Vasculitic neuropathy

Introduction: 

The vasculitides are a heterogeneous group of autoimmune diseases caused by inflammation in the blood vessel wall resulting in vascular injury, interruption of blood flow, and subsequent ischemia and damage of affected organs. The 2012 International Chapel Hill Consensus Conference classified vasculitis according to vessel size and the presence of antineutrophil cytoplasmic antibodies (ANCA). The Chapel Hill Consensus Conference also classified vasculitis associated with systemic diseases (eg, rheumatoid arthritis [RA] and systemic lupus erythematosus [SLE]) and vasculitis associated with other systemic disorders, including infections (eg, hepatitis B or hepatitis C), drug exposure (eg, minocycline), and malignancy, among others. 

Vasculitic Neuropathies: It is an immune-mediated disorder directed against blood vessels, which results in ischemia to end-organs supplied by the blood vessel and infarction of isolated peripheral nerves.  Axonal loss occurs.

Etiologies:  

The Peripheral Nerve Society has also published a classification tailored to peripheral nerve vasculitis 

ANCA-associated vasculitis includes microscopic polyangiitis, granulomatosis with polyangiitis, and eosinophilic granulomatosis with polyangiitis 

Clinical Features

Diagnostic Criteria for Definite, Probable, and Possible Vasculitis 

Pathologically Definite 

Pathologically Probable 

Pathologically Possible 


Primary Vasculitides

GCA:  Temporal arteritis and Takayasu arteritis.  PN occurs in the setting of temporal arteritis only.  ~14% of patients develop neuropathies in the form of multiple mononeuropathies, multifocal neuropathy, radiculopathies, plexopathies, or a generalized sensorimotor peripheral neuropathy.

Polyarteritis nodosa:  Most common of the necrotizing vasculitides.  It is a systemic disorder and involves small and medium sized arteries in multiple organs.  

Microscopic polyangiitis:

Granulomatosis with polyangiitis:

Eosinophilic granulomatosis with polyangiitis:

Behcet disease:

Laboratory evaluation for Vasculitic neuropathy: 

Secondary systemic vasculitides

Vasculitis associated with connective tissue disease

Infection related vasculitis

Malignancy related vasculitis 

Hypersensitivity Vasculitis

Drug-induced hypersensitivity vasculitis

Vasculitis secondary to essential mixed cryoglobulinemia

Livedoid vasculopathy 

Livedoid vasculopathy is a rare cutaneous disease manifesting as recurrent ulcers on the lower extremities.  The ulceration results in atrophic, porcelain white scars termed as atrophie blanche.  The pathogenesis is yet to be understood with the main mechanism being hypercoagulability and inflammation playing a secondary role.  The important procoagulant factors include protein C and S deficiency, factor V Leiden mutation, antithrombin III deficiency, prothrombin gene mutation and hyperhomocysteinemia.  Histopathology of livedoid vasculopathy is characterized by intraluminal thrombosis, proliferation of the endothelium and segmental hyalinization of dermal vessels.  The treatment is multipronged with anti-thrombotic measures such as anti-platelet drugs, systemic anticoagulants and fibrinolytic therapy taking precedence over anti-inflammatory agents.  Colchicine, hydroxychloroquine, vasodilators, intravenous immunoglobulin, folic acid, immunosuppressive therapy and supportive measures are also of some benefit.  A multidisciplinary approach would go a long way in the management of these patients resulting in relief from pain and physical as well as psychological scarring. 

The main mechanism in the pathogenesis is hypercoagulability while inflammation plays a secondary role.  Autoimmunity has recently been found to be contributory.  It is a rare disorder with an estimated incidence of 1:100,000.  There is female preponderance in the ratio of 3:1.  Disease manifestations start either in late adolescence or middle age with the mean age of onset at 32 years.   There is occlusion in cutaneous capillary microcirculation leading to thrombosis, ischemia and infarction.  This explains the debilitating pain, muscle spasms, paresthesia and hyperesthesia experienced by affected patients.  The thrombotic effect results from defects either in the endothelial cell plasminogen activation, platelet dysfunction or enhanced fibrin formation.  Pericapillary deposition of fibrin and formation of thrombus act as a diffusion barrier impairing tissue oxygen supply causing ischemic infarction.  Low tissue perfusion leads to poor wound healing.  In sluggish circulation, there is ineffective killing of the microorganisms by leucocytes enhancing the chance of infection.  A vicious cycle of tissue destruction, edema and thrombosis develops, further jeopardizing tissue perfusion.  


The important causative associations of livedoid vasculopathy are as follows:


Non-systemic Vasculitic Neuropathy

Self-limiting nonsystemic vasculitic neuropathies include postsurgical inflammatory neuropathy, neuralgic amyotrophy (possibly), painful diabetic and nondiabetic radiculoplexus neuropathy (lumbosacral, thoracic, cervical, or in combination), and painless diabetic radiculoplexus neuropathy.  Self-limiting nonsystemic vasculitic neuropathies differ from the nonsystemic vasculitic neuropathies.  First, they usually fit a well-recognized syndrome, and the diagnosis can be made clinically without a nerve biopsy.  Second, they are typically self-limiting, tend to improve on their own, and tend not to recur.

NSVN is a the most commonly reported type of vasculitis affecting the PNS.  It affects the small or medium sized arteries in the epineurium and perineurium.  It may represent one of several localized vasculitic disease mediated by immune response directed against tissue-specific antigens.  MMPs, in particular MMP-2, and MMP-9 (gelatinase A and B), are upregulated in the peripheral nerves in patients with NSV.  T-cells are the predominant source of MMP-2 and MMP-9, although some stromal cells of the perineurium and endoneurium may also secrete MMP.  These enzymes digest the subendothelial basement membrane and thus facilitate inflammatory cells to penetrate the blood-nerve barrier.  It has a unique predilection for peripheral nerves.  It is usually seen in adults, but children can also be affected.  The neurologic signs and symptoms and nerve pathology are similar to PAN/MPA related neuropathy, but the clinic course is free of non-PNS involvement.  Those affected manifest multiple mononeuropathies or a generalized symmetric sensorimotor polyneuropathy.  Weight loss, constitutional symptoms.  Elevated ESR, ANA, anemia, leukocytosis, thrombocytosis, and autoantibodies occur in 20% to 40% of patients.  It is primarily a disorder of small and medium vessels. Muscle biopsies occasionally reveal coexisting muscle vasculitis and often show ischemic changes or inflammation.  Involvement of the skin later in disease.  The diagnosis has generally depended on sural nerve biopsy evidence of definite or probable vasculitis, with muscle involvement in patients.  Diagnostic criteria is as follows:

Inclusions

Exclusions

When patients develop vasculitis clinically restricted to the PNS, known as nonsystemic vasculitic neuropathy (NSVN), the most commonly encountered vasculitic neuropathy in pathologically based series:  Diabetic and nondiabetic radiculoplexus neuropathies are clinical variants of NSVN.   NSVN is clinically similar to systemic vasculitis-associated neuropathies except for reduced severity.   Patients most commonly present with progressive, stepwise pain, weakness, and numbness over multiple months.  Almost all exhibit a multifocal or asymmetric, distally accentuated pattern of involvement. The most commonly affected nerves are the common peroneal nerve in the leg and the ulnar nerve in the arm. Sedimentation rate is mildly to moderately elevated in 50%; other markers of systemic inflammation are generally normal. Electrodiagnostic studies reveal a predominantly axonal, asymmetric, sensorimotor polyneuropathy, but pseudo-conduction blocks may occur. Definite diagnosis requires biopsy evidence of vascular inflammation and signs of active or remote vascular damage. In biopsies lacking definite vasculitis, the diagnosis is suspected if axonal alterations are accompanied by perivascular inflammation and such supportive features as Wallerian-like degeneration, asymmetric fiber loss, hemosiderin, vascular immune deposits, neovascularization, myofiber necrosis/regeneration, focal perineurial damage, and endoneurial purpura. NSVN preferentially affects larger epineurial arterioles. Epineurial infiltrates are composed primarily of T cells and macrophages, suggesting that cellular cytotoxicity is the primary effector mechanism. Systemic vasculitides with progressive neuropathy are usually treated with cyclophosphamide and prednisone. No randomized controlled trial of therapy has been performed in NSVN, but data from retrospective cohorts suggest that combination therapy is more effective than steroid monotherapy. Once remission has been induced, cyclophosphamide should be replaced with azathioprine or methotrexate. Refractory patients can be treated with intravenous immunoglobulin, mycophenolate, rituximab, infliximab, or alemtuzumab. Although long-term outcome is reasonably good, more than one third of patients relapse, infrequent patients die from the disease or its treatment, and still others develop chronic pain. 

Postsurgical inflammatory neuropathy

Most neuropathy that occurred following surgery are felt to be due to stretching of compression of nerves.  Some neuropathies may be secondary to inflammation.  This is suspected to be an autoimmune neuritis.

First line Treatment:

Second-line options for refractory patients:

Protocol for IV solumedrol + Cyclophosphamide IV (Vasculitic neuropathy)

Rituximab

Recently, rituximab was established as an effective treatment in patients with MPA and GPA and has been licensed for ANCA-associated vasculitis recently (RAVE trial).  RAVE

Rituximab is an anti-CD20 monoclonal antibody, targeting mainly B cells.   It  is considered as first-line treatment of ANCA-associated vasculitis.  In a recent study, rituximab was as effective as CYC in the treatment of ANCA-associated vasculitis (197 patients, more effective in induction of remission after relapse).   Rituximab was also effective in the treatment of cryoglobulinemic vasculitis.  Normal dosage is 375 mg/m2 four times every week.


Acetaminophen (TYLENOL) tablet 1,000 mg 03/24/20 1031 Given   Oral   1,000 mg   

DiphenhydrAMINE (BENADRYL) capsule 50 mg 03/24/20 1030 Given   Oral   50 mg   

RiTUXimab (RITUXAN) 1,000 mg in NS 250 mL infusion 03/24/20 1040 Start New Bag   IV Piggyback   1,000 mg Initial infusion: Start an infusion rate of 50 mg/hour (12.5ml/hour); if there is no infusion reaction, increase the rate by 50 mg/hour (12.5ml/hour) increments every 30 minutes, to a maximum rate of 400 mg/hour (100ml/hour).

Sodium chloride 0.9 % flush 3-10 mL.  Intravenous Flush   10 mL   

 

Plasma exchange is used in mixed cryoglobulinemia, since it is able to remove circulating cryoglobulins. However, no randomized controlled trials have been reported and only some of the patients seem to respond 

NSVN

Wegener's granulomatosis (now called GPA, granulomatosis with polyangiitis)

Classic PAN, MPA, and CSS (EGPA)

Nucala (mepolizumab)

HBV-associated PAN

HCV-associated cryoglobulinemic vasculitis

HIV-associated vasculitic neuropathy, CMV positive vasculitis

Cancer-associated vasculitic neuropathy

Modifications of the Standard Regimen for CYC

The perceived need to administer a less toxic "standard" regimen of cyclophosphamide (CYC) has prompted many modifications.  One such modification that has gained popularity is as follows:

ANCA-Associated-Vasculitis

Birmingham Vasculitis Activity Score

Vasculitis damage index

Microsoft Word - VDI form in word.doc (canvasc.ca) 

The VDI requires that disease manifestations be present for at least 3 months before being scored as damage rather than ongoing activity.  The minimum score is 0, which would raise doubts about the diagnosis of vasculitis, while the maximum score is 64.   Since “once positive always positive,” the score can only stay unchanged or increase; it can never decrease . 

Initiation of high-dose corticosteroids, maybe starting with 1 g of IV methylprednisolone times three, followed by 60 mg of prednisone daily 

 Initiation of cyclophosphamide either as IV pulse or a daily oral dose. 

PO CYC: Oral Cytoxan start at 50 mg a day x 1 weeks, if labs ok increase to 100 mg a day - goal 150 mg a day for 3 to 6 months

IV CYC 750mg/m2 with mesna

He will need gastric prophylaxis, PCP prophylaxis, osteoporosis prophylaxis, as well as surveillance labs and urinalysis for those treatments. The use of MESNA with cyclophosphamide should be considered 



Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy 

Granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA) are related systemic vasculitides that, along with eosinophilic granulomatosis with polyangiitis (Churg-Strauss), make up the antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitides.  Both GPA and MPA are associated with ANCA, have many identical clinical manifestations, have many similar histologic features, and may have similar outcomes. There is, however, substantial heterogeneity among these disorders. 

Therapy for GPA and MPA has two main components: induction of remission with immunosuppressive therapy and maintenance of remission with immunosuppressive therapy for a variable period to prevent relapse. 

GENERAL PRINCIPLES

Goals of therapy — The goal of therapy in patients with granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA) is to achieve long-standing remission.  Treatment consists of an initial induction phase aimed to put patients with active disease into remission, followed by a maintenance phase that is intended to extend remission and prevent relapse.

Definitions of response:

INITIAL TREATMENT APPROACH

Immunosuppressive therapy is warranted in almost all patients with active granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA). The choice of therapy is discussed below.

Our management strategy is generally consistent with guidelines developed by professional organizations including the American College of Rheumatology (ACR)/Vasculitis Foundation [9] and Kidney Disease: Improving Global Outcomes (KDIGO).

Assessment of disease severity — Our approach to initial therapy depends largely upon the severity of disease and the organ systems involved. Other factors that may influence initial choice of therapy include patient-specific factors.

Alternative regimens

Avacopan — Some clinicians use the complement C5a receptor inhibitor avacopan (Tavenos) as an adjunctive agent with standard induction therapy to limit the use of glucocorticoids. Avacopan is administered as 30 mg orally twice daily, typically in combination with a shorter, reduced-dose glucocorticoid regimen in which glucocorticoids are tapered over four to six weeks depending upon patient response.  Use of avacopan should be avoided in patients with active, untreated, and/or uncontrolled chronic liver disease and patients who are taking moderate to strong CYP3A4 inducers; the dose should be reduced to 30 mg daily in patients who are taking strong CYP3A4 enzyme inhibitors .

The use of avacopan is supported by evidence from trials demonstrating disease remission with limited use of glucocorticoids.  In a trial including 331 patients with newly diagnosed or relapsing antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis, patients were randomly assigned to receive either oral avacopan 30 mg twice daily or prednisone on a tapering schedule; all patients received standard remission-induction therapy with cyclophosphamide (followed by azathioprine) or rituximab.  Approximately 80 percent of patients had kidney involvement. At 26 weeks, the rates of disease remission were similar between the two groups (72 percent in the avacopan group versus 70 percent in the prednisone group).  At 52 weeks, sustained remission was higher in the avacopan group than in the prednisone group (66 versus 55 percent). The rate of overall serious adverse events (excluding worsening vasculitis) was similar for both regimens (37 versus 39 percent for avacopan and prednisone, respectively).  Similar safety data have been found in a smaller trial of avacopan added to standard-of-care treatment for ANCA vasculitis.  It should be noted that glucocorticoids were also used by some patients in the avacopan group in the first few weeks following initiation of treatment, but the mean total dose was approximately one-third of that in the prednisone group (1349 mg versus 3655 mg).  In addition, patients in the avacopan group experienced less glucocorticoid-related toxicity than those in the prednisone group.  The safety and efficacy of avacopan beyond 52 weeks have not yet been addressed.

Maintenance therapy — After attainment of remission with induction immunosuppressive therapy, almost all patients are switched to a maintenance regimen.  The authors and reviewers of this topic think that certain low-risk, newly diagnosed patients who were originally MPO-ANCA positive and have attained a complete remission may be safely followed without maintenance therapy.  Since PR3-ANCA-positive patients as a group have a higher risk of relapse compared with MPO-ANCA-positive patients, the former are not included in this group. The selection of such MPO-ANCA-positive patients is individualized and is based upon whether the patient has risk factors for relapse (eg, the presence of lung or upper respiratory tract involvement prior to remission) or a tenuous clinical status (eg, an older individual with reduced glomerular filtration rate [GFR] is less likely to tolerate a relapse than a younger individual with normal GFR). If patients are managed without maintenance immunosuppression, they should be followed with frequent clinic visits, regular testing of serum creatinine, and weekly home urine dipsticks.

When to start maintenance therapy — The combination of glucocorticoids plus either rituximab or oral or IV cyclophosphamide induces remission in the majority of patients, usually within three to six months after the initiation of therapy.  Patients in whom remission or evidence of progressive improvement is not attained within six months should be considered to have disease resistant to the chosen induction regimen and have their treatment regimen altered.

The timing of initiation of maintenance therapy depends upon the induction regimen used:

Examples of patient-specific factors that may influence the choice of the maintenance agent include a prior history of toxicity from a certain drug and/or a comorbid condition that increases the risk of toxicity with a specific agent.

As examples:

Dosing of drugs that are used for maintenance therapy is discussed below. (See 'Dosing of maintenance therapy' below.)

The major, well-designed, randomized trials that examined the efficacy of maintenance therapy in patients with GPA or MPA included newly diagnosed patients almost exclusively, rather than relapsed patients. These trials are summarized below:

Data from observational studies and small trials also suggest that mycophenolate mofetil can maintain remission in patients with GPA or MPA [57-62]. As an example, in an open-label trial including 14 patients with GPA who received induction therapy with daily oral cyclophosphamide and prednisone and who were subsequently treated with mycophenolate mofetil (2 g/day), six patients (43 percent) relapsed at a median of 10 months [58]. A similar rate of relapse was noted in a retrospective study of 29 patients who received mycophenolate mofetil for maintenance therapy (48 percent at a mean of 14 months) [59].

Another large trial, the Wegener Granulomatosis Etanercept Trial (WGET), compared etanercept with placebo as add-on therapy in patients who were receiving cyclophosphamide or methotrexate for maintenance [17]. Etanercept provided no additional benefit and may increase the risk for malignancy; therefore, this drug should not be used for maintenance therapy.

Dosing of maintenance therapy

Dosing of rituximab — A variety of rituximab dosing strategies have been used, and it is not clear whether there is any one best option. Maintenance rituximab therapy is typically administered as 500 to 1000 mg every six months [55,63]. Some experts redose rituximab at four-month rather than six-month intervals [47]. Others prefer an "on-demand" dosing strategy, in which peripheral B lymphocyte (CD19-positive cells) counts, which are depleted by rituximab, and ANCA titers are monitored and the drug is redosed when B lymphocytes reconstitute and the ANCA titer becomes positive. As an example, one study of 53 patients with GPA found that, after remission induction with rituximab, relapse only occurred in patients whose CD19-positive cell count increased above 20 cells/microL and whose PR3-ANCA titers were positive [64]. By contrast, another study found that 29 percent of relapsing patients had depleted CD19-positive cell counts [65]. A randomized trial comparing an individually tailored and fixed-schedule rituximab regimen (500 mg IV every six months) among 162 patients with newly diagnosed or relapsing GPA or MPA who achieved complete remission after induction therapy reported comparable rates of relapse over 28 months [66]. The rates of adverse events and infectious complications were also similar between the two groups.

Some experts also routinely monitor serum immunoglobulin levels and reduce the dose of rituximab in patients who develop hypogammaglobulinemia. Others only monitor serum immunoglobulin levels if the patient develops frequent infections. (See "Secondary immunodeficiency induced by biologic therapies", section on 'Hypogammaglobulinemia'.)

Rituximab should not be given to patients who are positive for HBsAg or anti-HBc, without concurrent HBV therapy, due to the elevated risk of reactivation and potentially fatal hepatitis. (See "Hepatitis B virus reactivation associated with immunosuppressive therapy".)

Dosing of azathioprine — Azathioprine is typically initiated at a dose of 50 mg/day and gradually increased if thiopurine methyltransferase (TPMT) testing has not been performed prior to initiation of therapy. If this dose is tolerated well at one week, the daily dose can be increased over several weeks to 2 mg/kg per day. If TPMT testing is performed prior to the initiation of therapy and is normal, azathioprine can be initiated at 2 mg/kg per day. The maximum dose should typically not exceed 200 mg/day. In some trials, the dose of azathioprine was reduced at one year to 1.5 mg/kg per day, but this corresponded to an increase in relapse rate [18,67]. Thus, we do not reduce the dose of azathioprine.

Azathioprine metabolism and toxicity is predominantly related to TPMT activity, which varies among individuals. However, there is uncertainty regarding the benefits of routine testing for TPMT deficiency before beginning azathioprine. Although some clinicians routinely perform TPMT testing prior to initiating azathioprine, others do not perform such testing but rather initiate therapy at a low dose with close monitoring as the dose is gradually increased. The use of TPMT testing along with other potential adverse effects are discussed in detail separately. (See "Pharmacology and side effects of azathioprine when used in rheumatic diseases", section on 'Pharmacogenetics and azathioprine toxicity' and "Pharmacology and side effects of azathioprine when used in rheumatic diseases", section on 'Adverse effects'.)

Dosing of methotrexate — Methotrexate is typically initiated at a dose of 15 mg/week, with increases in dose every two to eight weeks of 5 mg/week up to 25 mg/week. We use the same regimen and approach to titration as that used in rheumatoid arthritis (see "Use of methotrexate in the treatment of rheumatoid arthritis"). This dosing strategy is similar to that used in the WEGENT trial and other studies [54,68]. Although methotrexate can be given both orally and subcutaneously, the bioavailability at such doses is superior through the subcutaneous route.

Because methotrexate is a structural analogue of folic acid that can competitively inhibit the binding of dihydrofolic acid (FH2) to the enzyme, dihydrofolate reductase (DHFR), folic acid (1 to 2 mg per day), or folinic acid (5 to 10 mg per week, 24 hours after methotrexate) should be given concurrently to reduce potential toxicity.

Given the risk of methotrexate toxicity in patients with reduced kidney function, this drug should not be used in patients with an eGFR <60 mL/min/1.73 m2 or evidence of active renal vasculitis.

Dosing of mycophenolate — The target dose of mycophenolate mofetil is typically between 1.5 and 3 g daily, in divided doses. One option is the regimen from the IMPROVE study (starting at 2000 mg per day followed by a reduction to 1500 and 1000 mg per day after 12 and 18 months, respectively), although this dose reduction was associated with an increased rate of relapses when compared with azathioprine in one trial [56]. Additional formulations (eg, enteric-coated mycophenolate sodium), dosing, and monitoring considerations for mycophenolate can be found elsewhere. (See "Mycophenolate: Overview of use and adverse effects in the treatment of rheumatic diseases".)

Duration of maintenance therapy — Our approach to the duration of maintenance therapy is based upon available data and clinical experience; other authorities have a different opinion about when to stop maintenance therapy. In addition, the duration of maintenance therapy should be modified if toxicity occurs:

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In most patients, we continue maintenance therapy for 12 to 24 months after stable remission has been induced [17,18,54,69].

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In patients with multiple risk factors for relapse (eg, PR3-ANCA seropositivity, pulmonary involvement, and upper respiratory tract involvement), we continue maintenance therapy for 24 to 36 months. Some experts would treat such patients indefinitely if the degree of organ damage was severe and a relapse would be poorly tolerated.

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We continue maintenance therapy indefinitely in patients who have had one or more prior relapses, particularly in those who sustained significant organ damage (eg, those with limited residual kidney function) and therefore would not tolerate further injury due to relapse.

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In some patients who have a low risk of relapse (eg, MPO-ANCA seropositivity and no respiratory tract involvement prior to remission), we continue maintenance therapy for 6 to 12 months. However, in such patients who become MPO-ANCA negative at the end of induction therapy, some experts would provide careful monitoring without any maintenance therapy.

Only two randomized trials have compared different durations of maintenance therapy:

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One trial compared standard duration (two years) and extended duration (four years) azathioprine maintenance therapy in 131 patients with newly diagnosed PR3-ANCA-associated vasculitis who received oral cyclophosphamide and glucocorticoids for induction therapy [70]. At four years after diagnosis, rates of relapse-free survival were comparable between the two groups.

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The Maintenance of Remission using Rituximab in Systemic ANCA-associated Vasculitis (MAINRITSAN)3 trial evaluated the efficacy of an extended rituximab maintenance regimen (500 mg given every 6 months over an additional 18 months) among 97 patients who had achieved complete remission after induction therapy and completing an initial 18-month rituximab maintenance regimen [69]. After 28 months of follow-up, the extended rituximab maintenance group had a lower incidence of relapse compared with the placebo group (4 versus 26 percent, respectively). In the placebo group, relapses were more common among patients who were PR3-ANCA positive than among those who were MPO-ANCA positive (40 versus 12 percent, respectively). Only one patient out of 29 with persistently negative ANCA levels relapsed, and none of five patients with both negative ANCA levels and undetectable CD19+ B cells relapsed. No deaths occurred in either group, and the frequency of adverse events was similar in both groups.

In addition, patients at lower risk for relapse (eg, MPO-ANCA-positive disease) may remain in remission without maintenance therapy after induction of remission. Some observational studies have found that discontinuation of maintenance therapy has not been associated with a substantial increase in relapses [71,72]. (See "Granulomatosis with polyangiitis and microscopic polyangiitis: Management of relapsing disease", section on 'Risk factors for relapse'.)

Patients who progress to ESKD and are treated with chronic dialysis have a substantially lower rate of relapse than the same patients before they reached ESKD or patients with preserved kidney function. The management of patients with GPA or MPA who have ESKD is presented elsewhere. (See 'Maintenance dialysis' below.)

The use of ANCA titers to predict relapse is presented elsewhere. (See "Granulomatosis with polyangiitis and microscopic polyangiitis: Management of relapsing disease", section on 'Monitoring for relapse'.)

Non-organ- and non-life-threatening disease — Patients with non-organ- and non-life-threatening GPA include those with rhinosinusitis, arthritis, and/or pulmonary nodules with no other major organ involvement [73-78]. (See 'Assessment of disease severity' above.)

For patients with non-organ- and non-life-threatening GPA not involving the kidney, we suggest induction therapy with glucocorticoids combined with weekly oral methotrexate (20 to 25 mg per week orally), rather than glucocorticoids combined with cyclophosphamide, rituximab, or azathioprine. However, given the risk of toxicity in patients with kidney dysfunction, methotrexate should not be used when the eGFR is below 60 mL/min per 1.73 m2 or if there is evidence of active glomerulonephritis. Rituximab is a reasonable alternative as induction therapy, even in non-organ- and non-life-threatening disease. Azathioprine may be used as an alternative to methotrexate for pregnant patients or patients for whom methotrexate should be avoided due to moderate to severe kidney function impairment. However, there are no high-quality data regarding use of azathioprine for induction of remission in this patient population, and, in our experience, azathioprine may take longer than methotrexate to become maximally effective as an immunosuppressive agent. If rituximab is used, we use the same dose as that used for induction therapy in patients with organ- or life-threatening disease. If azathioprine is used, we use the same dose as that used for maintenance therapy in patients with organ- or life-threatening disease. (See 'Rituximab-based regimen' above and 'Dosing of azathioprine' above.)

Methotrexate may be continued as maintenance therapy at the same dose used for induction, provided that patients have responded to induction therapy. Similarly, if rituximab or azathioprine is used as induction therapy, it may also be continued as maintenance therapy. Maintenance dosing for rituximab and azathioprine is similar to that for patients with organ- or life-threatening disease and is discussed above. (See 'Dosing of rituximab' above and 'Dosing of azathioprine' above.)  

Patients with non-organ- and non-life-threatening disease may be able to be treated with lower doses of glucocorticoids than used for patients with organ- or life-threatening disease. We typically initiate prednisone at 0.5 mg/kg/day (or its equivalent) followed by a reduced-dose glucocorticoid taper. Details about glucocorticoid dosing and taper are presented elsewhere in this topic. (See 'Glucocorticoid dosing and taper' above.)

Available data suggest that methotrexate is as effective for induction of remission in patients with non-organ- and non-life-threatening disease but may be associated with a higher relapse rate. The Nonrenal Wegener's Granulomatosis Treated Alternatively with Methotrexate (NORAM) trial compared methotrexate and cyclophosphamide for both induction and remission in 89 patients with newly diagnosed GPA and six patients with MPA, none of whom had significant kidney involvement (mean serum creatinine of 1 mg/dL [85 micromol/L] and microscopic hematuria in only 28 percent); the majority of patients had upper respiratory tract involvement [76]. At six months, 90 and 94 percent of patients in the methotrexate and cyclophosphamide arms, respectively, achieved remission, although time to remission was two months longer in the methotrexate group. Among the patients who achieved remission, the relapse rate at 18 months was significantly higher with methotrexate (70 versus 47 percent with cyclophosphamide). There was a higher incidence of leukopenia among those treated with cyclophosphamide and a higher incidence of liver function test abnormalities among those treated with methotrexate. Two patients in each group died.

Methotrexate was also used for induction of remission among patients with nonsevere disease enrolled in the WGET trial; remission rates with methotrexate were similarly high in this subset of patients with GPA [17].

Monitoring the response to therapy — All patients receiving immunosuppressive therapy for GPA or MPA should be closely monitored.

Patients with organ- or life-threatening disease are typically admitted to the hospital for treatment with close monitoring of their clinical status and laboratory testing on a daily basis. If the patient has pulmonary hemorrhage, serial chest radiographs and/or a computed tomography (CT) of the chest are reasonable to monitor for worsening alveolar hemorrhage. When the patient's condition is stable enough for discharge from the hospital, we typically schedule follow-up visits every two to four weeks for the first three months. Subsequently, the duration between follow-up visits can then be extended to every two to three months. The goal of these visits is to evaluate the patient's response to therapy (ie, whether a clinical response is achieved) and the toxicity of the regimen (ie, adverse effects, infections due to immunosuppression). We perform the following assessments during these visits:

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History and physical examination

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Assessment of blood pressure

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Measurement of serum creatinine and electrolytes

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Urinalysis with microscopic examination of the urinary sediment

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Complete blood count

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Erythrocyte sedimentation rate and/or C-reactive protein level

Clinical practice varies in the monitoring of ANCA titers among patients being treated for GPA or MPA. Some authors and editors routinely monitor ANCA titers, particularly among patients with kidney involvement, to assess the response to therapy and risk of relapse [65,79-82]. Other contributors do not routinely monitor ANCA titers, since ANCA titers do not consistently reflect disease activity. Additional information about ANCA titers in patients with GPA or MPA is presented elsewhere. (See "Granulomatosis with polyangiitis and microscopic polyangiitis: Management of relapsing disease", section on 'Monitoring by the clinician'.)

Additional organ-specific testing may be required for some patients. As an example, repeat CT of the chest is advised for patients with tracheal and/or pulmonary involvement to document remission or prior active disease and/or to establish a new baseline. In addition, serial audiograms should be performed in patients with any form of hearing loss related to GPA or MPA.

Other treatment considerations

Treatment-associated toxicity — Cyclophosphamide, rituximab, azathioprine, methotrexate, mycophenolate, and glucocorticoids are all associated with important toxicity. In addition to the toxicities discussed below, cytotoxic agents are toxic to the fetus. (See "Pregnancy in patients with nondialysis chronic kidney disease" and "Safety of rheumatic disease medication use during pregnancy and lactation" and "General principles of the use of cyclophosphamide in rheumatic diseases".)

Adverse effects of these drugs are discussed in separate topics:

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Cyclophosphamide (see "General toxicity of cyclophosphamide in rheumatic diseases")

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Rituximab (see "Rituximab: Principles of use and adverse effects in rheumatoid arthritis" and "Infusion-related reactions to therapeutic monoclonal antibodies used for cancer therapy", section on 'Rituximab')

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Azathioprine (see "Pharmacology and side effects of azathioprine when used in rheumatic diseases")

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Methotrexate (see "Major side effects of low-dose methotrexate")

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Mycophenolate (see "Mycophenolate: Overview of use and adverse effects in the treatment of rheumatic diseases")

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Glucocorticoids (see "Major side effects of systemic glucocorticoids")

Prevention of opportunistic infections and vaccinations — We typically administer prophylaxis to prevent Pneumocystis jirovecii pneumonia in all patients initiating immunosuppressive therapy with cyclophosphamide or rituximab in combination with prednisone at a dose ≥20 mg/day (or equivalent dose of a different glucocorticoid). We discontinue prophylaxis when the dose of prednisone is tapered to less than 5 to 10 mg/day. Most commonly, we use trimethoprim-sulfamethoxazole (one single-strength [80 mg/400 mg] tablet daily or one double-strength [160 mg/800 mg] tablet three times per week). Other prophylactic regimens are discussed in detail separately (see "Treatment and prevention of Pneumocystis pneumonia in patients without HIV"). In one patient cohort, Pneumocystis pneumonia developed in 11 of 180 patients (6 percent) with GPA, all of whom were treated with daily glucocorticoids and a second immunosuppressive drug [83].

In addition to P. jirovecii pneumonia, patients treated with immunosuppressive therapy for GPA or MPA are at high risk for infections [84,85]. Given this increased risk of infection, patients should receive age-appropriate vaccinations, including those against pneumococcus, influenza, and herpes zoster (see "Immunizations in autoimmune inflammatory rheumatic disease in adults"). In one large study, for example, the cumulative incidence of infection was 51 percent during the first year of treatment [84]. Most infections involved the respiratory tract, and most positive cultures revealed Staphylococcus aureus.

Management of respiratory tract and upper airway involvement — The management of central airway obstruction and diffuse alveolar hemorrhage are discussed separately. (See "Clinical presentation, diagnostic evaluation, and management of malignant central airway obstruction in adults" and "The diffuse alveolar hemorrhage syndromes", section on 'Treatment'.)

The consequences of upper airway involvement are often not improved by initial immunosuppressive therapy and are not considered resistant disease.

Nasal ulcers and crusting are common manifestations of upper airway disease in ANCA-associated vasculitis, particularly in GPA. It is often difficult to determine whether these lesions are attributable to vasculitis, infection, or both. Although oral antibiotics are frequently required to treat more severe infections in the upper respiratory tract, some experts prefer a trial of topical therapy for nasal ulcers and crusting. This approach may involve direct application of antibiotic ointment just inside of the nares and/or nasal irrigation with a saline solution to which topical antibiotics have been added. Nasal saline sprays are available over the counter or may be made up as 1 quart of water with 1 teaspoon of brine or pickling salt and 1 teaspoon of baking soda.

Lesions of the tracheobronchial tree can cause a variety of problems. The most serious complications include tracheal or bronchial stenosis that can lead to respiratory failure or postobstructive pneumonia. Clinicians should have a low threshold for referring patients with any signs or symptoms of suspected subglottic stenosis (eg, stridor, hoarseness, or unexplained dyspnea) to an otolaryngologist familiar with this problem. Treatment options for these problems include airway dilation with or without stenting. For subglottic stenosis, intralesional injection of glucocorticoids in combination with endoscopic dilation may avoid the need for more invasive surgical procedures [86,87].

Tracheostomy should be avoided whenever possible. When tracheostomy is necessary, most patients are able to have the tracheostomy tube removed. This was illustrated in a retrospective report of 27 patients with ANCA-associated vasculitis: 11 required tracheostomy, and three could not be decannulated [88]. (See "Clinical presentation, diagnostic evaluation, and management of malignant central airway obstruction in adults".)

Stenosing lesions of the nasal passages and destructive lesions of the nasal cartilage and bones may cause discomfort and/or be disfiguring. Reconstructive surgery may provide a functional airway and can restore a more normal-appearing nose [89]. Grafts prepared from a patient's costal or auricular cartilage, iliac or other bone, or dura have been used with varying success.

SPECIAL POPULATIONS

Pregnant patients — There is only limited information on pregnancy complicated by granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA) [90,91]. The major challenges in treating active disease during pregnancy are the moderate to high risk of fetal harm associated with various therapies used for induction or maintenance of remission, including cyclophosphamide, methotrexate, and mycophenolate. In addition, there are limited data regarding the safety of rituximab in pregnancy:

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(See "Safety of rheumatic disease medication use during pregnancy and lactation", section on 'Cyclophosphamide'.)

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(See "Safety of rheumatic disease medication use during pregnancy and lactation", section on 'Methotrexate'.)

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(See "Safety of rheumatic disease medication use during pregnancy and lactation", section on 'Mycophenolate mofetil'.)

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(See "Safety of rheumatic disease medication use during pregnancy and lactation", section on 'Rituximab'.)

The immunosuppressive drugs considered safer during pregnancy that have been effective in GPA and MPA include glucocorticoids, azathioprine, and cyclosporine (or tacrolimus), particularly in mild to moderate disease. These drugs can also be tried for severe disease, but such an approach may necessitate prolonged use of high-dose glucocorticoids and a slower glucocorticoid taper. Alternatives that could be considered include rituximab or cyclophosphamide in the second or third trimester once organogenesis is complete, although data are limited and the risks and benefits must be weighed carefully.

The ongoing online Vasculitis Pregnancy Registry (V-PREG) study is collecting data on maternal and fetal outcomes in antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (and other vasculitides) in order to provide informed guidance to patients and clinicians on the management of vasculitis during pregnancy.

Older patients — Among patients with GPA or MPA, it is not uncommon for patients to present with new-onset disease at age 75 years or older. Studies have demonstrated that older age is an independent risk factor for worse outcomes in ANCA-associated vasculitis, both due to life-threatening infections and to disease-related morbidity, notably end-stage kidney disease (ESKD) [92,93]. The increased risk of serious infections in older patients and the substantive risk of infection associated with glucocorticoids highlight the need to use "glucocorticoid-sparing" approaches in this patient population.

Older patients with ANCA-associated vasculitis respond well to the same treatment approaches to induction of remission as do younger patients [24], and use of rituximab or cyclophosphamide (in reduced dosing based on kidney function and age) should not be withheld due to age. Regimens to maintain remission in ANCA-associated vasculitis are especially important for older patients to avoid repeat use of glucocorticoids and to preserve residual kidney function. However, as with all treatment of ANCA-associated vasculitis, the risks of prolonged immunosuppression and infection must be weighed against the benefits of avoiding a relapse of vasculitis.

Patients with end-stage kidney disease

Maintenance dialysis — Little is known concerning the optimal treatment of patients with GPA or MPA who develop ESKD and require maintenance dialysis. Such patients have a higher risk of death as compared with patients who do not develop ESKD. (See 'Prognosis and other outcomes' below.)

Further management varies with the clinical setting:

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No active disease – If the patient has no evidence of active kidney disease (ie, absence of hematuria with dysmorphic red cells in the urine sediment, which must be distinguished from isomorphic [normomorphic] hematuria that may be due to cyclophosphamide-induced bladder injury) and has no active extrarenal disease, we continue immunosuppressive therapy until the patient has completed three to six months of maintenance therapy. If, at that time, the patient continues to have inactive disease, then we typically discontinue immunosuppressive therapy. (See 'Maintenance therapy' above.)

It is unclear how much benefit is provided by usual maintenance therapy to prevent relapse in patients with ESKD since the rate of relapse is substantially reduced in dialysis [94,95]. In an analysis of 229 patients on maintenance dialysis followed for a mean of 4.6 years, the relapse rate decreased from 57 to 7 episodes per 100 person-years before and after dialysis initiation [95]. During the follow-up period, 45 percent of patients had a serious infection and 45 percent had a cardiovascular event, while 13 percent experienced disease relapse.

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Active kidney but not extrarenal disease – If the patient has persistent dysmorphic hematuria and no extrarenal disease, we treat with immunosuppressive therapy in a manner similar to patients without ESKD with appropriate dose adjustments in medications for the kidney failure. The purpose of continued therapy in patients with active kidney but without extrarenal manifestations is that control of the renal vasculitis might result in enough recovery of kidney function to permit the discontinuation of dialysis. However, treating such patients beyond four months is of limited benefit [96]. (See 'Induction therapy' above and 'Maintenance therapy' above.)

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Active extrarenal disease – We and other investigators treat patients on chronic dialysis with active extrarenal GPA or MPA in the same manner as those who do not require maintenance dialysis, with the duration of therapy and therapeutic regimen being based upon patient response and whether relapse has occurred and with appropriate dose adjustments in medications for the kidney failure. (See 'Induction therapy' above and 'Maintenance therapy' above.)

Even if a decision is made to discontinue immunosuppressive therapy in patients on chronic dialysis, it is imperative that all patients with a history of GPA or MPA be followed indefinitely for the potential to relapse in other organ systems, even many years following the onset of kidney failure.

The following immunosuppressive drugs should either not be used or not be used at standard doses in patients with ESKD:

●

Methotrexate should not be given as maintenance therapy to patients who are on dialysis or have moderate to severe chronic kidney disease.

●

Given the increased risk of severe bone marrow suppression in patients with ESKD, cyclophosphamide should be used cautiously with careful monitoring. Dose adjustment for cyclophosphamide in dialysis patients is not well defined. A suggested approach for oral cyclophosphamide is 50 percent of the usual dose after each hemodialysis session and 75 percent of the usual dose in patients on continuous ambulatory peritoneal dialysis (table 1).

Kidney transplantation — Patients who develop ESKD due to GPA or MPA are potential candidates for kidney transplantation. At a minimum, transplantation should be delayed for at least six months from the time of initial presentation or most recent relapse [97]. The presence of a positive ANCA titer at the time of transplantation does not appear to predict recurrence of glomerulonephritis in the transplanted organ. Thus, persistence of an isolated positive ANCA titer is not a contraindication to kidney transplantation.

It is likely that the immunosuppression administered for the prevention of allograft rejection contributes to the prevention of disease flares among patients with GPA or MPA [98,99].

Several studies have shown that long-term outcomes of patients with GPA or MPA who receive a kidney transplant are comparable to those of patients transplanted for other causes of ESKD [100-103].

Drug-induced ANCA-associated vasculitis — Certain medications (eg, hydralazine, propylthiouracil, minocycline) may induce vasculitis associated with antineutrophil cytoplasmic autoantibody (ANCA), mostly myeloperoxidase (MPO)-ANCA. (See "Clinical spectrum of antineutrophil cytoplasmic autoantibodies", section on 'Drug-induced ANCA-associated vasculitis'.)

The optimal management of drug-associated ANCA and the course of the disease are uncertain given the limited reports in the literature. Discontinuation of the offending agent may be the only intervention necessary for mild cases of ANCA-associated vasculitis induced by medications. Examples include cases presenting with constitutional symptoms, arthralgias/arthritis, or cutaneous vasculitis, but without lung or kidney involvement.

Patients with more severe disease manifestations such as lung or kidney involvement, which are common with hydralazine, require treatment with high doses of glucocorticoids and even rituximab or cyclophosphamide. As an example, in one series of 80 cases of hydralazine-induced ANCA-associated glomerulonephritis, 42 of 51 patients with long-term follow-up received immunosuppressive therapy [104]. (See 'Induction therapy' above and "Clinical spectrum of antineutrophil cytoplasmic autoantibodies", section on 'Hydralazine'.)

Patients with drug-induced ANCA-associated vasculitis do not typically require maintenance therapy; relapse should not occur if the responsible drug is discontinued. However, attributing ANCA-associated vasculitis to a drug may be incorrect, and therefore careful and frequent monitoring of the patient is required after discontinuation of the presumed causative agent.

The risk of recurrence with re-exposure to the drug is unclear. Given the potential morbidity associated with drug-induced ANCA-associated vasculitis, we do not advocate for rechallenge with the potentially offending agent.

Double-positive ANCA and anti-GBM disease — Patients who are double positive for antineutrophil cytoplasmic autoantibody (ANCA) and anti-glomerular basement membrane (anti-GBM) antibodies should be managed initially as patients with anti-GBM disease since this is the more severe lesion. The initial treatment of such patients should include plasmapheresis plus immunosuppressive therapy, even among those with dialysis-requiring kidney failure. These issues are discussed in more detail elsewhere. (See "Anti-GBM (Goodpasture) disease: Treatment and prognosis", section on 'Double-positive anti-GBM and ANCA-associated disease'.)

However, unlike patients with single-positive anti-GBM disease, double-positive patients will require maintenance therapy for ANCA disease because of the tendency of vasculitis to relapse. (See 'Maintenance therapy' above.)

INVESTIGATIONAL APPROACHES

Several investigational agents have been tried or are under investigation for patients with granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA), including abatacept [105], belimumab [106], vilobelimab, and B cell-targeted immunotherapy [107]. Additional studies are required before these therapies can be routinely used in clinical practice.

PROGNOSIS AND OTHER OUTCOMES

Granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA) are associated with considerable morbidity and mortality that are due to either irreversible organ dysfunction from inflammatory injury or the consequences of prolonged and/or intensive therapy with glucocorticoids and other immunosuppressive agents:

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Mortality – Untreated patients have a 90 percent mortality rate within two years. The long-term survival in patients with GPA and MPA has improved dramatically since the additions of cyclophosphamide and rituximab to the therapeutic regimen [108,109]. However, patients with GPA and MPA still have a higher mortality rate compared with the general population [110,111]. A meta-analysis of observational studies of patients with GPA and MPA reported a 2.7-fold increased risk of death in patients compared with the general population (95% CI 2.26-3.24) [110].

The major causes of death in patients with GPA and MPA are complications from immunosuppressive therapy (primarily infection), complications from the underlying disease (eg, kidney failure, pulmonary failure), and cardiovascular disease [94,112-114].

Higher mortality rates are observed among older adults and those who present with florid organ failure, such as patients with diffuse pulmonary hemorrhage requiring ventilatory support or advanced kidney dysfunction [115,116]. End-stage kidney disease (ESKD) and overall mortality are higher in older adult patients (age >80 years). As an example, a retrospective study including 78 patients >80 years old who had biopsy-proven pauci-immune glomerulonephritis, of whom 93 percent had a positive ANCA, found that ESKD was more common in the untreated group at one year (73 versus 36 percent) [117].

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Malignancy risk – Some studies suggest that patients with GPA or MPA may have a higher incidence of cancer compared with the general population, with estimates ranging from 10 to 26 percent [118]. The increased risk of malignancy has been described with non-melanoma skin carcinomas (NMSCs), hematologic malignancies, and bladder, breast, lung, prostate, and colorectal carcinomas [119,120]. To some degree, some of the increased risk is associated with immunosuppressive treatment [121]. As treatment regimens for GPA and MPA have evolved over the past decade to include shorter courses of cyclophosphamide, more contemporary studies have suggested that the risk of cancer may be decreasing [119,122].

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Infection – Approximately 25 to 30 percent of patients with GPA and MPA will develop a serious infection that requires hospitalization, with respiratory infections being the most common [123-126]. Patients are at highest risk for infection in the first year after diagnosis, which is most likely related to the higher intensity of immunosuppression during this time period, including the use of high-dose glucocorticoids [123,127,128].

The use of immunosuppressive agents to treat GPA and MPA is a primary factor contributing to the risk of infection in these patients. Several studies have evaluated the risk of infection associated with different immunosuppressive regimens used to treat GPA or MPA. As an example, two randomized trials found no difference in infection rates between patients receiving a rituximab-based regimen and those receiving a cyclophosphamide-based regimen as induction therapy [19,21]. Trials comparing different maintenance regimens have reported similar rates of infection among patients treated with azathioprine, methotrexate, mycophenolate mofetil, rituximab, or oral cyclophosphamide [18,54-56].

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End-stage kidney disease – Since the kidney is a frequent target organ in patients with either GPA or MPA, progressive kidney failure may be observed. In different series with a variable duration of follow-up, ESKD occurred in 10 to 26 percent of patients [2,94,112,115,129-132]. The incidence of ESKD among patients with GPA and MPA has fallen over the past several decades. In a study of an inception cohort of 554 patients with kidney disease at time of diagnosis, the five-year risk of ESKD decreased over time [108]. Serum creatinine at baseline was the only significant predictor of risk of ESKD.

The principal determinants of a poor kidney outcome include more severe kidney dysfunction at presentation, lack of response to initial treatment, renal relapses, age greater than 65 years, and prominent fibrotic changes, such as interstitial fibrosis and glomerulosclerosis on initial kidney biopsy [2,115,129,133-135]. By comparison, responsiveness to immunosuppressive therapy and improved kidney function over time can be observed among patients with predominantly active kidney lesions at disease presentation.

Severe initial kidney involvement does not preclude the induction of remission or clinically significant improvement in kidney function with appropriate therapy. In a report of newly diagnosed patients, remission was induced in 72 percent of 240 patients with an estimated glomerular filtration rate (eGFR) ≤30 mL/min/1.73 m2, 68 percent of 188 patients with an eGFR ≤20 mL/min/1.73 m2, and 57 percent of 96 patients with an eGFR ≤10 mL/min/1.73 m2 [129]. On the other hand, severe kidney disease at presentation was also a risk factor for cyclophosphamide resistance (odds ratio 1.28 per 1.13 mg/dL [100 micromol/L] elevation in serum creatinine).

Among patients who require dialysis during the acute phase of the disease, 55 to 90 percent recover enough function to come off dialysis [3,115,129,136-138], with 40 to 70 percent being maintained off dialysis for three years or more [3,139].

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Cardiovascular risk – Patients with GPA or MPA may have an increased risk of cardiovascular events, including thromboembolism [140-146]. In a cohort study that examined cardiovascular events among 2306 patients with GPA or MPA and 6918 controls, a diagnosis of GPA or MPA was associated with an increased risk of ischemic heart disease (HR 1.86, 95% CI 1.62-2.15), heart failure (HR 2.12, 95% CI 1.77-2.54), myocardial infarction (HR 1.62, 95% CI 1.26-2.09), atrial fibrillation (HR 2.08, 95% CI 1.82-2.39), ventricular arrhythmia/defibrillator implantation (HR 2.04, 95% CI 1.16-3.57), and ischemic stroke (HR 1.58, 95% CI 1.31-1.90) [142]. Patients with GPA or MPA also had an increased risk of undergoing percutaneous coronary intervention (HR 1.56, 95% CI 1.17-2.07) and in-hospital cardiac arrest (HR 2.27, 95% CI 1.49-3.48).

The reasons for an increased risk of cardiovascular disease among patients with GPA and MPA are not clear, but some investigators speculate this may relate to the impact of nontraditional risk factors, including chronic inflammation, use of glucocorticoids, and chronic kidney disease. As an example, in a retrospective multinational study of 2286 patients with ANCA-associated vasculitis, risk factors for myocardial infarction and stroke included pulmonary and kidney involvement (HR 1.5 and 3.0, respectively), older age, and history of smoking [147].

Clinicians and patients are advised to be vigilant about evaluating and treating established risks of cardiovascular disease, including hypertension, diabetes mellitus, hyperlipidemia, and obesity; these comorbidities may be more prevalent among patients with GPA and MPA.

SOCIETY GUIDELINE LINKS

Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Glomerular disease in adults" and "Society guideline links: Vasculitis".)

INFORMATION FOR PATIENTS

UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

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Basics topics (see "Patient education: Granulomatosis with polyangiitis (The Basics)")

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Beyond the Basics topics (see "Patient education: Vasculitis (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

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Goals of therapy – The goal of therapy in patients with granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA) is to achieve a rapid, long-standing remission. Treatment consists of an initial induction phase aimed to put patients with active disease into remission, followed by a maintenance phase that is intended to extend remission and prevent relapse. (See 'Goals of therapy' above.)

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Approach to initial therapy – Immunosuppressive therapy is warranted in almost all patients with active GPA or MPA. Our approach to initial therapy depends largely upon the severity of disease and the organ systems involved (algorithm 1):

•

Organ- or life-threatening features include, but are not limited to, active glomerulonephritis, pulmonary hemorrhage, cerebral vasculitis, progressive peripheral or cranial neuropathy, orbital pseudotumor, gastrointestinal bleeding due to vasculitis, or cardiac disease due to vasculitis (pericarditis, myocarditis).

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Patients with non-organ- or non-life-threatening disease have no evidence of "active glomerulonephritis" (ie, serum creatinine that is stable compared with baseline and no red cell casts or proteinuria) and no organ-threatening or life-threatening manifestations. (See 'Assessment of disease severity' above.)

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Organ- or life-threatening disease

•

Induction therapy

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Rituximab- or cyclophosphamide-based regimen – For patients with GPA or MPA who have organ- or life-threatening disease, we recommend an induction regimen consisting of glucocorticoids in combination with either rituximab or cyclophosphamide, rather than glucocorticoid monotherapy (Grade 1B). Some authors/editors choose a rituximab-based regimen for the majority of patients, given its comparable efficacy and different side-effect profile compared with cyclophosphamide. Other authors/editors favor a cyclophosphamide-based regimen as initial therapy, particularly in patients presenting with more severe kidney disease and/or pulmonary hemorrhage. Some authorities treat with glucocorticoids in combination with both rituximab and cyclophosphamide. (See 'Induction therapy' above.)

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Glucocorticoid dosing – For most patients with GPA or MPA receiving glucocorticoids in combination with a glucocorticoid-sparing agent, we recommend a reduced-dose glucocorticoid tapering regimen rather than the standard-dosing taper (Grade 1B). Dosing of glucocorticoids is discussed above. (See 'Glucocorticoid dosing and taper' above.)

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Role of plasma exchange – The authors/editors of this topic do not fully agree on the role of plasma exchange among patients with GPA or MPA. All authors agree with the use of plasma exchange in most patients with GPA or MPA who are concomitantly positive for anti-glomerular basement membrane (anti-GBM) autoantibody. Other authors would also offer plasma exchange in patients who present with pulmonary hemorrhage and/or severe active kidney disease with kidney biopsy findings showing active inflammation without significant glomerulosclerosis. (See 'Role of plasma exchange' above.)

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Maintenance therapy – In most patients who achieve remission after induction immunosuppressive therapy, we suggest treatment with rituximab for maintenance of remission (Grade 2C). Azathioprine, methotrexate, and mycophenolate are reasonable alternatives and may be preferred based on other patient-specific factors. Maintenance therapy in patients with newly diagnosed GPA or MPA is usually given for 12 to 24 months after stable remission has been induced. (See 'When to start maintenance therapy' above and 'Choice of maintenance therapy' above and 'Dosing of maintenance therapy' above and 'Duration of maintenance therapy' above.)

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Non-organ- and non-life-threatening disease – Patients with non-organ- or non-life-threatening disease have no evidence of "active glomerulonephritis" (ie, serum creatinine that is stable compared with baseline and no red cell casts or proteinuria) and no organ-threatening or life-threatening manifestations. For patients with non-organ- and non-life-threatening GPA not involving the kidney, we suggest initial therapy with glucocorticoids combined with weekly oral methotrexate rather than glucocorticoids combined with cyclophosphamide, rituximab, or azathioprine (Grade 2C). Rituximab is a reasonable alternative as initial therapy, even in non-organ- and non-life-threatening disease. Azathioprine may be used as an alternative to methotrexate for pregnant patients or patients for whom methotrexate should be avoided due to moderate to severe kidney function impairment. (See 'Non-organ- and non-life-threatening disease' above.)

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Monitoring – All patients receiving immunosuppressive therapy for GPA or MPA should be closely monitored. Patients with organ- or life-threatening disease are typically admitted to the hospital for treatment with close monitoring of their clinical status and laboratory testing on a daily basis. When the patient's condition is stable enough for discharge from the hospital, we typically schedule follow-up visits every two to four weeks for the first three months. Subsequently, the duration between follow-up visits can then be extended to every two to three months. The goal of these visits is to evaluate the patient's response to therapy and the toxicity of the regimen. (See 'Monitoring the response to therapy' above.)


Cytoxan (CYC) 50 mg daily for 2 weeks started on 2/10/2020, titrated up to 100 mg qd > WBC dropped > reduced CYC dose to 50 mg, then up to 75 mg qday.  3/31/2020 increased to 100 mg qd.  4/16/2020, increased ot 150 mg qday. 5/29/2020, reduced to 125 mg due to nausea.  Prednisone 7.5 mg a day.  July cytoxan 150 mg a day prednisone 7.5 mg a day -> tapered off oral cytoxan with plan for rituximab maintenance in August but did not start. 

Aug 2020 solumedrol pulse 1 gram x 5 doses and IVIG x 5 days

Cytoxan Eurolupus protocol (dose 1 August 28, dose 2 Sept 11, 2020, October 14th, October 28th and November 11) 

Rituxan 1 gram x 2 (dose 1 Sept 6, dose 2 October 1 , 2020) 

Cellcept started fall 2020

IVIG -HELD since Sept 2020 due to a new PE

Prednisone OFF since December 2020

Fall 2021 pulse steroids and PLEX, cellcept started 

TOTAL CYTOXAN ABOUT 20 GRAMS  

PLASMA EXCHANGE + IV CYCLOPHOSPHAMIDE PROTOCOL

Utility: This protocol is for use in patients with motor and anti-MAG neuropathies.


Treatment regimen: During each cycle of treatment patients receive plasma exchange (1.5 plasma volumes) with 5% albumin replacement on two consecutive days. This is followed by hydration (1 to 1.5 liters), then 1g/M2 of cyclophosphamide given intravenously over 3 to 4 hours, and, finally, further hydration (1 to 1.5 liters).


During a course of therapy this regimen is given 6 times, one every 4 weeks. The patient is treated with cyclophosphamide (Cytoxan), a total of 1.0 gm/M2 intravenously over a period of 3 hours. Patients should be otherwise healthy and without evidence of infection for the prior 1-2 weeks. The protocol should probably be modified in debilitated patients.


Precautions taken to avoid side effects include:


The Universal Checklist

Hep B/C screening? Checking hepatitis B today; hep C negative 

TB Quantiferon? Dual testing advised, IGRA favored over TST by ID negative 

Annual flu vaccine? Received 

Pneumonia vaccine every 5 years? Received a few years ago 

Shingrex vaccine? Did not receive 

Covid Due to receive booster tomorrow 

Live Vaccines? avoid none 

Pregnant/Breastfeeding? N/A 

Cancer history? Hemorrhagic cystitis diagnosed on biopsy, but not felt to be a bladder cancer 

Infections? Ongoing or Past none 

Switching Immunosuppressant? Give at least 1 month 'holiday' after discontinuing one prior to starting new agent 


Prednisone

Start Date? Started November 2021 

CBC Q1mo then Q3mo? Completes monthly 

BMP Q monthly then Q3mo (look for lo K)? Completes monthly 

Dose? Currently on 50mg daily 

WBC <4? 9.4 

PCP prophylaxis with Bactrim? If CCS + CCS-sparing agent or if ALC < 0.8 or CD4 lymph count <200-400 Taking 

DEXA? Has osteoporosis; seen PCP next week 

Calcium 1200mg daily 

Vitamin D 800 units daily Taking 

HgbA1c? / glucose Checking today 

Hypertensive? Does not check BP at home 

Cataracts? Annual eye exam Follows with

GI bleeding? ASA and NSAIDs incr risk none 

GI prophylaxis? Taking omeprazole 

Allopurinol or NSAID use? 

Lasix use? worsens hypokalemia 


IVIG

Start date TBD 

Monthly CBC? 

Leukopenia? Last WBC? normal 

Hemolytic anemia? Last Hgb noraml 

Monthly BUN / Cr? 

Last values? normal 

Infusion frequency? Weekly 

Dosing (g/kg)? 

Planned frequency or dose reduction?

Some Dutch studies advocate weaning trial at 6 months TBD 

Planned duration therapy? TBD 

Thrombosis? DVT, stroke, MI History of PE in September 2020 

Skin rash? 

Headache? Prophylaxis? Abortive? 


Methotrexate

Start Date 

Dose 25 mg weekly 

CBC weekly for 1mo then Q1mo for 3mo then Q3mo thereafter (last check)? Checking 

Absolute Neutrophil Count < 1.0? 8.60 

Absolute lymphocyte count <0.6? 0.50 

WBC <3? 9.4 

MCV > 100? predictor of folate depletion 96 

BUN/Cr Q1mo then Q3mo (last check)? normal 

LFTs monthly for 3 month then Q3mo? normal 

Hepatotoxicity/fibrosis history? normal 

Annual PFTs? Interstitial Lung Disease / pneumonitis? ILD is contraindication to MTX 

Cutaneous rash? usually within days of dose > reduce dose, if no improvement, discontinue 

Stomatitis? if present, increase folic acid to 2mg daily no 

Folate Supplementation?

Do not give at same time as MTX (lowers effect) Taking 

NSAID use? Myelosuppression and AKI more common with concomitant use no 

Down syndrome? increased risk BM suppression (esp with MTX) no  


Template case:

REASON FOR REFERRAL: Paresthesia.


HISTORY OF PRESENT ILLNESS:  PE is a 70-year-old, right-handed woman with history of strokes, seizures, cigarette smoking, and alcohol use COPD, hypertension, and hyperlipidemia is referred paresthesia with a specific question with regards to vasculitic neuropathy.


As per the referring clinician, patient had left sural and gastrocnemius muscle biopsy (8/3/2023): Report not available for review.  As per the referring clinician, Bradley H Gould (PA) Telephone communication note (8/9/2023): "D/w U ofM Pathologist that nerve biopsy is suggestive of necrotizing vasculitis and muscle biopsy prelim suggests neuropathic changes.  Reviewed course and labs.  Pt is indicated for urgent follow up with Rheumatology and Neuromuscular Neuro.  Will reach out to Rheum (urgent referral order also placed) and try to expedite Neuromuscular Neuro eval.  Attempted to call pt multiple times to explain this but goes to voicemail and her voicemail box is full."


xx states that she had developed feeling of numbness in her right foot around November last year.  Since then it has progressed to the left foot.  She notes occasional pins and needle and burning sensation across the dorsum of her toes and midfoot.  She was started on gabapentin by her PCP at 300 mg p.o. 3 times daily but notes it has not helped alleviate her symptoms.  She was also started on OxyContin which helped relieve her pain but made us sleep excessively.  As per chart review, she was also trialed on amitriptyline without benefit and with adverse effects.


As per chart review and clinic notes of the referring clinician (7/18/2023), she was admitted to the hospital on December 8, 2022 for further evaluation.  The reason for her admission was worsening peripheral paresthesias, numbness, and pain as well as new onset perioral numbness.  She also developed fever, worsening chronic productive cough, fatigue, and reduced appetite.  She presented with leukocytosis, fever, tachycardia, hypertension, and elevated WBC suggesting sepsis in the setting of worsening cough.  Elevated transaminases: AST and ALT of 535 and 580, respectively; hypomagnesemia with serum magnesium of 1.6, CRP: 13.2, ESR: 93, procalcitonin: 21.14.  Hepatitis work-up revealed elevated HBV core IgM and therefore HBV DNA was ordered which later on was not detectable/negative.  Patient was started on IV ceftriaxone and azithromycin for acute interstitial pneumonia and then transition to oral Ceftin and azithromycin on discharge.  Pulmonology also started patient on steroids and Bactrim.  Patient endorses having had an extensive work-up while in the hospital.  Of note, MRI of the brain (12/9/2022) revealed multiple small acute to subacute ischemic strokes, including bilateral thalamus, left posterior limb of internal capsule and left frontal lobe.  For neuropathic pain patient received Lyrica 50 mg p.o. 3 times daily and lidocaine gel.  Patient was discharged on 2/18/2023 with appropriate follow-up recommendations with different subspecialties. 


EMG/NCS of right upper and lower extremities was performed by Dr. xxx Normal study.


Since then she has had several ED visits and hospital admissions as noted (3/29/2023, admitted: 5/24/2023 and discharged on 5/26/2023).  At her 5/24/2023 admission neurology was consulted for generalized weakness, difficulty walking, somnolence and confusion.  There was history of jerky movements in her extremities which was new.  Patient had started using a walker due to weakness in her legs resulting in falls.  Reportedly as per documentation (5/24/2023) by neurology consult patient was reportedly drinking the day prior.  She denied any alcohol withdrawal seizures in the past.  Patient is a chronic alcohol drinker and drinks 1 pint to 1/5 of alcohol about 4-5 times a week, as per report.  Of note, ethanol levels and UDS were checked on 5/24/2023 and were normal.  She was started on Keppra 1 g p.o. twice daily since EEG showed findings suggestive of generalized epilepsy.  She was also put on long-term cardiac monitoring with Zio patch which did not show any evidence of atrial fibrillation; LINQ placement was recommended by neurology as outpatient.


As per clinic note by referring clinician (7/18/2023), patient was evaluated by rheumatology Dr. xx, who had a concern about ANCA vasculitic process.  She was started on prednisone.  Patient reports she took the prednisone for approximately a month and has stopped since a month.  She underwent left sural nerve (not fibular) and gastrocnemius (not fibular tertius muscle) muscle biopsies.  She complains of pain and tenderness over the left lateral malleolus (sural nerve biopsy site).  Preliminary report as per referring clinician is suggestive of necrotizing vasculitis.  


Patient reports that she continues to have burning paresthesias across both feet but more so over the surgical incisional sites.  She complains of cramps in her toes.  She has been using a cane over the past 6 months.  She reports her balance is unsteady if she does not use a cane for support.


She denies any history of wrist or foot drop.  No history of skin rashes around the ankles or limbs.  No history of hematuria.  No history of hemoptysis.  No history of epistaxis.  No GI bleed.  No history of paralysis of face or limbs.



REVIEW OF PRIOR LABORATORY AND DIAGNOSTIC STUDIES:

Lab Results

Component Value Date

WBC 9.7 05/26/2023

HGB 12.4 05/26/2023

HCT 37.3 05/26/2023

PLT 240 05/26/2023

CHOL 186 05/25/2023

TRIG 80 05/25/2023

HDL 77 05/25/2023

ALT 7 (L) 05/24/2023

AST 16 05/24/2023

NA 137 05/26/2023

K 4.1 05/26/2023

CL 102 05/26/2023

CREATININE 0.70 05/26/2023

BUN 9 05/26/2023

CO2 28 05/26/2023

TSH 1.89 05/24/2023

INR 1.0 05/24/2023

HGBA1C 4.7 02/16/2023

 

Labs (2/16/2023): ANCA (p-ANCA and c-ANCA).  This patient has a positive ANA that interferes with a titer of ANCA.  Because of this, please use the anti-MPO EIA to follow this patient.  The anti-PR-3 EIA was negative.


Component

    Latest Ref Rng 12/8/2022 2/17/2023

Myeloperoxidase Ab

    <=20 UNITS 27 (H) 16 

 

Legend:

(H) High


Labs (2/16/2023): ANA: Positive (1: 320) homogeneous.  SS-A and SS-B antibodies: Negative.  SCL-70-ab: Negative/unremarkable.  Histone-Ab and centromere antibody: Negative.  CCP: Negative.  RA: Positive (2580 <1280).  Glomerular basement membrane, C3, C4: Negative.  ESR: 93.  CRP: 13.2.


CSF studies (12/9/2022): Paraneoplastic autoantibody evaluation: Negative.  CSF protein: 66 mg/dL.


Component

    Latest Ref Rng 3/30/2023 5/24/2023 5/25/2023 5/26/2023

Magnesium

    1.7 - 2.5 mg/dL 1.4 (L) 1.6 (L) 2.0 1.7 

Magnesium

     1.6 (L)

 

Legend:

(L) Low


Component

    Latest Ref Rng 11/21/2022 2/16/2023

Hemoglobin A1C

    4.0 - 5.6 % 5.7 (H) 4.7 

Mean Bld Glu Estim.

    62 - 140 mg/dL 117 88 

 

Legend:

(H) High


Labs (5/24/2023): CK, TSH, ethanol: Normal.  UDS-7 (5/24/2023): Negative.


Component

    Latest Ref Rng 2/16/2023

Hepatitis C Antibody

    Nonreactive Nonreactive 

Hepatitis B Surface Ag

    Negative Negative 

Hepatitis A Antibody IgM

    Negative Negative 

Hep B Core IgM

    Negative POSITIVE ! 

Hepatitis C Virus RNA Qualitative

    Not detected IU/mL TNP 

Hepatitis C Virus RNA Quantitative

    IU/mL TNP 

HCV Quantitative Log

    Log (10) IU/mL TNP 

HCV Interpretation

    Not detected No HCV antibody detected 

 

Legend:

! Abnormal


Labs (2/7/2023): Hepatitis B virus DNA (qualitative/quantitative) unremarkable/not detected.


Component

    Latest Ref Rng 5/24/2023

Glucose, Urine

    Negative mg/dL Negative 

Color, Urine

    Amber, Colorless, Yellow, Straw Straw 

Clarity, Urine

    Clear Clear 

Specific Gravity, Urine

    1.005 - 1.030 1.010 

pH, Urine

    5.0 - 7.0 pH 7.0 

Leukocytes, Urine

    Negative Negative 

Nitrite, Urine

    Negative Negative 

Protein, Urine

    Negative mg/dL Negative 

Ketones, Urine

    Negative mg/dL Negative 

Urobilinogen, Urine

    Normal mg/dL Normal 

Bilirubin, Urine

    Negative Negative 

Blood, Urine

    Negative eryth/mcL Negative 



EMG/NCS of right upper and lower extremities was performed by xx: Normal study.


Vascular ultrasound (arterial Doppler) lower extremities (12/8/2022): Normal bilateral ABIs.  Slightly diminished bilateral toe brachial indicis suggestive of mild peripheral small vessel disease.


Vascular ultrasound duplex (venous) left lower extremity (12/7/2022): No sonographic evidence of DVT in left lower extremity.


CT chest without contrast for ILD, RA factor >1200 (11/7/2022): Chronic interstitial lung disease with areas of fibrosis and honeycombing.


MRI brain with and without contrast for left face paresthesia, right facial droop; lower extremity weakness (12/9/2022)-images reviewed: Multiple hemispheric small acute ischemic foci, including involvement of bilateral thalami.  Extensive chronic, microangiopathic white matter ischemic disease.  No evidence of hemorrhage.


MRI of the cervical spine with or without contrast (12/19/2022)-images reviewed: Multilevel degenerative disc disease most severely at C4-C5 with spinal canal stenosis and moderately severe to right neuroforaminal narrowing.  Broad-based posterior disc protrusion at C5-C6 more severe on the right than left.  


CTA of head and neck with and without contrast (12/9/2022): Prominent calcified plaque within the cavernous and supraclinoid segments of the right ICA with up to 70 to 80% stenosis.  Scattered atherosclerotic occasion within the carotid vasculature.  Right suprahilar soft tissue fullness noted.  CT of the chest was recommended (ordered by Dr. James Passinault) - pending. 


TTE (12/9/2022): LVEF: 56%.  No significant valvular dysfunction noted.


cVEEG (5/25/2023 at 03:17 to 5/26/2023 and 01:00) for encephalopathy and muscle jerks: Abnormal awake and sleep continuous EEG monitoring indicative of generalized epilepsy.  No electrographic seizures seen.  Paroxysmal high amplitude (up to 150 UV) generalized spike/polyspike and wave discharges (2-3 HZ, polyspike up to 19 HZ) are seen maximum in bilateral fronto-central regions with more consistence and prominence in the right fronto-central region (F4-C4), lasting 0.5 to 3 seconds with the frequency of 1 per 15-60 seconds throughout the record. No visible movement/jerk was noticed through the recorded video. 

 

Left sural and gastrocnemius muscle biopsy (8/3/2023): Report not available for review.  As per the referring clinician, Bradley H Gould (PA) Telephone communication note (8/9/2023): "D/w UofM Pathologist that nerve biopsy is suggestive of necrotizing vasculitis and muscle biopsy prelim suggests neuropathic changes.  Reviewed course and labs.  Pt is indicated for urgent follow up with Rheumatology and Neuromuscular Neuro.  Will reach out to Rheum (urgent referral order also placed) and try to expedite Neuromuscular Neuro eval.  Attempted to call pt multiple times to explain this but goes to voicemail and her voicemail box is full.



ALLERGIES:  Ace inhibitors, Aspirin, Caffeine, Margesic (propoxyphene), Tylenol [acetaminophen], and Valsartan


MEDICATIONS:  

Current Outpatient Medications

Medication Sig Dispense Refill

• amLODIPine (NORVASC) 10 mg tablet Take 1 tablet (10 mg total) by mouth 1 (one) time each day. 90 each 3

• aspirin 81 mg chewable tablet Chew 1 tablet (81 mg total) 1 (one) time each day. 90 each 3

• atorvastatin (LIPITOR) 40 mg tablet Take 1 tablet by mouth 1 (one) time each day. 30 each 11

• Combivent Respimat 20-100 mcg/actuation inhaler INHALE 1 PUFF BY MOUTH FOUR TIMES DAILY (BULK) (Patient taking differently: Inhale 1 puff 4 (four) times a day if needed.) 4 g 11

• cyanocobalamin (VITAMIN B-12) 1,000 mcg tablet Take 1 tablet (1,000 mcg total) by mouth 1 (one) time each day.

• diclofenac (VOLTAREN) 1 % topical gel Apply 2 g topically 2 (two) times a day. Apply to feet in tender area 50 g 0

• fluticasone propionate (FLONASE) 50 mcg/actuation nasal spray SHAKE LIQUID AND USE 1 SPRAY IN EACH NOSTRIL 1 TIME EACH DAY 16 g 0

• levETIRAcetam (KEPPRA) 1,000 mg tablet Take 1 tablet (1,000 mg total) by mouth 2 (two) times a day. 180 each 1

• meloxicam (MOBIC) 15 mg tablet Take 1 tablet by mouth 1 (one) time each day. 30 each 0

• montelukast (SINGULAIR) 10 mg tablet TAKE ONE TABLET BY MOUTH DAILY AT 9 PM AT BEDTIME 30 tablet 11

• omeprazole (PriLOSEC) 40 mg DR capsule TAKE 1 CAPSULE BY MOUTH 1 TIME EACH DAY 60 capsule 0

• pyridoxine (B-6) 50 mg tablet Take 1 tablet (50 mg total) by mouth 1 (one) time each day. 30 each 11

• thiamine (VITAMIN B-1) 100 mg tablet Take 1 tablet (100 mg total) by mouth 1 (one) time each day. 30 tablet 0

• venlafaxine XR (EFFEXOR-XR) 75 mg 24 hr capsule Take 3 capsules (225 mg total) by mouth 1 (one) time each day. Take with food. 90 each 11

• lidocaine 2 % Apply 20 mL topically 1 (one) time each day if needed (Mild pain). Apply to feet and hands when in pain (Patient not taking: Reported on 7/18/2023) 20 mL 0

• mometasone-formoterol (DULERA 200) 200-5 mcg/actuation inhaler Inhale 2 puffs 2 (two) times a day. Rinse mouth with water after use to reduce aftertaste and incidence of candidiasis. Do not swallow. (Patient not taking: Reported on 5/25/2023) 1 each 0

• nicotine (Nicoderm CQ) 14 mg/24 hr Place 1 patch on the skin 1 (one) time each day at the same time. 30 each 0

• nicotine polacrilex (COMMIT) 4 mg lozenge Dissolve 1 lozenge (4 mg total) in the mouth every 2 (two) hours if needed for smoking cessation. 100 lozenge 0

• oxyCODONE (ROXICODONE) 5 mg immediate release tablet Take 1 tablet (5 mg total) by mouth every 6 (six) hours if needed for severe pain. Max Daily Amount: 20 mg (Patient not taking: Reported on 8/14/2023) 6 each 0


No current facility-administered medications for this visit.


(Not in a hospital admission)



MEDICAL HISTORY:

Patient Active Problem List

Diagnosis

• Seasonal allergic rhinitis

• Essential hypertension

• Generalized anxiety disorder

• GERD (gastroesophageal reflux disease)

• Lumbosacral radiculopathy due to degenerative joint disease of spine

• Mixed hyperlipidemia

• Osteoarthritis of hip

• Primary insomnia

• Primary osteoarthritis of both knees

• Tobacco user

• Tobacco dependence syndrome

• Inflammatory disease of vagina and vulva

• Allergic conjunctivitis of both eyes

• Osteopenia

• COPD (chronic obstructive pulmonary disease) (CMS/HCC)

• Lichen sclerosus et atrophicus

• Age-related cataract of both eyes

• Chest pain

• Arthritis of knee

• Cough

• Pulmonary nodules

• Restrictive lung disease

• Decreased diffusion capacity

• Pneumonia due to infectious organism, unspecified laterality, unspecified part of lung

• Generalized pain

• Hypomagnesemia

• Generalized weakness

• Peripheral polyneuropathy

• Prediabetes

• Ischemic stroke (CMS/HCC)

• Weakness of both lower extremities

• Hypokalemia

• Vision changes

• Nonintractable epilepsy without status epilepticus (CMS/HCC)

• Generalized epilepsy (CMS/HCC)

• Abnormal finding on CT scan

• Stenosis of right carotid artery

• Decreased appetite

• Right foot pain

• Irregularly irregular pulse rhythm

• Healthcare maintenance

• Nodule of skin of both feet


Past Medical History:

Diagnosis Date

• Age-related cataract of both eyes 01/20/2021

• Anxiety

• Arthritis

• Cigarette smoker

• COPD (chronic obstructive pulmonary disease) (CMS/HCC)

• Difficulty sleeping

• GERD (gastroesophageal reflux disease)

• Hyperlipidemia

• Hypertension

• Postmenopausal state

• Seasonal allergic rhinitis

• Seizures (CMS/HCC)

• Stroke (CMS/HCC)



SURGICAL HISTORY:

Past Surgical History:

Procedure Laterality Date

• BUNIONECTOMY Left

• COLONOSCOPY

• D&C FIRST TRIMESTER / TX INCOMPLETE / MISSED / SEPTIC / INDUCED ABORTION

• LIPOMA RESECTION



FAMILY HISTORY:

family history includes Alcohol abuse in her father; Asthma in her mother; Breast cancer in an other family member; Colon cancer in an other family member; Lung cancer in her mother; Ovarian cancer in an other family member; Thyroid disease in her mother; Uterine cancer in an other family member.


SOCIAL HISTORY:  

Tobacco use:   reports that she has been smoking cigarettes. She has a 12.50 pack-year smoking history. She has never used smokeless tobacco.

Alcohol use:   reports current alcohol use.

Drug use:  reports that she does not currently use drugs after having used the following drugs: Methamphetamines.

Work and Living situation: Patient lives with her daughter.


PHYSICAL EXAMINATION:


VITAL SIGNS:  

Visit Vitals

BP 115/89 (BP Location: Left arm, Patient Position: Sitting, BP Cuff Size: Large adult)

Pulse 98

Ht 1.499 m (59")

Wt 60.9 kg (134 lb 3.2 oz)

BMI 27.11 kg/m²

OB Status Postmenopausal

Smoking Status Every Day

BSA 1.56 m²


General: Awake, no acute distress.  

Skin: Discoloration/hyperpigmentation of the skin over the dorsum of both feet in a patchy distribution.

CV: Regular rate and rhythm, normal S1, S2 auscultated, no murmurs. 

Lungs: Clear to auscultation.

Extremities: No cyanosis, no edema.  Incisional scar over the lateral aspect of left ankle behind the mid lateral malleolus and incisional scar over the left upper calf (biopsy sites); tender and painful to touch.

Skeletal: No joint or skeletal deformities noted. 


Neurological Exam:  Patient is alert and oriented to person, place, and time.  Speech is clear, spontaneous and fluent.  Language function is preserved.  MoCA: not tested.  Thought process is organized, sequential, and goal-direct.  Olfaction is not tested.  Visual fields are full to confrontation and visual acuity is intact to finger counting, OU.  Pupils are equal, round and reactive to direct and consensual response to light. There is no RAPD.  Extraocular movement are with normal fixation, ductions, versions, smooth pursuits, and saccades and no nystagmus.  Strength of masticatory muscles are normal, bilaterally. Normal facial sensation, symmetry, and strength.  Normal hearing to finger rub, bilaterally.  Palatal elevation is symmetrical.   Tongue protrusion in midline and lateral thrust is normal, no atrophy or fasciculations.  Neck flexion/extension/lateral rotation strength: 5/5.  Shoulder shrug: 5/5, bilaterally. 

Motor exam is normal muscle bulk and tone.  No adventitious movement noted.  Motor testing reveals no drift and full strength: 5/5 in all muscle groups in upper and lower extremities, bilaterally.  

Sensory exam is notable for increased sensitivity to pinprick and cold temperature sensation over the dorsum of both feet.  She has exquisite tenderness over the incisional sites over the left lateral malleolus as well as left calf.  Vibration sensation is normal at both halluces in feet and both index fingers in hands.  Semmes Weinstein monofilament testing: Right foot: 9/10.  Left foot: 8/10.  Romberg present.  She is able to stand up from the chair with some effort.  Gait is wide-based, slow cadence, short stride length but symmetrical.  She is able to walk better, steadier, slightly faster with using a cane.  She is unable to perform forced walking maneuvers.  Coordination is intact to FNF, bilaterally but demonstrates mild intention tremor on approaching the target (left > right).

MSR are 2+ in upper extremities, 2+ knees, and absent ankle reflexes, bilaterally.  Plantars are downgoing (flexor), bilaterally. 



ASSESSMENT:

70-year-old, right-handed woman with history of strokes, seizures, cigarette smoking, and alcohol use COPD, hypertension, and hyperlipidemia is referred paresthesia with a specific question with regards to vasculitic neuropathy.  Neurological examination is notable for sensory dysfunction to small fiber sensory modalities with increased sensitivity to pinprick sensation over the dorsum of both feet, mild sensory ataxia, absent ankle reflexes, bilaterally.


1. Paresthesias 

2. Dysesthesia 

3. Vasculitic neuropathy (CMS/HCC) 

4. Ischemic stroke (CMS/HCC) 

5. Seizures (CMS/HCC) 

6. Generalized weakness 

 

Paresthesia/dysesthesia/Vasculitic neuropathy.  Chronic onset paresthesias in both feet with a subacute worsening.  Exam is notable for sensory dysfunction to small fiber sensory modalities in a distal to proximal gradient with absent ankle reflexes, localizes to the peripheral nerves in particular small fiber nerves.  Onset of symptoms were asymmetrical with initial involvement in right foot around November, 2022 and since then it has progressed to the left foot and confluent.  No motor deficit such as foot drop or wrist drop.  Her risk factors for- neuropathy based on history include alcohol use.  EMG/NCS of right upper and lower extremities did not demonstrate involvement of the large nerve fibers.  She had left sural nerve biopsy which based on preliminary report is notable for necrotizing vasculitis.  If so she has pathologically definite vasculitic neuropathy.


Patient has history of paresthesias/dysesthesias and pain with worsening course; multiple ischemic embolic strokes felt due to ICAD (artery to artery) but unclear, with encephalopathy, abnormal EEG suggestive of epilepsy, constitutional symptoms including fever, worsening chronic productive cough, fatigue, and reduced appetite.  She also has history of pulmonary dysfunction including COPD (attributed to smoking cigarettes).  Serology is positive for ANA and suggestive of ANCA positivity with specificities to anti-MPO. anti-PR-3 EIA was negative.  RA positive with elevated ESR and CRP.  CSF studies were unremarkable other than slightly elevated CSF protein at 66 mg/dL.  CT chest without contrast (11/7/2022): Chronic interstitial lung disease with areas of fibrosis and honeycombing.  Repeat CT of the chest which was ordered is still pending.   MRI brain with and without contrast for left face paresthesia, right facial droop; lower extremity weakness (12/9/2022)-images reviewed: Multiple hemispheric small acute ischemic foci, including involvement of bilateral thalami.  Extensive chronic, microangiopathic white matter ischemic disease.  No evidence of hemorrhage.  No history of skin rashes around the ankles or limbs.  No history of hematuria.  No history of hemoptysis.  No history of epistaxis.  No GI bleed.  No history of paralysis of face or limbs.


Given the history and evolution of her clinical features and the results of current work-up findings, there is a concern for systemic vasculitis, likely ANCA associated vasculitis; small vessel vasculitis -MPA except that there is no diffuse pulmonary or renal involvement.   Secondary causes of systemic vasculitides such as RA and MCTD is a possibility.  


Vasculitis Damage Index (VDI) Score: 6

Impaired lung function

Diastolic BP ? 95 or requiring antihypertensives

Cognitive impairment

Seizures

Cerebrovascular accident

Peripheral nerve involvement (based on result of left sural nerve bx - as reported)


I discussed with the patient the concerns regarding systemic vasculitis.  I discussed treatment options including cyclophosphamide (EUVAS CYCLOPS regimen) and SE profile.  Patient and her daughter are concerned about side effects profile of CYC and not amenable to this option.  I discussed Rituximab (RAVE trial) and explained that Rituximab therapy was not inferior to cyclophosphamide treatment for induction of remission in severe ANCA-associated vasculitis and may be superior in relapsing disease.  She is amenable to this option.  I will ask my office to try and obtain the nerve biopsy report.  I will repeat EMG/NCS of bilateral lower extremities (scheduled with me) to be expedited.  She will require direct admission to treat her expeditiously as there is a increased likelihood of accruing increased morbidity.


Following admission:  Start IV Solu-Medrol 500 mg intravenous infusion twice daily for 3 days, followed by prednisone 60 mg p.o. daily (a.m. dose) for 4 weeks, then based on stability response and assessment may be tapered to 50 mg p.o. for two weeks, then 40 mg p.o. for 4 weeks, then 30 mg p.o. for 4 weeks, then 25 mg p.o. for 4 weeks, then 20 mg p.o. daily and eventually tapered to 10 mg p.o. daily for up to 6 months.  Concomitant treatment with Tavenos (avacopan) may facilitate the use of an even shorter, reduced-dose glucocorticoid regimen.  Caution: Monitor baseline LFTs prior to starting avacopan and monitor LFTs as clinically indicated.


For prednisone: 

Check CBC, CMP: monthly, check HbA1c every 3 months, DEXA.  

Calcium 1200mg daily.  

Vitamin D 800 units daily

GI bleeding: Avoid ASA and NSAIDs.

GI prophylaxis: Taking omeprazole or Famotidine.

Lasix use with prednisone  worsens hypokalemia 

Referral to dietician for dietary precautions on steroids: Low sodium, low-carbohydrate, high protein diet and to avoid excessive weight gain, while on steroids. 

PCP to monitor blood pressure

Ophthalmology evaluation to check for glaucoma.  Patient has had cataracts removed.


Induction to begin after completion of IV solumedrol 3rd dose (Inpatient): Rituximab (375 mg/m2 per week for four weeks) intravenous infusions.

Maintenance:  For patients treated with rituximab for induction of remission, maintenance therapy typically begins between months 4 and 6 after the last induction dose with Rituximab 1000 mg IV infusion given 2 weeks apart OR an "on-demand" dosing strategy, in which peripheral B lymphocyte (CD19-positive cells) counts, which are depleted by rituximab, and ANCA titers are monitored and the drug is redosed when B lymphocytes reconstitute and the ANCA titer becomes positive.  Recheck hepatitis-B prior to repeat dosing with Rituximab. 


Prevention of opportunistic infection vaccinations.  Bactrim DS p.o. thrice weekly (for  P. jirovecii pneumonia).  Influenza/pneumonia and COVID 19 vaccinations, up-to-date.


Check TB qunatiferon (IGRA) - prior to starting Rituximab.  



PLAN:

EMG/NCS of bilateral lower extremities (scheduled with me) to check for polyneuropathy.  Please expedite.

Obtain the report of left sural nerve biopsy for review.

Patient may need direct admit as inpatient to start therapy expeditiously.

Follow up in about 3 months (around 11/14/2023) for Dr. Melanie Taylor..