Rheumatology

ANCA-associated Vasculitis - MPA

Does this patient have microscopic polyangiitis (MPA)?

Microscopic polyangiitis (MPA) is a rare disease characterized by the presence of necrotizing vasculitis involving small and medium sized vessels in various organs.

Although MPA and GPA are commonly included under the broad term, "ANCA associated vasculitides," they are probably distinct diseases, and will be compared in this chapter to illustrate the similarities and differences. Genetic differences have been found in these two diseases supporting the possibility that they are, indeed, separate entities.

  • Clinical features in patients with MPA vary based on the presence and severity of organ involvement.

  • Systemic features such as fatigue, fever, weight loss, night sweats, anorexia are common and present in GPA and MPA.

Organ specific involvement can result in specific clinical features:

  • Ear, nose, throat (usually mild and typically non-destructive compared with GPA): nasal congestion, sinusitis, epistaxis.

  • Eyes (redness, pain, blurred vision, diplopia, retinitis). Ocular involvement is uncommon in MPA compared with GPA.

  • Lower airway (cough, shortness of breath, hemoptysis or asymptomatic lung infiltrates detected on imaging, diffuse alveolar hemorrhage). Lung nodules, particularly if cavitating, are uncommon in MPA and should raise concern for other etiologies or an alternative diagnosis such as GPA.

  • Joint (pain with or without joint swelling).

  • Skin (palpable purpura more common in MPA, typically on the lower extremities, ulceration, nodules, splinter hemorrhages).

  • Nerve involvement (sensory or motor; typically mononeuritis multiplex presenting as a wristdrop or footdrop). Mononeuritis multiplex occurs more commonly in MPA than GPA.

  • Renal (microscopic hematuria, proteinuria, symptoms resulting from uremia). Renal involvement occurs in both MPA and GPA.

  • Gastrointestinal (abdominal pain from GI tract ischemia).

What tests to perform?

Laboratory testing

Laboratory testing in patients with MPA should include tests that will provide information regarding diagnosis, disease severity, or for monitoring purposes (disease activity or medication toxicity).

Complete blood count with differential

Typical findings include leukocytosis (with predominant neutrophils), anemia (normochromic normocytic) as a result of anemia associated with chronic disease or possible blood loss (alveolar hemorrhage or other source) and normal or elevated platelet count. Leukopenia and thrombocytopenia are not seen with MPA, and should raise suspicion for an alternative diagnosis or cytotoxic medication toxicity.

Comprehensive metabolic panel

May reveal hypoalbuminemia (negative acute phase reactant) and elevated blood urea nitrogen and creatinine (depending on severity of renal involvement).

Urinalysis

Renal involvement is quite common in MPA and, therefore, urinalysis is an invaluable simple bedside test. The urine should be tested by dipstick for microscopic hematuria and proteinuria and, if found to be positive, should be followed by microscopy for presence of significant dysmorphic RBC or RBC casts (indicative of glomerular inflammation). Examining a fresh urine sample is strongly recommended, as RBC casts tend to degenerate over time and may cause a false negative result.

Sedimentation rate and C-reactive protein

Both are commonly elevated during the acute illness. Although they are considered as "markers of systemic inflammation", these tests are non-specific. A disconnect may occur between ESR and CRP due to conditions such as polyclonal hypergammaglobulinemia. Therefore, elevated ESR and/or CRP levels in patients who are felt to be in remission clinically deserve evaluation for active disease or other etiologies and close follow up, but do not automatically warrant change in immunosuppression.

Anti-neutrophil cytoplasmic antibody (ANCA)

These should be ordered in patients suspected to have MPA on clinical grounds (symptom complex listed earlier), and should be requested by both immunofluorescence and enzyme immunoassay. The combination of p-ANCA/anti-MPO (~ 80%) has high specificity (>95%) and is consistent with a diagnosis of MPA (much less common in GPA), but can occur in drug induced vasculitis.

Other testing for alternative etiologies such as infections or other diagnoses should be driven by clinical suspicion. Inappropriate broad testing is not recommended, and may result in false positive or inconclusive results that are unhelpful and potentially harmful to the patient.

Imaging

Chest imaging is useful in detecting both asymptomatic and symptomatic pulmonary involvement. Alveolar hemorrhage can be asymptomatic if mild and should be suspected in patients with the clinical trial of hypoxia, anemia and a new infiltrate on chest imaging. CT chest without contrast is preferable, as it is more sensitive than chest x-ray at detecting pulmonary involvement. CT chest may also reveal radiographic patterns that are suggestive of other diagnoses such as infection or malignancy.

Like GPA, active MPA may be associated with an increased incidence of venous thromboembolism, although this is not so clear at the present time. In patients suspected to have deep venous thromboses or pulmonary embolism, pertinent imaging is indicated.

Bronchoalveolar lavage (BAL)

This may be indicated in patients with pulmonary manifestations, such as suspected diffuse alveolar hemorrhage, to confirm the diagnosis and, more commonly, to obtain samples (lavage fluid or biopsies) for excluding infection or, sometimes, malignancy.

Biopsy

Tissue biopsy is useful in most situations for the diagnosis but is equally helpful in excluding other diagnoses. Biopsies should be sought from involved organs and never blindly (from unaffected sites). Open lung biopsies and renal biopsies have the highest yield. Granulomatous inflammation is not observed, another point differentiating MPA from GPA. Pulmonary capillaritis may be observed on lung biopsies.

Other accompanying features on histopathology of the lung include interstitial fibrosis, bronchiolitis (including bronchiolitis obliterans), and evidence of fresh and old alveolar hemorrhage (including hemosiderin laden macrophages). Features consistent with vasculitis (transmural infiltration with leukocytes, endothelial cell swelling, leukocytoclasia, thrombosis) may be observed in other tissue specimens such as skin biopsies.

Renal biopsy in MPA is identical to GPA and reveals a necrotizing crescentic glomerulonephritis, with few/absent immune complexes on immunofluorescence or electron microscopy (referred to as "pauci-immune"). Interstitial inflammation or fibrosis may be also observed. If a medium sized vessel is present in the biopsy, it may show evidence of vasculitis in the form of transmural inflammation, fibrinoid necrosis, and luminal thrombosis.

Diagnosis/Prognosis

The diagnosis of MPA is based on a combination of compatible clinical features, serology, and findings on tissue biopsy. The prognosis depends on the severity of disease/organ involvement, specific organ involved, time to treatment, and choice of therapy.

Controversies

ANCA testing

The combination of p-ANCA/anti-MPO (~ 80%) has high specificity for the diagnosis of MPA. However, ANCA positivity is not a pre-requisite for diagnosis. Similar to GPA, a rising ANCA titer (if serial testing is performed) should not be reason alone to escalate immunosuppression, but closer clinical follow-up may be warranted.

Chest imaging

Non-contrast CT chest imaging is a valuable tool to gain insight regarding disease activity from MPA involving the lungs, especially during asymptomatic relapses. There are no guidelines regarding the frequency of serial CT chest imaging. However, CT chest imaging should be performed for assessing disease activity, especially when major changes in therapy are being contemplated (such as switching from induction to maintenance immunosuppression or re-instating induction therapy for a relapse of the disease).

Need for tissue biopsy

Biopsy may be unnecessary in the presence of strongly compatible clinical features accompanied by compatible positive ANCA serology with reasonable exclusion of infection or other diagnoses. However, biopsy is required in most cases to confirm the diagnosis and exclude other competing diagnoses, as well as to gain insight into disease severity.

How should patients with microscopic polyangiitis (MPA) be managed?

The treatment strategy for MPA follows that of GPA, as most of the data regarding treatment comes from trials that have included patients with both diseases (under the term "ANCA associated vasculitis"). Treatment should be urgently instituted after confirming the diagnosis. In patients with severe organ-threatening or life-threatening manifestations, high dose glucocorticoids may be used even while diagnostic confirmation is in progress.

Treatment of MPA involves two-stages: induction of remission and maintenance of remission.

Induction therapy includes high dose glucocorticoids (typically prednisone 1 mg/kg/day with or without preceding intravenous methylprednisolone 1000 mg for 3 doses) along with methotrexate (MTX) or rituximab (RTX) for non-severe disease and cyclophosphamide (CYC) or RTX for severe disease should be used.

Untreated severe MPA has high mortality. Glucocorticoids form the cornerstone of treatment. The choice of the second agent is determined by disease severity, which can be ascertained using the Five Factor Score. Although the use of CYC for induction of remission was a major advance in treatment, administration over extended periods has significant toxicity.

In 2010, the RAVE study in the United States and RITUXIVAS study from Europe compared rituximab (RTX) and CYC for induction of remission in patients with both GPA and MPA. The study included patients with a new diagnosis of and relapsing disease.

In the RAVE trial, RTX was non-inferior to CYC in inducing remission in patients with a new diagnosis of GPA/MPA, whereas in patients with relapsing disease, it was superior to CYC. RTX was approved by the FDA in 2011 for the treatment of patients with GPA/MPA. However, the availability of RTX has not obviated the need for CYC use and still has a place in the management of patients with severe MPA. Glucocorticoids are tapered generally after the first month on high dose glucocorticoid therapy.

In a post hoc analysis of the RAVE study, in patients with renal disease in both the CYC and RTX groups, no differences in remission rates or increases in GFR at 18 months were observed based on ANCA type, the diagnosis (GPA versus microscopic polyangiitis), or new diagnosis versus relapse at enrollment.

The route of administration of CYC is controversial. Oral daily CYC is administered at 2 mg/kg/day orally while intravenous CYC is given as 15 mg/kg every 2 weeks for the first three doses, every 3 weeks thereafter until remission, and then for another 3 months (CYCLOPS study protocol), usually for a maximum of 6 months. The maximum pulse dose allowed in the CYCLOPS study was 1.2 grams.

There was no difference in time to remission in the two groups or the proportion of patients in each group achieving remission. Although there was a difference in the relapse rates (13 patients in the IV versus six patients in the oral group), the study was not powered to detect these differences. In patients with non-severe disease, MTX in combination with high dose glucocorticoids is effective in achieving disease remission (an approach borrowed from success of MTX in GPA).

MTX should be started at 15 mg/week and increased to 20-25 mg/week (subcutaneous administration should be considered at weekly doses of >20 mg) over 2-4 weeks as tolerated. MTX should be avoided in patients with significant renal dysfunction.

The role of plasma exchange (plasmapheresis) (PLEX) in the management of MPA is unclear. In patients with severe manifestations, such as rapidly progressive glomerulonephritis (RPGN) or diffuse alveolar hemorrhage resistant to standard-of-care induction therapy, plasmapheresis may have a role in achieving rapid control of inflammation.

In the MEPEX study, a randomized controlled trial (RCT) that included patients with both GPA and MPA with severe renal involvement (biopsy proven and creatinine >5.8 mg/dL), the use of seven cycles of PLEX in addition to cyclophosphamide and oral prednisolone resulted in a greater proportion of patients being independent of dialysis at 3 months (primary outcome) compared to patients who received methylprednisolone 3000 mg. However, at one year follow-up, patient survival was comparable in the two groups. There are no existing RCTs regarding the use of plasma exchange in patients with severe diffuse alveolar hemorrhage.

An ongoing study, PEXIVAS (plasma exchange and glucocorticoid dosing in the treatment of anti-neutrophil antibody associated vasculitis: an international randomized controlled trial) may be able to provide further data regarding the role of PLEX in the management of patients with MPA. If a decision is made to use RTX, PLEX should precede RTX therapy, as it can be removed from the circulation by PLEX.

The induction period is typically 3-4 months, but in the rare patient with smoldering active disease, it may be extended to 6 months. Once remission is achieved, CYC is switched to maintenance immunosuppression such as MTX or azathioprine (AZA) or mycophenolate mofetil (MMF) (based on the effectiveness of MMF in GPA). In patients who were on MTX for induction therapy, it is continued with continued taper of the glucocorticoids.

The choice of maintenance immunosuppression should be individualized based on comorbidities, patient and physician preferences, and risk of medication toxicity. For example, MTX is relatively contraindicated in patients with hepatic or renal disease, whereas azathioprine is contraindicated in patients homozygous recessive for the thiopurine methyltransferase (TPMT) gene (0.3% of the population).

Following the effectiveness of RTX as an induction agent, there is growing interest regarding its role as a possible maintenance immunosuppressant in GPA. The French Vasculitis Study Group has published a randomized study (MAINRITSAN) of 115 patients with newly diagnosed or relapsing GPA, microscopic polyangiitis, or renal-limited ANCA-associated vasculitis assigned to either RTX 500 mg on days 0 and 14 (induction) and at months 6, 12, and 18 after study entry or daily azathioprine until 22 months. Patients were followed until month 28. They reported a higher proportion of patients relapsing in the azathioprine group compared to the RTX group. In the U.S., a randomized controlled trial of RTX versus azathioprine (RITAZAREM) is presently underway (ClinicalTrials.gov Identifier: NCT01697267).

All immunosuppressants used for treating MPA are associated with considerable toxicities. Therefore, clinical and laboratory monitoring in patients with MPA on immunosuppression cannot be overemphasized. There are no formal guidelines for monitoring medication toxicity; however, some recommendations can be made. Patients should have monthly complete blood counts (CBC), comprehensive metabolic panel, acute phase reactants (sedimentation rate and C-reactive protein), and urinalysis, even while in remission and more frequently during acute stages of the illness and during adjustment of therapy.

Patients on CYC may develop hematologic toxicities, such as significant leukopenia (defined as WBC count <4000/mm3 and absolute neutrophil count <1500/mm3), from the cumulative effects of daily oral CYC. Patients on CYC are also on concomitant high dose glucocorticoids, which compounds the risk of severe infection. Monitoring for leukopenia does not assess the functional aspects of leukocyte dysfunction caused by CYC, but it is inexpensive and possibly cost-effective in preventing potentially severe infections.

Weekly CBC monitoring in patients on CYC has been shown to be potentially cost-effective in preventing severe leukopenia and consequent infection in patients with GPA when compared with monthly CBC monitoring; this has not been investigated in MPA, but is likely applicable to this disease as well. In patients without initial renal involvement, teaching weekly home urine dipstick testing may help detect renal relapses early.

Patients with non-severe relapses of MPA following induction therapy with rituximab or cyclophosphamide benefit from the temporary use of a higher dose of glucocorticoids, but may need a change in background maintenance immunosuppression to stave off frequent relapses.

The importance of adjunctive prophylactic therapies cannot be overemphasized. Similar to patients with GPA, patients with MPA on high dose glucocorticoids and a second immunosuppressant (CYC, RTX, MTX, AZA or MMF) should receive prophylaxis against Pneumocystis jirovecii (PJP)(trimethoprim-sulfamethoxazole, inhaled pentamidine, dapsone or atovaquone). The exact duration of PJP prophylaxis is unclear.

Since patients with MPA are also expected to be on relatively long-term glucocorticoids, calcium and vitamin D supplementation should be used. Bone density testing (dual energy x-ray absorptiometry [DXA]) should be performed in keeping with osteoporosis management guidelines.

What happens to patients with MPA?

Timely treatment can lead to optimal outcomes in patients with MPA. Mortality during the first year of illness is attributable to both infection and uncontrolled disease. As noted above, close monitoring, even during periods of clinical remission, cannot be overemphasized. Patients with MPA are reported to have less frequent relapses than patients with GPA, however, this may not be true in an individual patient.

Alveolar hemorrhage (severe or recurrent) may lead to pulmonary fibrosis that may significantly impair lung function from resultant damage. Renal involvement may be also severe and lead to renal damage, with ensuing chronic kidney disease/end stage renal disease and the need for long term renal replacement therapy or transplantation. Patients with neuropathy may experience long term morbidity. It is very difficult to predict outcomes or prognosticate on recovery of nerve function in these patients.

The Vasculitis Damage Index (VDI) is used to document organ damage in patients with MPA. Manifestations that qualify as damage need to be present for at least 3 months. Other glucocorticoid-induced comorbidities, such as weight gain, glucose intolerance/diabetes mellitus, may also be unpredictable in terms of reversibility after tapering of glucocorticoids.

How to utilize team care?

Consultations with specialists are determined by the affected organ(s). Involvement of a pulmonologist and nephrologist is likely necessary in the management of severe pulmonary and renal manifestations of MPA. Other specialists may have to become involved for specific disease manifestations.

Are there clinical practice guidelines to inform decision making?

No formal clinical guidelines exist for decision making in patients with MPA.

Other considerations

Typical length of stay: 3-5 days at time of diagnosis for evaluation and administration of initial intravenous glucocorticoid therapy.

What is the evidence?

Jennette, JC, Falk, RJ, Bacon, PA, Basu, N, Cid, MC, Ferrario, F. "2012 revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides". Arthritis Rheum. vol. 65. 2013. pp. 1-11.

(Revised nomenclature criteria for granulomatosis with polyangiitis [Wegener's]; previously Wegener's granulomatosis.)

Lhote, F, Cohen, P, Généreau, T, Gayraud, M, Guillevin, L. "Microscopic polyangiitis: clinical aspects and treatment". Ann Med Interne (Paris). vol. 147. 1996. pp. 165-177.

(Clinical aspects of MPA.)

Hoffman, GS, Specks, U. "Antineutrophil cytoplasmic antibodies". Arthritis Rheum. vol. 41. 1998. pp. 1521-1537.

(A review of antineutrophil cytoplasmic antibodies with regard to indications for testing, testing methods and strategies.)

Tomasson, G, Grayson, PC, Mahr, AD, Lavalley, M, Merkel, PA. "Value of ANCA measurements during remission to predict a relapse of ANCA-associated vasculitis--a meta-analysis". Rheumatology (Oxford). vol. 51. 2012. pp. 100-109.

(A meta-analysis on the predictive value of ANCA in assessing disease activity in patients with GPA andMPA.)

Langford, CA. "Complications of cyclophosphamide therapy". Eur Arch Otorhinolaryngol. vol. 254. 1997. pp. 65-72.

(A review on the complications of cyclophosphamide therapy.)

Stone, JH, Merkel, PA, Spiera, R, Seo, P, Langford, CA, Hoffman, GS. "Rituximab versus cyclophosphamide for ANCA-associated vasculitis". N Engl J Med. vol. 363. 2010. pp. 221-232.

(Randomized controlled trial of cyclophosphamide versus rituximab in patients with GPA and MPA in the United States.)

Guillevin, L, Pagnoux, C, Karras, A, Khouatra, C, Aumaître, O, Cohen, P. "Rituximab versus azathioprine for maintenance in ANCA-associated vasculitis". N Engl J Med. vol. 371. 2014. pp. 1771-1780.

(A randomized controlled trial from the French Vasculitis Study Group comparing RTX and azathioprine in patients with GPA and MPA.)

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