Cleveland Clinic Journal of Medicine

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

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

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.

Granulomatosis with polyangiitis (GPA [Wegener’s granulomatosis]) is a vasculitis that affects the renal and respiratory systems. Remission can be induced in most patients with the combination of glucocorticoids and cyclophosphamide. Unfortunately, patients often suffer disease relapses requiring re-treatment and exposure to the cumulative toxicities of repeated cyclophosphamide use. In recent years, improved understanding of the mechanisms of action of cyclophosphamide has led to investigation of treatment strategies that target the role of B cells more specifically in the pathogenesis of the disease.

This article reviews the results of recent studies involving the use of biologic therapy in the treatment of GPA, with a brief examination of historic events that influenced the design of recent trials.

HISTORICAL PERSPECTIVE

The natural history of GPA was characterized in 1958¹ in a retrospective study showing that 50% of those afflicted died within 6 months, and 80% died by 18 months. Prednisone and cyclophosphamide changed this dismal outcome. The combination markedly improved the status of 91% to 93% of patients,^2,3 with most achieving complete remission. Treatment came with a price, however. Almost all patients suffered serious morbidity or side effects, including chronic renal insufficiency (11% requiring dialysis), recurrent infections, hearing loss, infertility, and diabetes. In addition, most patients (99 of 155 in one study) suffered relapse and a significant number (19 of 155) died because of the disease or its treatment.

Investigators’ pursuit of treatment alternatives included foregoing cyclophosphamide in patients who had limited or early systemic GPA and reducing the duration of treatment for patients with severe disease.⁴ Studies conducted in the late 1990s defined what eventually became standard therapy for GPA: remission induction with glucocorticoids and methotrexate for limited GPA and with glucocorticoids and cyclophosphamide for severe disease. Following remission induction, after 3 to 6 months cyclophosphamide is replaced by azathioprine or methotrexate for remission maintenance. While helpful, these alternatives still fell short of achieving safe, long-term remission.

THERAPY WITH BIOLOGICS

Targeting tumor necrosis factor

The first randomized placebo-controlled trial of a biologic agent in GPA, the Wegener’s Granulomatosis Etanercept Trial (WGET),⁴ evaluated whether etanercept, a soluble inhibitor of tumor necrosis factor (TNF), would be an effective adjunct to standard therapy. The results showed that etanercept did not confer any beneficial effect and, in fact, if combined with exposure to cyclophosphamide, etanercept increased the risk for solid tumors. Thus, anti-TNF therapy has a limited or no role in the management of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV).

Targeting B cells

The mechanisms of cyclophosphamide effects on disease activity were not clearly understood. In the late 1970s, however, National Institutes of Health investigators found that cyclophosphamide, at the doses administered for GPA, had a profound effect on B-cell function.⁵ Later investigations showed that disease activity of GPA was clearly related to the frequency of activated B cells detectable in the peripheral blood, while abnormally activated T cells were also detectable in patients in remission.⁶ These findings suggested that activated B cells might be responsible for disease activity, whereas persistently activated T cells might explain the chronically relapsing nature of the disease.⁶

B cells are the precursors of short-lived plasma cells, which are thought to be the primary source of autoantibodies, including ANCA. Based on clinical observations as well as in vitro and some animal model experiments, investigators have ascribed pathogenic roles to ANCA. Consequently, targeting the cells that produce these autoantibodies (short-lived plasma cells of B-cell origin) might form the basis of a novel treatment. Why not target cells of the B-cell lineage, thereby eliminating the short-lived plasma cells that would otherwise produce autoantibodies? This might be achieved with rituximab, a monoclonal antibody directed against the CD20 molecule found on pre-B and mature B cells.⁷ Our group first successfully deployed this strategy in the early 2000s, followed by an open-label pilot study.^8–10

The RAVE trial

The Rituximab in ANCA-Associated Vasculitis (RAVE) trial was a multicenter, randomized, placebo-controlled trial that compared rituximab for remission induction and maintenance with standard therapy consisting of cyclophosphamide followed by azathioprine in patients with severe AAV.¹¹ The results of a pilot trial in 2006¹⁰ set the stage for the RAVE trial, which hypothesized that treatment with rituximab plus glucocorticoids would not be inferior to daily cyclophosphamide plus glucocorticoids. Both would induce remission and permit discontinuation of prednisone after 6 months.

Nine centers enrolled a total of 197 patients with severe GPA or microscopic polyangiitis (MPA), all positive for ANCA, with active disease severe enough to warrant treatment with prednisone and cyclophosphamide. All participants received 1 to 3 g of methyl-prednisolone intravenously followed by prednisone (1 mg/kg per day). The treatment group received rituximab (375 mg/m² once weekly for 4 weeks) and the control group received standard therapy with cyclophosphamide (2 mg/kg per day) followed by azathioprine (2 mg/kg per day) after 3 to 6 months when remission was achieved.

The primary end point was complete remission, defined as a Birmingham Vasculitis Activity Score for Wegener’s Granulomatosis (BVAS/WG) of 0 and successful tapering of prednisone by 6 months. Secondary end points included rates of disease flares, cumulative glucocorticoid doses, rates of adverse events, and Medical Outcomes Study 36-item short-form health survey (SF-36, a measure of quality of life) scores. Among patients receiving rituximab, 64% reached the primary end point compared with 53% of patients in the control group. Rituximab was judged not inferior to standard therapy.

Results were similar for the secondary end point of disease remission while taking less than 10 mg/d of prednisone, with 71% of rituximab patients and 62% of control-group patients achieving remission. Rituximab was also as effective as cyclophosphamide in the treatment of patients with major renal disease or alveolar hemorrhage. Most strikingly, rituximab proved superior to the cyclophosphamide-based regimen for inducing remission in patients who entered the trial with relapsing disease (67% rituximab versus 42% cyclophosphamide) (Figure 1). Those who entered the trial with a new diagnosis did not show the same difference in efficacy.

Rituximab also proved significantly more effective than cyclophosphamide for patients who had proteinase-3 (PR3) ANCA, whereas the efficacy of both agents was equivalent among patients who had myeloperoxidase ANCA. Patients in the cyclophosphamide arm experienced more leukopenia compared with the rituximab arm, but this did not lead to more infections.

In summary, the RAVE trial showed that rituximab matched the efficacy of cyclophosphamide (standard therapy) in inducing remission in patients with severe AAV. The results held true for subsets of patients with major renal disease and those with alveolar hemorrhage. Most strikingly, among patients who entered the trial with a severe relapse, those who received rituximab responded better than those treated with cyclophosphamide. There were no significant differences in flare rates by 6 months and no difference in the rate of severe adverse events. However, participants receiving cyclophosphamide experienced more selected adverse events, particularly leukopenias.

Clinically speaking, rituximab represents the first proven alternative to cyclophosphamide for remission induction in this patient population. The treatment presents the preferred option for patients interested in preserving fertility or who need to be re-treated for a severe disease flare. Based on these data, the US Food and Drug Administration recently extended the labeling of rituximab for treatment of GPA and MPA.

The European Vasculitis Study Group (EUVAS) launched another trial comparing the efficacy of rituximab with cyclophosphamide for remission induction.¹² The trial design differed from that of the RAVE trial in that investigators did not discontinue prednisone in all patients, followed patients for 12 months, and assessed sustained remission as the primary end point. In this trial, patients in the rituximab arm also received two single intravenous cyclophosphamide infusions, and cyclophosphamide in the control arm was given intravenously. All 44 patients enrolled in the trial and randomized 3:1 to the rituximab versus the cyclophosphamide control arm were ANCA-positive and had active renal disease. The patient population overall was older and had more severe renal disease than the patients enrolled in the RAVE trial. Overall, one course of rituximab achieved the same results as 6 months of intravenous pulse cyclophosphamide followed by oral azathioprine in terms of rate of sustained remission at 12 months, time to relapse, improvement of renal function, and rate of adverse events.

Mayo Clinic cohort study

Our group at Mayo Clinic evaluated the safety and effectiveness of rituximab when used repeatedly in order to maintain long-term remission.¹³ The study involved 53 patients who had a long-term (10 years, on average) diagnosis of refractory AAV. The patients received, on average, four courses of rituximab. All of these patients had GPA and all but one were PR3-ANCA–positive.

In this cohort, rituximab was effective and safe for induction and maintenance of remission in patients with relapsing GPA. The study showed that B-cell depletion effectively maintains remission in these patients, supporting the notion that B cells play an important role in GPA. Because rituximab works by depleting B cells and ANCA, timing of re-treatment can be individualized based on B-cell counts and ANCA levels. Thus, rituximab represents a promising alternative to standard therapy and a means for long-term patient management, particularly for those in whom other agents have failed to achieve or maintain remission in the past.

On a cautionary note, rituximab is an immunosuppressive agent. Risk of infection during treatment seems similar to that associated with carefully monitored cyclophosphamide followed by azathioprine. To avoid complications, physicians should also maintain Pneumocystis prophylaxis for at least the duration of B-cell depletion.

CONCLUSION

Enhanced understanding of the mechanism of action of cyclophosphamide has led to investigation of the role of B cells in the development of AAV and, from there, to the potential for treatment with biologics such as rituximab. Rituximab is equivalent in efficacy to cyclophosphamide for remission induction in AAV. It effectively restores remission and prevents relapse, and it is a better option than cyclophosphamide for PR3-ANCA–associated relapsing vasculitis. Future investigations should further address how to best prevent relapses after B-cell reconstitution.