Hospital Medicine

Microscopic polyangiitis

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I. What every physician needs to know.

Microscopic Polyangiitis (MPA) is a vasculitis in the category of small vessel vasculitides. It can be categorized as one of the Anti-neutrophil cytoplasmic antibodies (ANCA) positive vasculitides which includes MPA, Granulomatosis with Polyangiitis (GPA), formerly Wegener’s, Eosinophilic Granulomatosis with Polyangiitis (EGPA), formerly Churg-Strauss, and renal limited vasculitis. Pathophysiologically, these small vessel vasculitides are characterized by neutrophilic inflammation in the walls of small vessels (capillaries, venules or arterioles). This inflammation is manifested in myriad ways including renal injury, pulmonary disease, and skin abnormalities.

II. Diagnostic Confirmation: Are you sure your patient has Microscopic Polyangiitis?

While there are no strict criteria for diagnosing MPA, there are several helpful guidelines. The American College of Rheumatology does not have diagnostic criteria for MPA, and consider MPA part of the category of small vessel ANCA positive vasculitides. The Chapel Hill Consensus Conference (CHCC) defines MPA as "necrotizing vasculitis with few or no immune deposits affecting small vessels". Further details include "Necrotizing arteritis of small and medium-sized arteries may be present. Necrotizing glomerulonephritis is very common. Pulmonary capillaritis often occurs." In short, it is difficult to be sure that your patient has MPA, but establishing a diagnosis of small vessel ANCA positive vasculitis is the right first step.

A. History Part I: Pattern Recognition:

MPA is characterized by constitutional symptoms of fever, malaise, arthralgias, anorexia, and weight loss. Organ systems that tend to be affected are pulmonary, renal, nervous system, and skin. The pulmonary manifestations of MPA are varied, and range from mild cough and dyspnea, to severe hemoptysis, alveolar hemorrhage, and pulmonary fibrosis. Renal disease is common, but may be asymptomatic. Skin involvement is common, and patients may complain of a rash. Nervous system involvement is characteristically a mononeuritis multiplex, with predilection for the extremities.

B. History Part 2: Prevalence:

MPA is a disease that affects men and women equally, and does not have a particular age or ethnic predominance.

C. History Part 3: Competing diagnoses that can mimic Microscopic Polyangiitis.

It can be challenging to distinguish MPA from other pulmonary renal syndromes, particularly GPA. In fact, there is substantial overlap between MPA and GPA including size of vessels and organ systems affected, and well as histopathology and serologies. While GPA has characteristic granulomas on biopsy, these are absent in MPA.

D. Physical Examination Findings.

While MPA is a disease entity with myriad symptoms and important histopathologic characteristic, the physical findings can be sparse. If renal disease predominates there may be no abnormal physical findings. If there is a substantial pulmonary component, an abnormal lung exam could include unilateral or bilateral rales. A careful neurologic exam may reveal mononeuritis multiplex, particularly with unilateral foot drop.

E. What diagnostic tests should be performed?

While there is no one test to diagnose MPA, the constellation of physical findings, laboratory test and biopsy are the mainstay of diagnosis. Biopsy of the affected organ will be of highest yield, and likely targets are kidneys, lungs, nerves, and skin.

1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

Renal involvement is common, and urinalysis and evaluation of urine sediment should be the first laboratory tests, as well as serum blood urea nitrogen (BUN) and creatinine. A complete blood count may be normal, and may help to rule out other diseases which have overlapping constitutional symptoms. Serologies for ANCA are an important, specific test, and should be sent if there is suspicion for a small vessel vasculitis. Further sub-categorization of ANCA into myeloperoxidase (MPO) or proteinase 3 (PR3) may be helpful. Although erythrocyte sedimentation rate (ESR) and c-reactive protein (CRP) would be elevated in MPA, they may be too non-specific to aid in diagnosis. Excluding other processes with antinuclear antibodies, anti-glomerular basement membrane antibodies, complement C3 and C4, cryoglobulins, hepatitis serologies, human immunodeficiency virus (HIV), liver function tests, and tuberculosis screen may be useful in confirming your diagnosis.

2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

Imaging studies may be helpful if there is pulmonary involvement. Chest x-ray and more specifically computed tomography (CT) scan of the chest may reveal infiltrates, effusion, nodule, or hemorrhage, all of which are associated with MPA.

F. Over-utilized or “wasted” diagnostic tests associated with this diagnosis.

The tests for systemic inflammation such as ESR and CRP while abnormal in MPA, may be too non-specific to be useful in narrowing the diagnosis. Similarly, general tests for auto-immune disease such as antinuclear antibody (ANA), rheumatoid factor (RF), complement levels may be warranted if renal disease predominates, but may be wasted if the clinical picture points to a small vessel vasculitis.

III. Default Management.

Treatment for acute and chronic MPA is aimed at immunosuppression. In the acute setting, systemic corticosteroids and cytotoxic agents are the mainstay of treatment. A common regimen is prednisone plus cyclophosphamide (2 milligram/kilogram/day [mg/kg/day] adjusted for renal dysfunction) for 3-6 months, followed by remission maintenance therapy with azathioprine or methotrexate. Rituximab may be an effective, alternative first line treatment in the acute setting.

A. Immediate management.

There is no immediate treatment necessary for MPA. Rather, it is important to narrow the diagnosis sufficiently to tailor the immunosuppressive regimen accordingly.

B. Physical Examination Tips to Guide Management.

If a hospitalized patient is diagnosed with MPA, the likely organ systems to be involved are pulmonary and renal. In this case, oxygen requirement or tachypnea may improve with initial treatment. The renal dysfunction is unlikely to present with physical exam abnormalities. MPA is an inflammatory disease when if treated appropriately improves over the course of months. The hospitalist is unlikely to see improvement acutely, even with appropriate treatment.

C. Laboratory Tests to Monitor Response To, and Adjustments in, Management.

While MPA is typically responsive to immunosuppression, the clinical and laboratory improvement does not occur acutely. The astute hospitalist should ensure appropriate follow up with specialists, namely rheumatology, nephrology or pulmonary for long term monitoring of response to treatment.

D. Long-term management.

Long-term management of MPA includes follow up with rheumatologists, nephrologists, and pulmonologists. As immunosuppressive agents are used for months to years in management of MPA, care needs to be taken for appropriate monitoring for infection. It is standard for patients to be on prophylaxis for Pneumocystis jiroveci with oral trimethoprim/sulfamethoxazole.

E. Common Pitfalls and Side-Effects of Management.

The acute and ongoing treatment for MPA with immunosuppressives should be done in consultation with specialists. The greatest initial pitfall is in misdiagnosing the vasculitis and choosing the wrong immunosuppressive regimen. Therefore, if a small vessel vasculitis is suspected, early consultation with appropriate speciality is warranted.

A known side effect of systemic corticosteroids and cytotoxic agents is immune suppression. If a patient with MPA on steroids and cytotoxic agents is admitted to the hospital, there should be a low threshold to diagnose or treat an acute infection. There is no standard recommendation for altering dose of initial glucocorticoid or cyclophosphamide in patients with renal impairment.

In addition to systemic corticosteroids side effects, cyclophosphamide also has a significant list of complications including cystitis. The cystitis caused by cyclophosphamide is common, and is challenging to diagnose because many patients already have hematuria from MPA itself. This can be diagnosed by evaluating the urine sediment. Red blood cells found in the setting of cystitis will be normal, as opposed to the dysmorphic red blood cells characteristic of the glomerulonephritis associated with MPA. Cyclophosphamide induced hematuria should resolve 3-4 weeks after the last cyclophosphamide treatment. Cyclophosphamide is unlikely to cause hepatic dysfunction or a perturbation in transaminases. There is known cardiotoxicity of cyclophosphamide, but it usually occurs at higher doses than those used to treat MPA.

IV. Management with Co-Morbidities.

There are no standard recommendations for adjusting the dose of initial corticosteroids or cyclophosphamide in a patient with renal impairment, although renal impairment is common in MPA. Prompt immunosuppression is crucial in preserving renal function.

In young women, there is a risk to fertility with use of cytotoxic agents. The decision to alter the standard regimen or egg harvesting in order to preserve fertility should be made in consultation with specialists before therapy initiation.

A. Renal Insufficiency.

Renal insufficiency is common in MPA, yet there is no standard recommendation to reduce the dose of corticosteroid or cyclophosphamide for the acute treatment of MPA. Patients who have a serum creatinine >5.7 mg/dL, requiring dialysis or have diagnosed alveolar haemorrhage should undergo plasma exchange in addition to cyclophosphamide and glucocorticoid therapy.

B. Liver Insufficiency.

There is no standard dose reduction for corticosteroids or cyclophosphamide in the setting of hepatic insufficiency.

C. Systolic and Diastolic Heart Failure.

There is no recommendation to alter dosing or choice of initial therapy in the setting of heart failure.

D. Coronary Artery Disease or Peripheral Vascular Disease.

There is no standard recommendation to alter the acute treatment of MPA in the setting of known coronary artery or peripheral vascular disease.

E. Diabetes or other Endocrine issues.

Since acute treatment of MPA involves sustained systemic corticosteroids, hyperglycemia is an expected side effect. In patients with diabetes, close attention to glucose control and adjustment of baseline agents may be necessary. The patient with new renal impairment and diabetes will need close attention to glucose control particularly if oral hypoglycemics have been part of his regimen.

F. Malignancy.

If MPA occurs in concert with a malignancy, adjustment of immunosuppressive regimen should be done together with rheumatology and oncology input. There have been reports of MPA occurring as part of a paraneoplastic syndrome.

G. Immunosuppression (HIV, chronic steroids, etc).

It is uncommon for MPA to present in a patient with HIV; an immunosuppressed patient, from a different disease or treatment regimen, is unlikely to present acutely with MPA.

H. Primary Lung Disease (COPD, Asthma, ILD).

When MPA occurs in the setting of known underlying pulmonary disease, the hospitalist needs to be vigilant in monitoring the pulmonary status. A superimposed pulmonary vasculitis may exacerbate their underlying condition.

I. Gastrointestinal or Nutrition Issues.

Although it is less common, MPA can affect the gastrointestinal system. It typically manifests as bleeding, ulceration, and ischemia. If the patient has an underlying GI disorder, consultation with a gastroenterologist is necessary to coordinate management of concurrent diseases.

J. Hematologic or Coagulation Issues.

One of the known side effects of cyclophosphamide is cytopenias, thus the patient with an underlying hematologic disorder warrants particular attention to blood count monitoring.

K. Dementia or Psychiatric Illness/Treatment.

When managing MPA in the setting of dementia, one should anticipate the psychiatric side effects of systemic corticosteroids.

V. Transitions of Care.

A. Sign-out considerations While Hospitalized.

A patient with newly diagnosed MPA who is in the hospital likely has pulmonary or renal involvement or both. Signout to covering conditions should include monitoring of pulmonary status and renal function, as well as being alert for side effects of treatment. MPA is disease which may affect multiple organ systems, care of this patient will likely require careful coordination among specialists, namely rheumatology, pulmonary and renal services.

B. Anticipated Length of Stay.

For a patient with MPA, the length of stay is likely dependent on the degree of pulmonary and/or renal impairment. .

C. When is the Patient Ready for Discharge.

A patient's readiness for discharge should depend on pulmonary and renal function, and appropriate follow up. While there are no strict criteria, a patient with renal or pulmonary failure needs continued hospitalization until clinically improved.

D. Arranging for Clinic Follow-up.

1. When should clinic follow up be arranged and with whom.

If the patient is newly diagnosed with MPA, follow up should be arranged with the specialist – rheumatologist, pulmonologist, or nephrologist - who will be monitoring the immunosuppressive regimen. In addition, follow up with the primary care physician is necessary, as this patient may require careful coordination of multiple subspecialists.

2. What tests should be conducted prior to discharge to enable best clinic first visit.

None

3. What tests should be ordered as an outpatient prior to, or on the day of, the clinic visit.

None

E. Placement Considerations.

While it is rare, MPA may cause significant renal impairment requiring dialysis. If this occurs, careful coordination with the nephrologist and dialysis center is necessary.

F. Prognosis and Patient Counseling.

MPA typically responds well to immunosuppressive therapy. However, this response occurs over weeks to months, and the patient is unlikely to improve substantially during the hospitalization. It is important to communicate this time frame to the patient, who may feel reluctant to be discharged in the absence of marked improvement.

VI. Patient Safety and Quality Measures.

A. Core Indicator Standards and Documentation.

None

B. Appropriate Prophylaxis and Other Measures to Prevent Readmission.

When advising patients about immunosuppressive regimens, it is important to counsel them on continuing to take the medication even when they notice clinical improvement. The patient with MPA should be counselled to expect months to years of ongoing immunosuppression. A failure to take the immunosuppressive regimen may cause re-hospitalization.

VII. What's the evidence?

Chung, SA, Seo, P. "Microscopic polyangiitis". Rheum Dis Clin North Am. vol. 36. 2010 Aug. pp. 545-58.

Jennette, JC, Falk, RJ, Andrassy, K, Bacon, PA, Churg, J, Gross, WL, Hagen, EC, Hoffman, GS, Hunder, GG, Kallenberg, CG. "Nomenclature of systemic vasculitides. Proposal of an international consensus conference". Arthritis Rheum. vol. 37. 1994 Feb. pp. 187-92.

Guillevin, L, Durand-Gasselin, B, Cevallos, R, Gayraud, M, Lhote, F, Callard, P, Amouroux, J, Casassus, P, Jarrousse, B. "Microscopic polyangiitis: clinical and laboratory findings in eighty-five patients". Arthritis Rheum. vol. 42. 1999 Mar. pp. 421-30.

Seo, P, Stone, JH. "The antineutrophil cytoplasmic antibody-associated vasculitides". Am J Med. vol. 117. 2004 Jul 1. pp. 39-50.

Gómez-Puerta, JA, Hernández-Rodríguez, J, López-Soto, A, Bosch, X. "Antineutrophil cytoplasmic antibody-associated vasculitides and respiratory disease". Chest. vol. 136. 2009 Oct. pp. 1101-11.

Chung, SA, Seo, P. "Advances in the use of biologic agents for the treatment of systemic vasculitis". Curr Opin Rheumatol. vol. 21. 2009 Jan. pp. 3-9.

Talar-Williams, C, Hijazi, YM, Walther, MM, Linehan, WM, Hallahan, CW, Lubensky, I, Kerr, GS, Hoffman, GS, Fauci, AS, Sneller, MC. "Cyclophosphamide-induced cystitis and bladder cancer in patients with Wegener granulomatosis". Ann Intern Med. vol. 124. 1996 Mar 1. pp. 477-84.

Hogan, SL, Falk, RJ, Chin, H, Cai, J, Jennette, CE, Jennette, JC, Nachman, PH. "Predictors of relapse and treatment resistance in antineutrophil cytoplasmic antibody-associated small-vessel vasculitis". Ann Intern Med. vol. 143. 2005 Nov 1. pp. 621-31.

Corral-Gudino, L, Borao-Cengotita-Bengoa, M, Del Pino-Montes, J, Lerma-Márquez, JL. "Overall survival, renal survival and relapse in patients with microscopic polyangiitis: a systematic review of current evidence". Rheumatology (Oxford). vol. 50. 2011 Aug. pp. 1414-23.

Langford, CA, Kerr, GS. "Pregnancy in vasculitis". Curr Opin Rheumatol. vol. 14. 2002 Jan. pp. 36-41.

Schäcke, H, Döcke, WD, Asadullah, K. "Mechanisms involved in the side effects of glucocorticoids". Pharmacol Ther. vol. 96. 2002 Oct. pp. 23-43.

Heijl, C, Harper, L, Flossmann, O, Stücker, I, Scott, DG, Watts, RA, Höglund, P, Westman, K, Mahr, A. "Incidence of malignancy in patients treated for antineutrophil cytoplasm antibody-associated vasculitis: follow-up data from European Vasculitis Study Group clinical trials". Ann Rheum Dis. vol. 70. 2011 Aug. pp. 1415-21.

Abe, H, Momose, S, Takeuchi, T. "Microscopic polyangitis complicating double carcinoma of the stomach and duodenum: improvement after the resection of these carcinomas". Rheumatol Int. vol. 31. 2011 Jan. pp. 105-8.

Gisselbrecht, M, Cohen, P, Lortholary, O, Jarrousse, B, Gayraud, M, Lecompte, I, Ruel, M, Ghérardi, R, Guillevin, L. "Human immunodeficiency virus-related vasculitis. Clinical presentation of and therapeutic approach to eight cases". Ann Med Interne (Paris). vol. 149. 1998 Nov. pp. 398-405.

Kershner, P, Wang-Cheng, R. "Psychiatric side effects of steroid therapy". Psychosomatics. vol. 30. 1989. pp. 135-9.

Merino, JL, Galeano, C, Espejo, B, Rivera, M, Fernández-Lucas, M, Caldés, S, Plana, MN, Letosa, M, Teruel, JL, Quereda, C, Ortuño, J. "A retrospective study on outcome of microscopic polyangiitis in chronic renal replacement therapy". Nephrol Dial Transplant. vol. 26. 2011 Apr. pp. 1360-6.

Lee, T, Gasim, A, Derebail, VK, Chung, Y, McGregor, JG, Lionaki, S, Poulton, CJ, Hogan, SL, Jennette, JC, Falk, RJ, Nachman, PH. "Predictors of treatment outcomes in ANCA-associated vasculitis with severe kidney failure". Clin J Am Soc Nephrol. vol. 9. 2014 May. pp. 905-13.

(Prognosis relative to renal failure.)

Specks, U, Merkel, PA, Seo, P, Spiera, R, Langford, CA, Hoffman, GS. "Efficacy of remission-induction regimens for ANCA-associated vasculitis". N Engl J Med. vol. 369. 2013 Aug 1. pp. 417-27.

(Rituximab vs. cyclophosphamide therapy remission success.)

de Groot, K, Harper, L, Jayne, DR, Flores Suarez, LF, Gregorini, G, Gross, WL. "Pulse versus daily oral cyclophosphamide for induction of remission in antineutrophil cytoplasmic antibody-associated vasculitis: a randomized trial". Ann Intern Med. vol. 150. 2009 May 19. pp. 670-80.

(Assessing pulse versus daily oral cyclophosphamide tx on remission; no significant difference on remission rates, less leukopenia w/ pulse doses.)

Jayne, D. "The diagnosis of vasculitis". Best Pract Res Clin Rheumatol. vol. 23. 2009 Jun. pp. 445-53.

(Importance of early diagnosis for treatment regimen.)
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