success came only after investigators introduced cyclophosphamide (CYC) in combination with the glucocorticoid prednisone.²

A key 1992 study showed that the CYC/prednisone combination markedly improved the disease status in 91% of patients,³ with 75% achieving complete remission. The treatment came at a price, however, with almost all patients suffering serious morbidity or side effects. The results also highlighted concerns about potential malignancies caused by prolonged use of CYC and glucocorticoids. Those concerns motivated the European Vasculitis Study Group in the late 1980s and early 1990s to design and validate testing for antineutrophil cytoplasmic antibody (ANCA)–associated vasculitides (AAV) and pursue consensus regarding treatment.⁴

ALTERNATIVES TO STANDARD THERAPY

The accepted therapeutic strategy for GPA is to first induce remission using high doses of CYC and then prevent relapse with longer-term, less toxic therapeutic alternatives. These less toxic therapies include newer agents as well as new methods of delivery, particularly for patients with nonsevere forms of disease.

Methotrexate—effective for early treatment

Methotrexate showed early promise in several nonrandomized trials of patients with nonsevere disease. In one such study, de Groot et al subclassified 100 patients at diagnosis according to the extent and severity of the disease.⁵ Patients were then randomized to receive either standard oral CYC or methotrexate, each combined with prednisolone. Remission rates (90% to 94%) were comparable regardless of whether patients received CYC or methotrexate, although patients with more severe disease who were taking methotrexate took longer to achieve remission. At the same time, relapse rates were higher for methotrexate-taking patients (70%) compared with the CYC group (47%). Thus, while methotrexate could replace CYC for initial treatment of early AAV, CYC had a greater influence on subsequent relapse rates, particularly in patients with more severe forms of disease.

Pulse cyclophosphamide—a new method

Investigators tested pulse delivery of CYC compared with oral daily administration as a means of reducing the CYC dose. An analysis of 14 relatively small studies showed that pulse CYC had the same survival and renal failure rates as continuous therapy.⁶

One such trial, the CYC Daily Oral Versus Pulsed (CYCLOPS) trial, involved 149 patients with generalized disease (nephritis, GPA, and microscopic polyangiitis [MPA]) who were administered either an intravenous (IV) pulse or a daily oral CYC regimen.⁷ The pulse CYC neither shortened patients’ time to remission nor increased the proportion of patients who achieved it. Patients receiving pulse CYC suffered one-third the rate of leukopenia experienced by patients who received the oral regimen. Since infection is a source of mortality in vasculitis, this finding is an important consideration when balancing the benefits of day-to-day control offered by oral administration against the safety of at-risk patients such as the elderly.

This treatment strategy may be relevant for patients with renal impairment. It was once thought that patients with renal failure after receiving CYC had more aggressive disease and therefore needed higher dosages. Investigators who studied the impact of renal insufficiency and hemodialysis on the pharmacokinetics of CYC found that clearance of CYC is impaired in patients with reduced renal function.⁸ Thus, when renal function is suppressed, the CYC dosage should be reduced rather than increased.

Mycophenolate mofetil—efficacy not yet confirmed

Another alternative to CYC, mycophenolate mofetil (MMF), has gained much attention, although its effectiveness is not yet certain. Pilot data show that 13 of 17 patients with MPA achieved remission after 6 months of treatment with MMF.⁹ Meanwhile, the so-called MYCYC trial, in which patients with newly diagnosed AAV receive either the CYCLOPS regimen or MMF, is under way.¹⁰

Deoxyspergualin—remission not sustained

A nonstandard drug that warrants attention is deoxyspergualin (now called gusperimus), licensed in Japan for 15 years. In a prospective, open-label trial of 45 patients with relapsing or refractory GPA, investigators showed that 95% achieved partial remission and 45% full remission, although remission was not sustained when therapy was stopped.¹¹ Because the drug must be administered daily for 21 days by subcutaneous injection, deoxyspergualin is not easy to use. It may represent an alternative, however, because it permitted prednisolone dosage reduction.

EVALUATING RISK AND CHOOSING THERAPIES