Branch - medicine , orthopaedics , pmr and rheumatology




1 Granulomatosis with polyangiitis (GPA) is a rare form of vasculitis.

2 The term Wegener’s granulomatosis has largely been superseded by GPA which is considered to be a more accurate reflection of its aetiology.

3 It is thought to be an autoimmune inflammatory process affecting endothelial cells.

4 It is a multisystem disease which can affect many parts of the body, categorised by the ELK classification

5 it most commonly presents with lesions in the upper respiratory tract (E indicating ears/nose/throat, almost 100%), lungs (L most patients) and kidneys (K >75%).

6 Many other areas of the body may also be affected, with joint inflammation occurring in 25-50% of all cases.

7 The sinuses, eyes and skin may also be affected.

8 The higher incidence in winter suggests an infective aetiology but the data are inconclusive.

9 GPA has been linked to parvovirus and to chronic nasal carriage of Staphylococcus aureus.

10 The involvement of the upper airways in this condition has led to the search for possible inhaled allergens, although none has yet been positively identified.

11 The mainstay of treatment for granulomatosis with polyangiitis (GPA) is a combination of corticosteroids and cytotoxic agents.

12 Treatment should be tailored to appropriately treat GPA manifestations while minimizing long-term toxicities to the patient.

13 Untreated generalized or severe GPA typically carries a dismal prognosis, with up to 90% of patients dying within 2 years, usually of respiratory or renal failure.

14 Even non-renal GPA carries a mortality rate of up to 40%

15 Outcomes for this previously fatal disease improved dramatically with the introduction in the 1970s of cyclophosphamide, which is administered in combination with corticosteroids.

16 Approximately 90% of patients with GPA respond to cyclophosphamide, with approximately 75% experiencing complete remission.

17 However, 30%-50% of those who initially respond experience at least one relapse, requiring another course of therapy.

18 In general, limited disease does not require as aggressive therapy as does severe disease.

19 Additionally, treatment recommendations are different for induction of remission and maintenance of remission.

20 Grading - Current treatment recommendations in GPA depend on the severity and activity of disease.

21 The European Vasculitis Study Group recommends grading disease severity of antineutrophil cytoplasmic antibody (ANCA) – associated vasculitis (AAV) into the following 5 categories :

A ) Localized - Upper and/or lower respiratory tract disease without any other systemic involvement or constitutional symptoms

B ) Early systemic - Any, without organ-threatening or life-threatening disease

C ) Generalized - Renal or other organ-threatening disease, serum creatinine level less than 5.6 mg/dL

D ) Severe - Renal or other vital-organ failure, serum creatinine level exceeding 5.6 mg/dL

E ) Refractory - Progressive disease unresponsive to glucocorticoids and cyclophosphamide

22 Contact sports are to be avoided for 1 month following a kidney biopsy.


1 Ulcers, sores and crusting, in and around the nose, with destruction of nasal cartilage.

2 Rhinorrhoea, often bloody.

3 Haemoptysis.

4 Haematuria.

5 Subglottic stenosis (38% in one study) - causing hoarseness, stridor, dyspnoea, or cough.

6 Rashes (up to 50%) - often small red/purple raised areas or blister-like lesions, ulcers or nodules.

7 Conjunctivitis, scleritis and episcleritis.

8 Chronic ear infections.

9 Mononeuritis multiplex.

10 Peritonitis


1 Fatigue, malaise

2 Fever, night sweats

3 Weakness

4 Loss of appetite

5 Weight loss

6 Rhinorrhoea

7 Sinusitis

8 Facial pain

9 Hoarseness

10 Cough

11 Dyspnoea

12 Wheezing

13 Chest pain

14 Joint pains

15 Hearing loss

16 Abdominal pain



1 Since introduced by Fauci et al in the 1970s, oral cyclophosphamide in combination with high-dose glucocorticoids (ie, prednisone 1mg/kg/day) has been the criterion standard for induction of remission in AAV.

2 Eventually, intravenous cyclophosphamide was investigated as an alternative to oral cyclophosphamide in an effort to decrease treatment-associated toxicities, and, while the emphasis has been placed on optimizing treatment by minimizing exposure to cyclophosphamide and seeking alternative comparable therapies

3 the combination of cyclophosphamide (intravenous or oral) and glucocorticoids remained the recommended therapy for induction of remission in generalized/severe GPA for years.

4 The recommended daily oral dose of cyclophosphamide is 2 mg/kg/day (not to exceed 200 mg/day).

5 Pulsed (intravenous) cyclophosphamide (15 mg/kg every 2 weeks for the first 3 pulses, then every 3 weeks for the next 3-6 pulses) is an alternative to daily oral cyclophosphamide - it results in less cumulative exposure to cyclophosphamide and, therefore, theoretically causes fewer adverse effects.

6 Cyclophosphamide therapy is usually continued until significant disease improvement or remission occurs, typically 3-6 months.

7 The patient is then transitioned to a less toxic medication for maintenance of remission.

8 Cyclophosphamide toxicity manifests as hemorrhagic cystitis (in 15-43% of cases after oral treatment), bladder cancer (30-fold increased incidence as compared with controls), increased risk of other malignancies, cytopenias, infertility, and opportunistic infections, typically occurring during cyclophosphamide-induced leukopenia.

9 Patients receiving pulse cyclophosphamide should also be given oral or intravenous 2 mercaptoethanesulfonate sodium (Mesna), which binds to acrolein, the toxic metabolite of cyclophosphamide responsible for hemorrhagic cystitis.

10 Once bound to acrolein, the toxic metabolite can no longer bind to cell-surface proteins in the bladder, limiting the risk of local cyclophosphamide-associated toxicity.

11 Mesna may also be beneficial in patients receiving continuous oral cyclophosphamide

12 The recommended IV dosing of mesna is equal to 20% (weight/weight) of the IV cyclophosphamide dose, divided into 3 equal doses.

13 The first dose of IV mesna is administered 15-30 minutes prior to IV cyclophosphamide.

14 The 2 remaining doses are then given 4 hours and 8 hours following IV cyclophosphamide. Peak urinary concentrations with IV mesna dosing occur in 1 hour.

15 The dose of oral mesna should be equal to 40% of the cyclophosphamide doses (oral or IV), based on a 50% oral bioavailability, and divided into 3 equal doses.

16 The first dose of oral mesna should be given 2 hours before cyclophosphamide (oral or IV).

17 The second and third oral doses can still be given 4 hours and 8 hours after cyclophosphamide, as with IV mesna dosing.

18 The bioavailability is not affected by food intake, and peak urinary concentrations occur in 3 hours.

19 Frequent urinalyses should be performed while the patient is receiving either intravenous or oral cyclophosphamide, and should also be performed throughout the patient’s life to screen for the development of bladder cancer.

20 Urine cytology can also be considered.

21 Additionally, complete blood count (CBC) monitoring should be performed every 1-2 weeks throughout the course of daily oral cyclophosphamide to detect and prevent leukopenia.

22 CBC counts should be performed on day 10 and 14 after each intravenous pulse and immediately before the next intravenous dose as well.

23 Finally, infertility may be of great concern to both male and female patients who desire future childbearing.

24 A study of 42 women in the WGET trial, aged 14 to 46 years (mean age 35 years), found that daily oral cyclophosphamide, even when administered for less than 6 months, was associated with diminished ovarian reserve, as evidenced by decreased anti-Müllerian hormone (AMH).

25 If there is time prior to the initiation of cyclophosphamide therapy, men may wish to pursue sperm banking and women of childbearing age should consider oral contraceptives and gonadotropin-releasing hormone analogues (ie, leuprolide) to help preserve fertility.

B ) Rituximab

Rituximab combined with high-dose glucocorticoids represents an alternative to cyclophosphamide for induction of remission in GPA

2 it is the first treatment ever approved by the FDA for AAV.

3 The evidence for this approval came from the Stone et al’s RAVE (Rituximab in Antineutrophil Cytoplasmic Antibody ̶ Associated Vasculitis) trial.

4 Rituximab is a chimeric monoclonal anti-CD20 IgG1 antibody that induces apoptosis of B cells, with the exception of plasma cells and pre-B cells.

5 Infusion of rituximab typically causes a 6-month depletion of circulating B cells and therefore may decrease the production of autoantibodies such as ANCAs.

6 The RITUXVAS trial, by The European Vasculitis Study Group (EUVAS), examined the use of rituximab in severe GPA with renal involvement in older patients and found rituximab was not superior to cyclophosphamide and was associated with a similar number of adverse events, although the rituximab group also received cyclophosphamide.

7 Both studies confirmed the efficacy and superiority of rituximab over cyclophosphamide in reducing ANCA positivity.

8 Rituximab is typically thought to be more effective in the vasculitic phase rather than the granulomatous phase, but small studies have shown good results even in limited disease.

9 Adverse effects associated with rituximab include infusion reactions, mucocutaneous reactions, increased risk of infections (to include opportunistic infections such as progressive multifocal leukoencephalopathy), cytopenias, and malignancy.

A ) In rheumatoid arthritis patients, hypogammaglobulinemia before rituximab seemed to be more closely associated with risk of infection than during or after rituximab.

10 Whether rituximab-associated hypogammaglobulinemia is associated with risk of infection in AAV remains to be determined, although a retrospective study did not show an association.

11 Late-onset neutropenia has also been associated with rituximab in GPA appropriate laboratory monitoring should be considered.

C ) Corticosteroids

1 Historically, glucocorticoid monotherapy prolonged median survival in GPA by only 7.5 months.

2 There have been no clinical trials evaluating the role or dosing of glucocorticoids in AAV, but every clinical trial has used glucocorticoids in combination with other immunosuppressants.

3 Thus, corticosteroids remain the cornerstone of treatment for AAV, especially for the induction of remission.

D ) Trimethoprim-sulfamethoxazole

1 Pneumocystis pneumonia has an annual incidence of 1% but is a potentially deadly complication of immunosuppressive therapy in patients with GPA, especially with prolonged lymphocytopenia.

2 Prophylaxis against Pneumocystisjiroveci pneumonia should be instituted while patients are taking cyclophosphamide and corticosteroids (particularly high-dose corticosteroids).

3 Typically, trimethopim-sulfamethoxazole (TMP-SMZ) at 160/800 mg 3 times weekly is used. If the patient has a sulfa allergy, dapsone 100 mg daily can be substituted.

4 Pneumocystis prophylaxis has also been recommended during rituximab treatment and for at least 6 months following the last rituximab infusion.

5 Reports have examined TMP-SMZ use in isolation without other immunosuppressive medications in the induction phase of treatment in patients with very limited disease; however, prospective trials of TMP-SMZ as monotherapy have been disappointing.

6 In adults, TMP-SMZ has been shown to prevent relapses of GPA in remission. This action of TMP-SMZ may be due to anti-inflammatory action or decrease in infections, particularly respiratory tract infections.


1 Plasma exchange may be considered in patients with rapidly progressive renal disease (serum creatinine level >5.65mg/dL) in order to preserve renal function.

2 Additionally, plasma exchange, along with aggressive immunotherapy, may be helpful in DAH.

3 Plasma exchange is used with daily oral cyclophosphamide and glucocorticoids, usually pulse methylprednisolone.

4 Plasma exchange has not been shown to improve overall survival rates or relapse rates but has been associated with improved long-term survival, free of hemodialysis.

5 The proposed mechanism of action of plasma exchange in AAV includes removal of pathologic circulating factors (eg, ANCA, activated lymphocytes), removal of excess physiologic factors (eg, complement, coagulation factors, cytokines/chemokines), replacement of deficient plasma factors, and other, less well-defined mechanisms.

6 Potential adverse events associated with plasma exchange include electrolyte disturbances, anaphylaxis, hemorrhage, and transfusion-related lung injury


1 Localized, milder disease generally requires less aggressive therapy.

2 A combination of methotrexate (oral or subcutaneous) and glucocorticoids can be considered as a less-toxic alternative to cyclophosphamide for the induction of remission of non–organ-threatening or non–life-threatening GPA.

3 Methotrexate (20-25 mg/wk, oral or subcutaneous) can be used in patients with normal renal function.

4 It may take longer to reach remission with methotrexate than with cyclophosphamide, but methotrexate has been shown to be equal to cyclophosphamide in terms of its capacity to induce remission in early AAV

5 Daily folic acid 1 mg/day is recommended to lessen some of the adverse effects of methotrexate.

6 Azathioprine for induction of remission has not been shown to be effective


1 Leflunomide (20-30 mg/day) is as effective as methotrexate, but it is associated with more adverse effects.

2 Leflunomide targets T cells by inhibiting the mitochondrial enzyme dihydroorotate dehydrogenase and thus limits pyrimidine synthesis.

3 It is used in the treatment of rheumatoid arthritis.

4 Leflunomide is metabolized by the liver and thus may be used in patients with renal insufficiency.

5 Is assoc with higher onset of peripheral neuropathy

H ) Mycophenolate mofetil

1 Mycophenolate mofetil (MMF) (2 g/day) is a derivative of the fungus Penicillium stoloniferum that, similar to azathioprine, limits purine synthesis.

2 MMF is primarily used for immunosuppression in transplant patients and suppresses B and T cells.

3 Because of its favorable side-effect profile and clinical potency, MMF is being increasingly used in the management of systemic connective-tissue disorders and is typically used in combination with prednisone.

4 A study of microscopic polyangiitis, a myeloperoxidase (MPO)-ANCA ̶ associated vasculitis, suggested that MMF may be an alternative to cyclophosphamide in mild-to-moderate microscopic polyangiitis.

5 MMF has been used in small series of refractory GPA cases, for both induction and maintenance, with varying responses

II Surgical care

Surgical treatment may be needed for:

A ) Nasal deformity.

B ) Subglottic stenosis.

C ) Obstruction of lacrimal ducts.

D ) Bronchial stenoses.

E ) Eustachian dysfunction (insertion of grommets).

F ) Acute kidney injury (renal transplant).

III Complications

1 Acute kidney injury

2 Respiratory failure

3 Chronic conjunctivitis

4 Nasal septum perforation