Fig. 36.1
Case study 1 – chest radiograph showing bilateral air space opacities consistent with pulmonary hemorrhage
Introduction
Granulomatosis with polyangiitis (GPA), previously known as Wegener’s granulomatosis [1], is a chronic systemic vasculitis involving small- to medium-sized arteries. It is characterized by granulomatous inflammation primarily involving the upper and lower respiratory tracts (Fig. 36.2), necrotizing pauci-immune glomerulonephritis and vasculitis that frequently involve other organs. In the most recent International Chapel Hill Consensus Conference (CHCC 2013) on vasculitis classification and nomenclature, GPA is subclassified within the small vessel vasculitis category as antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) [2] together with microscopic polyangiitis (MPA) and eosinophilic granulomatosis with polyangiitis (EGPA) (previously known as Churg-Strauss syndrome).
Fig. 36.2
Saddle-nose deformity in a girl with granulomatosis with polyangiitis
Although childhood GPA is rare, the burden on the individual child, their caregivers, and the healthcare system is relatively high: the disease may be acutely and chronically organ threatening or life-threatening; children with GPA account for disproportionate number of deaths and admissions to intensive care among all pediatric rheumatology patients [3]; the large majority of patients require cytotoxic or other immunosuppressive therapies [4]; many affected children have continuing therapy requirements, with sustained disease activity and damage from disease and treatment extending long into adulthood. Early recognition and treatment of GPA is critical to minimizing short- and long-term morbidity and improving outcome. The differential diagnosis of GPA in children presenting with acute severe disease involving lungs and kidneys may be relatively obvious, such as in the above case study. For children who present more insidiously with manifestations only overtly affecting one organ, there needs to be a high index of suspicion to distinguish the child with GPA among many children presenting with recurrent bloody noses, with a persistently red eye, chronic sinusitis, or a resistant pneumonia with persisting fever, for example.
Because of disease rarity in children, most data on GPA is derived from the adult literature although evidence for its applicability to the growing child is lacking. Other than case reports and small case series, there is also limited literature relating to Indian patients (adults or children) with GPA. In this chapter, information relating to childhood disease and disease in India will be presented when available. The need for international pediatric collaborations including registries to study sufficient patient numbers has been recognized [5, 6], and recent efforts are starting to generate pediatric data.
Classification
The 1990 American College of Rheumatology (ACR) criteria for classifying vasculitis [7] including GPA [8], derived primarily from adult-patient data, are suboptimal in classifying children with vasculitis. A proposed pediatric adaptation of ACR criteria, taking into account common pediatric manifestations and the presence of ANCA [9], was ultimately improved upon and validated using a cohort of pediatric patients. The final validated criteria having been endorsed by the European League Against Rheumatism, the Pediatric Rheumatology European Society, and Pediatric Rheumatology International Trial Organization are known as the EULAR/PRINTO/PReS criteria for pediatric vasculitis [10]. ACR and EULAR/PRINTO/PReS criteria for classifying vasculitis are shown in Table 36.1. While these pediatric criteria show improved sensitivity over the ACR criteria, both sets are limited by their failure to provide criteria for microscopic polyangiitis (MPA). Thus, some patients classified as having GPA by either of these criteria might concurrently be defined as having MPA, for example, using the Chapel Hill Consensus Conference definition [4]. The difficulty in distinguishing GPA from MPA both diagnostically and for classification purposes initially led to the convenient grouping of GPA and MPA in clinical trials under the rubric of ANCA-associated vasculitis (AAV) and subsequently to its inclusion as a formal subcategory of small vessel vasculitis. From a practical perspective, there are no major differences in therapeutic implications for one or other diseases, and this is unlikely to change until such time as there is a distinguishing biomarker, or there is a different paradigm for classification.
Table 36.1
Comparison of the ACR and EULAR/PRINTO/PReS criteria for classification of granulomatosis with polyangiitis (GPA)
ACR | EULAR/PRINTO/PReS |
|---|---|
A patient is said to have GPA when two of the following four criteria are present | A patient is said to have GPA when three of the following six criteria are present |
1. Nasal or oral inflammation | 1. Upper airway involvement: chronic purulent or bloody nasal discharge or recurrent epistaxis/crusts/granulomata; nasal septal perforation or saddle-nose deformity; chronic or recurrent sinus inflammation |
2. Abnormal chest radiograph | 2. Pulmonary involvement: chest x-ray or CT scan showing the presence of nodules, cavities, or fixed infiltrates |
3. Abnormal urinalysis | 3. Renal involvement: abnormal urinalysis (proteinuria, hematuria or red blood cell casts) or necrotizing pauci–immune glomerulonephritis |
4. Item 4 under ACR criterai should align with item 4 fo EULAR/PRES/PRINTO criteria | 4. Granulomatous inflammation: within an artery or in the perivascular or extravascular area of the artery or arteriole |
5. Laryngo–tracheo–bronchial involvement: with subglottic, tracheal, or bronchial stenosis | |
6. ANCA positivity: by immunofluorescence or by ELISA (MPO/p or PR3/cANCA) |
Epidemiology
The reported incidence of GPA ranges from 0.2 to 1.2 per 100,000 persons per year [11–13]. Reports of a rising incidence between the 1970s and 1990s are described for some regions [14–17] and are partly attributed to improved case recognition after the introduction of ANCA testing in the 1980s. GPA is described as occurring at higher incidences in higher latitudes such as Norway and areas of the UK compared with Spain and Japan [18, 19] and similarly in the high versus low latitudes of New Zealand [20]. There is no data on epidemiology of vasculitis from India, but by extrapolation and considering the latitude and the predisposition of GPA for Caucasian populations, the incidence is likely to be on the low end of the described spectrum. Summary data reported in 2006, from general rheumatology clinics in nine Indian cities, describe patients with primary systemic vasculitis comprising less than 1 % of their clinic caseload [21]. GPA accounted for 14 % of vasculitis patients (equal frequency to Behcet’s disease), and only Takayasu’s and IgA vasculitis (Henoch-Schönlein purpura) were more frequent, each accounting for about 20 % of cases. A more recent retrospective study from Mumbai describes the spectrum of AAV subtype diagnoses among 75 adult patients seen between 2003 and 2011 as follows: GPA 44 %, EGPA 9 %, MPA 2.5 %, and “unclassified AAV” 44 %; details reported in the abstract are limited [22].
Information on the incidence of GPA in children and adolescents is limited. From American [23] and Norwegian [24] population studies from the 1980s and 1990s, calculated annual incidences for patients with disease onset before 20 or 16 years of age are, respectively, 0.02 and 0.06 per 100,000. A recent Canadian study demonstrated an increase in the incidence of childhood GPA over 5 years from 0.028 to 0.064 per 100,000 per year in Southern Alberta [25]. Using the lowest reported incidence, figures and assuming 30 % of the 1.2 billion population of India are below 16 years of age, a roughly estimated total incidence of childhood GPA would be approximately 250 new patients per year.
Etiology and Pathogenesis
The cause of GPA is unknown, but like other polygenic systemic autoimmune diseases, it is likely a result of interactions between genetic factors predisposing to loss of self-tolerance and triggering environmental exposures [31, 32]. Infections probably contribute to the etiology as suggested by peaks of incidence in 3–4 year cycles [33], seasonal peaks (especially winter) [34, 35], and the association with increased rates of nasal carriage of Staphylococcus aureus [36]. Exposure to crystalline silica and certain farming and livestock exposures have also been reported as potential triggering factors [25, 37–39].
ANCAs likely have a role in the pathogenesis and may also determine the extent or severity of disease manifestations, being more strongly associated with generalized versus limited disease [40]. ANCAs associated with GPA can have a cytoplasmic (c) or perinuclear (p) immunofluorescence pattern, with their primary antigenic targets being proteinase 3 (PR3) or myeloperoxidase (MPO), respectively [41]. The cANCA pattern and PR3 specificity are the more frequent ANCA in both children [4, 28] and adults [24, 42] with GPA. The overlapping clinical features of MPA with GPA and EGPA likely reflect the small vessel vasculitis component of the diseases, whereas the differences reflect the presence of an additional granulomatous inflammatory process in GPA, and eosinophilia and granulomatous inflammation in EGPA [2, 7].
Clinical Features
Disease Presentation in Children
Although pediatric GPA can be limited to a single organ system, this probably occurs much less frequently than in adults, and the large majority of children with GPA present with multiple organ involvement [28, 43]. The clinical course may also be rapidly progressive as described in the case study. The most frequent manifestation at presentation, as described in the largest cohort of 130 patients, collected within a registry for children with vasculitis (ARChiVe), was nonspecific constitutional features (including fatigue, weight loss, and fever). This was followed by pulmonary (81 %), renal (79 %), and upper respiratory tract (75 %) manifestations [43], and this triad of organ involvement is characterized as the hallmark of the disease in all studies [4, 28–30, 43, 44].
The spectrum of presenting pulmonary findings in GPA includes hemoptysis or alveolar hemorrhage (42 %), imaging findings of pulmonary nodules (54 %), or fixed pulmonary infiltrates (34 %). Pulmonary function tests were abnormal in 61 % of the 67 patients tested in the Canter et al. study [43]. Upper respiratory tract manifestations involved the nose (saddle-nose deformity, nasal septal perforation, bleeding) in 52 %, sinusitis (48 %), otitis or mastoiditis (17 %), subglottic inflammation (12 %), hearing loss (12 %), oral ulcers (12 %), conjunctivitis 12 %, and scleritis 8 % [43]. Subglottic stenosis is an upper respiratory manifestation, relatively specific to GPA. It was described in an early pediatric study of GPA to occur five times more commonly in children compared to adults [30], and this lead to its inclusion as one of the EULAR/PRINTO/PReS criteria for pediatric GPA [10]. Renal disease most frequently manifests at presentation with abnormal urinalysis in about 80 % of patients, but 36 % of patients also had significantly elevated serum creatinine and 13 % required dialysis [28, 43]. Other involved organ systems at presentation were skin (55 %), musculoskeletal (64 %), gastrointestinal (39 %), nervous (27 %), and cardiovascular, including thrombosis (5 %) [43].
Laboratory Examination
Laboratory findings are often nonspecific and reflect systemic inflammation or underlying organ involvement. Leukocyte counts may be elevated and associated with a normocytic anemia, thrombocytosis, and elevated erythrocyte sedimentation rate or C-reactive protein level [26, 45]. Inflammatory markers can be significantly elevated in generalized disease as was described in the case study; however, they can also be normal or only slightly abnormal in limited disease. If the kidneys are affected, the urinalysis typically shows proteinuria and microscopic hematuria. Examination of fresh spun urine will often show red blood cell casts indicative of glomerular involvement [8, 45]. Serum urea and creatinine levels may only be elevated in the presence of significant renal disease.
Rheumatoid factors are present in approximately 50 % of adult and pediatric patients [28, 45]. Antinuclear antibodies are present in about 20–36 % of pediatric patients [4, 28]. Antiphospholipid antibodies have been reported in a small percentage of patients and may be associated with an increased risk of venous thrombosis [4, 28, 46].
ANCAs are present in the majority of children with GPA. Either cANCA or PR3 ANCA is present in approximately three quarters of children, and either pANCA or MPO ANCA is present in approximately one quarter [43]. While cANCA and anti-PR3 are seen in the majority of GPA patients, pANCA and anti-MPO antibodies may occur especially in so-called renal limited pauci-immune glomerulonephritis [47].
Imaging
Imaging in children being evaluated for GPA should be guided by presenting symptoms and suspected organ involvement. Children with pulmonary symptoms should have a chest radiograph and computed tomography (CT) scan. Approximately 78 % of children with GPA have abnormalities on chest radiographs [28, 43]. Findings include nodules, fixed infiltrates, cavitations, pleural effusions, and pneumothoraces [52, 53]. High-resolution CT may detect changes that are not seen on radiographs such as small nodules, linear opacities, fluffy centrilobular perivascular densities, and focal low-attenuation infiltrates [52, 54, 55].
In children with suspected sinus disease, sinus radiographs should be ordered and in some cases a sinus CT or magnetic resonance imaging (MRI). Findings on sinus imaging may include thickening of the sinus mucosa, opacification of the sinuses or paranasal sinuses, or bony thickening and destruction [56]. MRI may be better at demonstrating soft tissue abnormalities, including granulomas, but are less commonly ordered [57, 58].
Case 2 [59]
A 14–year–old previously healthy boy was admitted to the general inpatient ward with a 2–week history of myalgias, fever, sore throat, and a 6 kg weight loss. He had initially been treated in the community as a viral and then subsequent bacterial throat infection. On admission to hospital, he had a minimally inflamed throat and tonsils and was afebrile. Initial laboratory investigations showed an ESR 85 mm/h, normal white blood cell count, differential, and platelet count, with a normocytic anemia 85 g/L. Liver enzymes, blood urea nitrogen, and creatinine were normal. He had proteinuria and hematuria on urinalysis. A chest x–ray was normal. The initial working diagnosis was that of poststreptococcal glomerulonephritis. Investigations for infections were normal including cultures of throat; blood and urine; serological studies for Streptococcus, Mycoplasma, Epstein–Barr virus, Cytomegalovirus, and HIV; and a Quantiferon-Gold Tuberculosis Test. Complement levels were normal. On day 4 while still under evaluation, he developed acutely painful tonsils and was found to have necrotic ulcers and purulent discharge with no other mouth lesions. Renal biopsy and bilateral tonsillectomy were performed the next day. Histology of his tonsils demonstrated frank ulceration with necrosis, vascular congestion, and hemorrhage, and cultures demonstrated only mixed normal flora. Renal histology demonstrated focal necrotizing glomerulonephritis with crescent formation, and immunofluorescence staining was significant for lack of immunoglobulins and complement, i.e., pauci–immune. He was also found serologically to be highly positive for cANCA with antibodies to PR3, and together with the finding of pauci–immune glomerulonephritis and upper airway disease, he was diagnosed with GPA.
In the postoperative period, the patient developed new onset respiratory distress and hypoxia, and with the development of hemoptysis and frank pulmonary hemorrhage, he required intubation and mechanical ventilation. He was treated with corticosteroids (IVMP) and oral daily cyclophosphamide and co–trimoxazole prophylactic against Pneumocystis jiroveci, and because of ongoing pulmonary hemorrhage and critical respiratory status, he underwent seven rounds of plasma exchange. He ultimately responded to these treatments and was discharged from hospital after 3 weeks for ongoing outpatient care.
Diagnosis
The first step toward making a diagnosis of chronic primary vasculitis, and GPA specifically, is to have a high index of suspicion and to consider the diagnosis. Any patient presenting with fever, other constitutional features, laboratory evidence of persisting inflammation, and no evidence of acute infection should be carefully evaluated for involvement of specific organs while carefully considering the possibilities of an underlying primary systemic vasculitis and other diseases such as systemic lupus erythematosus (SLE) or malignancy for which timely diagnosis is also critical. As was illustrated in case study 2, when the patient was not responding to treatment for his presumed infection and his blood work showed evidence of persisting inflammation, he was investigated further for evidence of other organ involvement including renal disease (urinalysis, urea, and creatinine), liver disease (liver enzymes), and pulmonary disease (chest radiograph), which ultimately led to the identification of glomerulonephritis. Even in the absence of overt constitutional features, chronic primary vasculitis should be considered in the differential diagnosis of persisting noninfectious inflammation involving single or multiple organs. The gold standard for making a diagnosis of primary or secondary vasculitis is identification of characteristic histopathological features on biopsy specimens of affected organs.
Diagnosing GPA specifically is based on a combination of characteristic clinical features (in particular, the triad of upper and lower respiratory tract disease and renal manifestations), the presence of serological markers (specifically ANCA and most commonly PR3 ANCA or cANCA), and characteristic histopathology (pauci-immune granulomatous inflammation of predominantly small to medium arteries, capillaries or small veins, or pauci-immune glomerulonephritis). Realistically all of these diagnostic requirements are not always present, and there is a greater imperative to exclude secondary vasculitis or mimics of vasculitis associated with drug and toxic exposures, infections, malignancy, and other autoimmune or systemic inflammatory disorders.
Differential Diagnosis
Clinical Features
In the presence of prolonged fever and constitutional symptoms with or without specific organ involvement, it is imperative at the outset to exclude malignancy (leukemia, lymphoma), other autoimmune diseases such as SLE or inflammatory bowel disease, and infections by looking for characteristic features and serological markers and by doing appropriate laboratory testing. In countries such as India, where tuberculosis is prevalent, it is particularly important to differentiate GPA and TB (see below). As was shown in the case studies, both patients were evaluated for TB and had extensive investigations for infections prior to definitively being diagnosed with GPA.
There may be apparent involvement of a single organ only, often within the upper respiratory tract and specifically including recurrent bloody noses, chronic sinusitis, mastoiditis or otitis media, nasal bridge collapse, nasal septal perforation, subglottic stenosis, scleritis, dacryocystitis, or a retro-orbital mass. While some of these examples are more specific for GPA than others, tissue diagnosis will also help exclude other diseases. Notable differential diagnoses include infections (mycobacteria, fungi, or helminths which may be associated with granulomatous vasculitis) [45, 60], neoplastic disease [61], sarcoidosis [62], and in young children, chronic granulomatous disease. In adult patients it is known that one third of those with GPA present with asymptomatic kidney and lung disease [26]; therefore in children with apparently isolated upper respiratory tract manifestations, it is essential to examine fresh spun urinary sediment for cellular casts and examine the lungs radiographically and with pulmonary function testing.
The Role of ANCA in the Differential Diagnosis
While the presence of ANCA, specifically PR3 ANCA (or cANCA), is supportive of the diagnosis of GPA [42], nearly one half of patients with localized disease are ANCA negative [63]. PR3 ANCA (or cANCA) is also found in up to 30 % of patients with MPA and perhaps less than 5 % of patients with EGPA. MPO ANCA is found in up to 70 % of patients with MPA [64] but may also be found in about 10 % of patients with GPA [41, 65] and a majority of patients with so-called renal limited vasculitis [66]. ANCA-associated vasculitis may also be associated with drug use and most commonly with drugs used for the treatment of hypothyroidism including propylthiouracil, methimazole, and carbimazole. Other drugs that have been reportedly associated with ANCA and/or vasculitis include hydralazine, minocycline, penicillamine, phenytoin, indomethacin, allopurinol, rifampicin, isoniazid, and cefotaxime [67–70]. A careful drug history should be obtained in patients in whom a diagnosis of vasculitis is being considered. ANCA, usually not specifically directed against PR3 or MPO, has been described in association with other autoimmune disorders including Crohn’s disease, primary sclerosing cholangitis, and cystic fibrosis. In tuberculosis patients, ANCA may be present in 30 % (specific for MPO in 47 % and PR3 in 19 %) [71], and patients may share other clinical features that are also typical for GPA including hemoptysis, pulmonary infiltrate, and hematuria. In reports from the Indian literature, GPA patients have been identified among patients being treated for tuberculosis only after they had failed to respond to antitubercular drugs [71, 72].
Pathology
Histopathological examination of tissue is the most valuable means to secure a diagnosis of GPA especially in patients who are ANCA negative or there is a degree of diagnostic uncertainty. When tissue is sent for other tests including culture, it can also help rule out some mimickers and differential diagnoses. We recommend that consideration be given to obtaining a tissue biopsy in all patients with suspected AAV, when feasible and if there is an accessible tissue. However, there are situations in which a tissue biopsy is either not feasible (because biopsy would be hazardous and/or none of the affected organs can be easily biopsied) or not necessary in making a diagnosis. The proportion of patients with disease and a “positive” biopsy, demonstrating features of either granuloma or vasculitis or both, has been quoted in the region of 70 % [73], but the diagnostic yield varies greatly depending on the organ biopsied. It is important to recognize that a negative or “nondiagnostic” biopsy does not exclude a diagnosis of GPA; this is particularly true of ENT biopsies that on the one hand offer sites for relatively noninvasive biopsy [74], but on the other hand, sensitivity is below 53 % [75]. Lung biopsies also have a low yield when performed with fine needle aspirations, but are better with transbronchial or open lung procedures [76, 77]. Biopsy can occasionally guide therapeutic decisions and provide valuable prognostic information; for example, it can distinguish active renal vasculitis from renal damage in patients with deteriorating renal function and a prior history of renal involvement.
Clinical Course and Outcome in Pediatrics
Only a few studies have been published about the course of disease and outcome of children with GPA. Three series from 1993, 2007, and 2011, respectively, report on 23, 25, and 8 patients [28, 30, 78]. The series of eight patients describes follow-up on seven GPA patients and one MPA patient with the longest follow-up being 27 years [78]. In this long-term follow-up study, four of eight patients became infertile, two had severe bone complications of osteoporosis or avascular necrosis of the femoral head, one patient developed breast cancer at the age of 30 years, and one patient died 25 years from initial presentation [78]. In the 1993 report, cyclophosphamide treatment was associated with hemorrhagic cystitis in 50 %, infertility in 28 %, and two patients died, one from severe lung disease and cor pulmonale and one from sepsis. In all three series, most patients achieved remission but all had relapsing disease, and infections were common [28, 30, 78]. In the last decade or so, newer treatment strategies have resulted in patients receiving lower cumulative doses of cyclophosphamide, and thus, the reported outcomes from these older studies may not reflect more recent standards of practice.
Pediatric patients are at significant risk for developing ENT disease even if they do not present with it. In the Rottem et al. series, 4 % of patients had ENT involvement at presentation, but 48 % developed ENT disease during follow-up, and half of these required tracheostomy [30]. In the 2011 series, half of the patients developed hearing impairment and nasal septal or upper airway deformities [78]. Another retrospective report focused primarily on ENT manifestations of GPA in children describes the occurrence of multiple levels of upper airway stenosis requiring multidisciplinary treatment [79].
Important Considerations from Recent Adult Studies
A high frequency (44 %) of patients described as “unclassified” among 75 AAV patients in Western India is unexplained [22]. Notably, and unlike patients in most pediatric series, a majority of these 75 patients had relatively mild disease at presentation staged as being localized (11 %) or early systemic disease (53 %) according to the European Vasculitis Group classification scheme described below [22].
A recent adult study including 445 patients suggests improving outcomes for GPA patients with reduced delays in diagnosis, reduced mortality, lower relapse rates, and less cumulative exposure to cyclophosphamide [63]. Prior to the aggressive use of glucocorticoids and cyclophosphamide, the disease was fatal in the majority of patients [80, 81], whereas more recent studies report 5-year mortality rates of treated patients in the order of 10–25 % [26, 82, 83]. Reduced rates of malignancies are also suggested by more contemporary cohorts, and this is probably attributable to the reduced cyclophosphamide exposure [84].
Compared to the age- and sex-matched population, adult patients with GPA have a higher mortality, with death in the first year after disease onset being due to infection or active vasculitis, whereas later in the disease course mortality is related to cardiovascular disease, malignancy, and infection [85]. An increased frequency of fibromyalgia, depression, and sleep disorders in adult patients with GPA has also been recently suggested [86].
Management
Overview
Combined aggressive use of glucocorticoids and cyclophosphamide for the treatment of GPA has led to marked improvement in early outcomes [87]. More than 90 % of patients now achieve remission compared to the 1950s when there was 80 % one-year mortality for adults (possibly worse in children) with death from renal or pulmonary failure, or from infection [26, 45, 82]. Although cyclophosphamide has been lifesaving, it has not prevented relapses from occurring in 50 % of patients within 5 years [88], and it has been associated with significant short- and long-term toxicity risks particularly an increased incidence of life-threatening infections, malignancy, and infertility [26, 89]. Current treatment strategies, and recommendations based on a number of clinical trials in adult patients, aim to reduce the cyclophosphamide burden without undertreating aggressive disease. These strategies include: giving cyclophosphamide by intermittent intravenous pulse infusions rather than daily oral therapy, the concept of two-phase treatment described as remission–induction and remission–maintenance whereby cyclophosphamide is given for a period less than 6 months and then treatment switched to a less toxic immunosuppressive agent, complete avoidance of cyclophosphamide for less severe disease, and finally using rituximab instead of cyclophosphamide although the relative roles of these two medications are still being determined [88]. Because pediatric GPA is rare, the experience in treating patients is limited, and management guidelines are generally adapted from adults. Notwithstanding the effects of the disease and treatment on growing children is not necessarily the same as in adults. Management is best coordinated through a pediatric center, ideally by pediatric rheumatologists (and/or pediatric nephrologists when there is renal involvement), but otherwise in close collaboration with specialists or centers with special expertise in vasculitis.
Treatment (Refer Also to Table 36.2)
Table 36.2
Recommended therapy of granulomatosis with polyangiitis adapted from EULAR recommendations [90]
Drug | Regimen |
|---|---|
Remission-induction (3–6 months) | |
Severe disease (life-threatening or organ threatening) | |
Prednisone | 1–2 mg/kg/day PO in two or three divided doses (max, 60 mg); (exceptionally ill patients initially receive intravenous methylprednisolone pulse, 30 mg/kg/day (max, 1 g) for 1–3 days IV) After 4 weeks, consolidate to single daily dose and wean down by no more than 25 % every 2–4 weeks if patient is remaining well. Wean dose to a minimum of 0.2 mg/kg or 10 mg (whichever the lesser) by 6 months |
Plus | |
Cyclophosphamide (maximum duration 6 m) | 15 mg/kg IV every 2 weeks for 3 doses and then 3 weekly (alternatively 0.5–1.0 g/m 2 monthly IV pulses have been traditionally used following NIH SLE protocol) or 2 mg/kg/day PO
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