TABLE 15-1. VASCULITIDES ASSOCIATED WITH PERIPHERAL NEUROPATHYVasculitis is an immune-mediated disorder directed against blood vessels, which results in ischemia to end organs supplied by the affected blood vessels.1–5 The vasculitides can be distinguished and classified based on at least three nosologic categories. They can be differentiated based on the caliber of vessel involved (i.e., small, medium, or large vessel). They can be distinguished on whether the disorder is primary [e.g., polyarteritis nodosa (PAN), microscopic polyangiitis (MPA), granulomatosis with polyangiitis (GAN, formerly known as Wegener granulomatosis), and Churg–Strauss syndrome (CSS)] or secondary to other systemic disorders (e.g., connective tissue disease, malignancy, infection, or drug reaction). Furthermore, the vasculitides can be separated based on whether they are systemic or isolated to the peripheral nervous system (PNS), and if associated with antineutrophil cytoplasmic antibodies (ANCAs) (Table 15-1).2,3 Vasculitis is much more common in adults but can develop in children.6
TABLE 15-1. VASCULITIDES ASSOCIATED WITH PERIPHERAL NEUROPATHY
Primary Vasculitis
Large vessel vasculitis
Giant cell (temporal) arteritis
Medium and small vessel vasculitis
Polyarteritis nodosa
Churg–Strauss syndrome
Granulomatosis with angiitis
Microscopic polyangiitis
Nonsystemic vasculitic neuropathy
Secondary Vasculitis
Vasculitis associated with connective tissue diseases
Vasculitis associated with Behçet disease
Vasculitis associated with sarcoidosis
Vasculitis associated with malignancies
Vasculitis associated with infections
Vasculitis associated with cryoglobulinemia
Vasculitis associated with hypersensitivity reaction (leukocytoclastic angiitis)—uncommonly associated with a peripheral neuropathy
CLINICAL FEATURESPNS vasculitis can present as (1) a mononeuropathy or multiple mononeuropathies, (2) overlapping mononeuropathies, or (3) distal symmetric polyneuropathies (Fig. 15-1).3–8 In the first pattern, patients may present with just a mononeuropathy, but usually multiple nerves eventually become affected over time, giving a distinct asymmetric pattern of involvement in the distribution of individual nerves. With the second pattern, different nerves on both sides of the body are affected but to varying degrees, leading to a generalized, yet asymmetric, pattern of involvement. Finally, with gradual progression, somewhat uniform and generalized involvement of peripheral nerves results in what looks like a distal symmetric polyneuropathy. Approximately 60–70% of patients present with mononeuropathy or multiple mononeuropathies (multifocal neuropathy or mononeuropathy multiplex pattern), while 30–40% of patients present as a distal symmetric polyneuropathy.7 There is a large differential diagnosis of patients with a multiple mononeuropathy (Table 15-2). For this reason, multifocal neuropathy, multiple mononeuropathies, or mononeuropathy multiplex are preferable terminologies to mononeuritis multiplex because the latter term implies a histologically defined disorder rather than a clinically defined syndrome.
TABLE 15-2. MULTIFOCAL NEUROPATHIES/MULTIPLE MONONEUROPATHIES: DIFFERENTIAL DIAGNOSIS
Peripheral Nerve Vasculitis
Polyarteritis nodosa
Granulomatosis with angiitis
Churg–Strauss syndrome
Microscopic polyangiitis
Connective tissue disorders associated with vasculitic neuropathies (e.g., SLE, RA, MCTD)
Nonsystemic vasculitic neuropathy
Remote effect of cancer
Other Immune-Medicated Neuropathies
Multifocal acquired demyelinating sensory and motor neuropathy [MADSMN, asymmetric chronic inflammatory demyelinating polyradiculoneuropathy (CIDP)]
Multifocal motor neuropathy
Sensory perineuritis
Lumbosacral/brachial plexus neuritis
Postsurgical neuritis
Granulomatous Infiltration
Sarcoid
Lymphomatoid granulomatosis
Infectious Neuropathies
Leprosy
Herpes zoster
Lyme disease
HIV
CMV
Hepatitis B and C
Compression Neuropathy
Primary compression neuropathies (e.g., traumatically induced)
Secondary compression neuropathies (e.g., superimposed on generalized peripheral nerve disease; e.g., diabetes mellitus and carpal/cubital tunnel syndrome)
Hereditary liability to pressure palsy
Other Disorders
Diabetes mellitus
Amyloidosis
Neoplastic infiltration (particularly lymphoma and leukemia)
Peripheral nerve tumors (e.g., neurofibromatosis)
Atherosclerotic vascular disease (monomelic neuropathy secondary to acute large artery occlusion of AV shunts/fistulas)
Drug induced (e.g., interferon-α, leukotriene receptor antagonist, tumor necrosis factor-α inhibitors, leflunomide, amphetamine, sulfonamides)
Figure 15-1. Patterns of involvement in vasculitic neuropathy. Vasculitis can present as (A) a mononeuropathy or multiple mononeuropathies, (B) overlapping mononeuropathies, or (C) distal symmetric polyneuropathies.
Patients usually complain of burning or tingling pain in the distribution of the affected nerve(s). On examination, weakness and sensory loss are evident as well. Rare patients have purely sensory symptoms and signs.9 Muscle stretch reflexes may be normal or diminished, depending on whether or not the involved nerve innervating is in a reflex arc. For example, involvement of the sciatic nerve would lead to a diminished ankle jerk, but a median nerve infarct would not result in a loss of a biceps or triceps reflex.
LABORATORY FINDINGSMost patients have elevated erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP).2,10 Some vasculitides are associated with ANCAs, antinuclear antibodies (ANAs), cryoglobulins, rheumatoid factor, leukocytosis, and anemia. ANCAs are of particular importance as they are 85% sensitive and 99% specific for vasculitis.11 The ANCAs are subclassified as cytoplasmic (cANCA) or perinuclear (pANCA) based on their immunofluorescence staining pattern and antigenic target; cANCAs are directed against proteinase 3 (PR3), while pANCAs target myeloperoxidase (MPO). PR3/cANCA is associated with granulomatosis with polyangiitis, while MPO/pANCA is typically associated with MPA, CSS, and less commonly PAN. MPO/pANCA has also been seen in minocycline-induced vasculitis.
Affected nerves may appear enlarged and hypoechoic with ultrasound.12–14 MR imaging may also be useful to identify nerve lesions.15,16 Motor and sensory nerve conduction studies demonstrate unobtainable potentials or reduced amplitudes.3,7,8,17–20 In particular, it is important to look for side-to-side asymmetries in amplitudes that reflect the multifocal nature of the pathology. Distal latencies are normal or slightly prolonged, while conduction velocities are normal or only mildly reduced. Conduction block or pseudoconduction block may be demonstrated in some affected nerves.21–24 The presence of conduction block or temporal dispersion in a patient with a multifocal neuropathy pattern should suggest a disorder such as the multifocal acquired demyelinating sensory and motor (MADSAM) neuropathy variant of chronic inflammatory demyelinating polyneuropathy (CIDP). The needle electromyography (EMG) reveals denervation changes in affected muscle groups. Again, the EMG abnormalities are often also asymmetric.
HISTOPATHOLOGYThe sural, superficial peroneal (sensory branch), and superficial radial sensory nerves are the most common nerves that are biopsied.1,4,5,25 Suspected vasculitis is one of the few clinical situations in which we routinely perform nerve biopsy. We usually biopsy the superficial peroneal nerve, if it is involved clinically and by nerve conduction studies (NCS). This is because the peroneus brevis muscle can also be biopsied from the same incision site, and the diagnostic yield is increased when the nerve and muscle both are biopsied (Fig. 15-2).5,25–27 Diagnostic criteria for pathologically definite vasculitis include transmural inflammatory cell infiltration and fibrinoid necrosis of the vessel wall (Fig. 15-3).1,4,7,19,28–31 Supportive features of acute vasculitis also include loss or fragmentation of internal elastic lamina and loss/fragmentation/separation of smooth muscles in the media (can be highlighted by elastin and antismooth muscle actin staining), vascular or perivascular hemorrhage, acute thrombosis, and leukocytoclasia. Immunocytochemistry may reveal immunoglobulin (IgM and/or IgG), complement, and membrane attack complex deposition on blood vessels.32 Signs of repair may be seen in chronic vasculitis and include intimal hyperplasia, fibrosis of media, adventitial/periadventitial fibrosis, and recanalization of the lumen. Common findings are asymmetrical nerve fiber loss between and within individual nerve fascicles and active axonal degeneration. Nerve biopsies can also demonstrate immunostaining for the receptor for advanced glycosylation end products, nuclear factor-kappaB, and interleukin-6 that are expressed by CD4(+), CD8(+), and CD68(+) cells invading nerves. Immunostaining can be identified in mononuclear cells, epineurial and endoneurial vessels, and in the perineurium.33 This data suggest that the receptor for advanced glycosylation end products pathway plays a critical proinflammatory role in vasculitic neuropathy. Matrix metalloproteinases (e.g., MMP-9) are upregulated as well and may play an important role as means for inflammatory cell invasion.34 In addition to vasculitis, muscle biopsies may show evidence of muscle infarction (Fig. 15-4). Skin biopsies have also demonstrated reduced epidermal nerve fiber density in some cases of vasculitic neuropathy.26,35,36
Figure 15-2. Superficial peroneal nerve and peroneus brevis muscle biopsy. The superficial peroneal nerve can usually be biopsied at a site between one-third and one-fourth the distance between the lateral aspect of the ankle and the fibular head and about 1.5–2 cm anterior to the fibula. After the nerve is biopsied, the underlying peroneus brevis muscle can be biopsied. This combination increases the yield of finding vasculitis and can be made through one incision. (Modified with permission from Mendell JR, Erdem S, Agamonolis DR. Peripheral nerve and skin biopsies. In: Mendell JR, Kissel JT, Cornblath DR, eds. Diagnosis and Management of Peripheral Nerve Disorders. New York, NY: Oxford University Press; 2001.)
Figure 15-3. Vasculitis. Superficial peroneal nerve biopsy demonstrates transmural inflammatory cell infiltrate with fibrinoid necrosis and obliteration of the lumen, paraffin sections stained with H&E (A). The fibrinoid material stains pink on H&E. An elastin stain on higher power of same field demonstrates fragmentation of internal elastic lamina (B). Longitudinal section with Masson trichrome stain also demonstrates transmural inflammation and fibrinoid necrosis of the vessel wall that stains bright red (C). Longitudinal section with fibrin stain reveals transmural inflammation and fibrinoid necrosis of the vessel wall that stains bluish-purple (D). The peroneus brevis muscle biopsy also demonstrates vasculitis on frozen section stained with hematoxylin and eosin (E).
Figure 15-4. Muscle biopsy demonstrates an area of muscle infarct and some hemorrhagic conversion at low (A) and high power (B) paraffin sections stained with H&E.
PRIMARY SYSTEMIC VASCULITIC DISORDERS AFFECTING LARGE- AND MEDIUM-SIZED VESSELSTemporal arteritis and Takayasu arteritis are the two forms of giant cell arteritis, but peripheral neuropathy only occurs in the setting of temporal arteritis.10,37 Giant cell arteritis affects medium- and large-sized vessels, particularly the aortic arch and the internal and external carotid arteries, and the vertebral arteries. Patients may present with headaches, jaw and tongue claudication, generalized myalgias, vision loss secondary to ischemic optic neuropathy, or stroke. Approximately 14% of patients develop multifocal neuropathy/multiple mononeuropathies, radiculopathies, plexopathies, or a generalized sensorimotor peripheral neuropathy.10 The temporal artery is often tender and a palpable cord can be felt. Ultrasound of the arteries may reveal thickening. Temporal artery biopsies reveal inflammatory infiltrate with giant cells in only two-thirds of suspected cases. Patients generally respond quite well to treatment with corticosteroids.
PRIMARY SYSTEMIC VASCULITIC DISORDERS AFFECTING MEDIUM- AND SMALL-SIZED VESSELSPAN, the most common of the necrotizing vasculitides, is a systemic disorder involving small- and medium-caliber arteries in multiple organs.1,2,4,11,28 PAN has an incidence ranging from 2 to 9 per million and usually presents between 40 and 60 years of age. The most common pattern of nerve involvement is multifocal neuropathy/multiple mononeuropathies. The sciatic nerve or its peroneal or tibial branches are the most frequently involved nerves. Cranial neuropathies and central nervous system (CNS) involvement are rare, occurring in <2% of patients.2 Other organ systems affected include the heart, liver, kidneys, gastrointestinal that may lead to liver or renal failure, abdominal pain, and gastrointestinal bleeding. Notably, the lungs are generally spared. Myalgias and arthralgias occur in 30–70% of patients. Vasculitis involving the skin results in petechiae, livedo reticularis, subcutaneous nodules, and distal gangrene.38 Orchitis is also a common complication. Constitutional symptoms include weight loss, fever, and loss of appetite.
Although not as commonly found as in MPA and CSS, approximately 10–20% of PAN patients have MPO/pANCA. An elevated ESR is seen in the majority of patients.2 One-third of cases are associated with hepatitis B antigenemia,2,38 but PAN can also complicate hepatitis C virus (HCV) and human immunodeficiency virus (HIV) infections.2,39 Abdominal angiograms can reveal a vasculitic aneurysm, a useful finding in patients with nondiagnostic biopsies.
Medium-sized arteries are usually affected; however, smaller-sized vessels can be involved in PAN.2,4 Nerve biopsies may demonstrate transmural infiltration of CD8+ T cells, macrophages, and polymorphonuclear cells along with fibrinoid necrosis of the vessel wall. IgM, IgG, complement, and membrane attack complex deposition may be appreciated on blood vessels. Unlike CSS, granulomas and eosinophilic infiltration are not seen on nerve biopsies in PAN. The pathogenic mechanism of PAN is unknown, although a T cell–dependent process with secondary complement-mediated vascular damage has been postulated.4
CSS manifests with signs and symptoms similar to PAN except that respiratory involvement is common in CSS.1,2,40–44 The incidence of CSS is about one-third that of PAN, but the frequency of neurological complications is about the same. In this regard, multifocal neuropathy/multiple mononeuropathies develop in as many as 75% of individuals who are affected.2 People with CSS typically present with allergic rhinitis, nasal polyposis, sinusitis, and late-onset asthma (after the age of 35 years). Symptoms and signs of systemic vasculitis occur an average of 3 years after the onset of asthma and even longer after the onset of nasal symptoms. Anywhere from 16% to 49% of patients with CSS develop a necrotizing glomerulonephritis as opposed to an ischemic nephropathy that can complicate PAN. Several cases of CSS have been reported in patients treated with leukotriene antagonists after weaning corticosteroids.45
Routine laboratory workup reveals eosinophilia, leukocytosis, elevated ESR, CRP, rheumatoid factor, and serum IgG and IgE levels. One should consider CSS in any patient with a neuropathy and peripheral eosinophilia. Approximately two-thirds of individuals who are affected have MPO/pANCA.2,11 Chest x-rays reveal that pulmonary infiltrates are present in nearly half of patients.
Nerve biopsies may demonstrate necrotizing vasculitis with CD8+ cytotoxic T lymphocytes, CD4+ cells and, to a lesser extent, eosinophilic infiltrates (Fig. 15-5).2,42,46 In addition, intravascular and extravascular granulomas are occasionally found in and around affected blood vessels.
Figure 15-5. Churg–Strauss syndrome. Nerve biopsy demonstrates transmural infiltration of a vessel wall that includes eosinophils and obliteration of the lumen. Paraffin section stained with H&E.
Granulomatosis with polyangiitis (GAN) was formerly referred to as Wegener granulomatosis. The latter term is no longer recommended as Dr. Wegener was a high-ranking Nazi physician, and the facility he was assigned to in Poland was associated with unethical humane experimentation. GAN is characterized by necrotizing vasculitis and granulomas involving the upper and lower respiratory tract and kidneys (glomerulonephritis).1,4,47–54 Early respiratory symptoms (e.g., nasal discharge, cough, hemoptysis, and dyspnea) can help distinguish this from other vasculitides. In a large prospective study of 128 patients with granulomatosis with polyangiitis, 64 patients (50%) developed CNS or PNS involvement.47 Peripheral neuropathy occurred in 56 patients and in 9 cases the CNS was involved. Thirty-one patients had a distal symmetric polyneuropathy, while 25 had multifocal neuropathy/multiple mononeuropathies. Neuropathy is more common in patients with severe renal involvement.51 Cranial neuropathies, particularly the second, sixth, and seventh nerves, develop in approximately 5–10% of cases as a result of extension of the nasal or paranasal granulomas rather than vasculitis.47,53
The majority of affected individuals have PR3/cANCAs, and this test has a specificity of 98% and sensitivity of 95%.51 The histological appearance of the vasculitis is similar to PAN, with involvement of medium- and small-sized blood vessels. In addition, granulomatous infiltration of the respiratory tract and necrotizing glomerulonephritis are also seen. The absence of peripheral eosinophilia, eosinophilic infiltrates on biopsy, and asthma help distinguish granulomatosis with polyangiitis from CSS.
MPA clinically resembles PAN and CSS, except that diffuse alveolar damage and interstitial fibrosis develop due to involvement of pulmonary capillaries.1,2,4,42,43,55 The incidence of MPA is about one-third that of PAN. The average age of onset is 50 years and polyneuropathy complicates MPA in 14–36% of cases.2,4,55
Laboratory evaluation is remarkable for renal insufficiency, hematuria, and MPO/pANCA in most patients. PR3/cANCA can also occasionally be detected. As suggested by the name, MPA affects small arterioles, veins, and capillaries.2,4 In contrast to PAN, there are few or no immune deposits on the blood vessels. Kidney biopsies reveal focal segmental thrombosis and necrotizing glomerulonephritis.
This disorder is characterized by recurrent oral and genital ulcerations, inflammation of the eye, arthritis, thrombophlebitis, skin lesions, and vasculitic lesions of these organs involving the small- to medium-sized arteries.56–59 The CNS complications (brainstem strokes, meningoencephalitis, and psychosis) are more common than peripheral neuropathy.
SECONDARY SYSTEMIC VASCULITIDESNeuropathies are not uncommon in people with connective tissue diseases, although necrotizing vasculitis as the cause is infrequent (see Chapter 16). That said, secondary vasculitis can complicate rheumatoid arthritis, systemic lupus erythematosus and Sjögren syndrome, and, less frequently, systemic sclerosis.18,60,61 The clinical, histological, and electrophysiological features are similar to PAN. In addition, vasculitis may be seen in sarcoidosis (see Chapter 16).
Vasculitic neuropathy can arise as a complication of a variety of infections.39,62,63 The most common infectious agents associated with vasculitic neuropathy are HIV, hepatitis B and C, cytomegalovirus, Epstein–Barr viruses, and herpes varicella zoster (discussed in Chapter 17). Multifocal neuropathy/multiple mononeuropathies related to HIV or cytomegalovirus infection occur in up to 3% of patients with acquired immune deficiency syndrome (AIDS).64 As previously discussed, hepatitis B and C infections are associated with PAN, a medium-sized systemic vasculitis, as well as a small vessel vasculitis associated with cryoglobulinemia. Vasculitic neuropathy may also complicate Lyme disease.
Rarely, cancers have been associated with vasculitic neuropathy. Small cell lung cancer and lymphoma are the most common implicated malignancies, but leukemia, other myelodysplastic syndromes, and carcinomas of the kidneys, bile duct, prostate, and stomach have also been described.65–74 However, most of the reported cases were not associated with a necrotizing vasculitis, rather only nonspecific transmural or perivascular inflammation of small blood vessels without fibrinoid necrosis was seen on biopsy. In this regard, several of the cases with “vasculitic” neuropathy associated with lung cancer and anti-Hu antibodies were reported as having vasculitis, although this disorder is not a true necrotizing vasculitis (see Chapter 19).65 Multiple mononeuropathies or generalized neuropathy associated with lymphomas are often paraneoplastic in etiology or due to lymphomatous infiltration of the nerves. However, rare cases of vasculitic neuropathy have been reported in the setting of lymphoma.72
Hypersensitivity vasculitis is often secondary to drug reactions and is a self-limited process as opposed to the systemic necrotizing vasculitides.4 Skin manifestations (e.g., petechiae) predominate the clinical picture of hypersensitivity vasculitis and neuropathy is uncommon (Fig. 15-6). Minocycline may be an exception as we and others have seen typical vasculitic neuropathy as a complication.16,75,76 Drugs of abuse (e.g., amphetamine, cocaine, and opioids) also can cause vasculitis of the CNS or PNS.77,78 The pathogenesis most likely relates to a complement-mediated leukocytoclastic reaction.
Figure 15-6. Hypersensitivity vasculitis. Severe petechial lesions are evident on bilateral lower extremities.
Cryoglobulins are circulating immune complexes consisting of immunoglobulins directed against polyclonal immunoglobulins. These complexes precipitate out of solution when exposed to a cool temperature but dissolve back into solution when rewarmed, thus the name cryoglobulin. There are actually three types of cryoglobulins. Type I cryoglobulins are monoclonal immunoglobulins, usually IgM, directed against polyclonal IgG. These are most commonly seen in individuals with plasma cell dyscrasias. Type II cryoglobulins are composed of a combination of monoclonal IgM and polyclonal immunoglobulins directed against polyclonal IgG. Type III cryoglobulins are a mixture of polyclonal IgM, IgG, and IgA directed against polyclonal IgG. Type II and III cryoglobulins are seen in patients with so-called mixed cryoglobulinemia and typically occur in the setting of lymphoproliferative disorders, connective tissue diseases, HIV, and hepatitis B and hepatitis C infection. Most patients with mixed cryoglobulinemia are associated with hepatitis C antigenemia. Essential mixed cryoglobulinemia is the term used when mixed cryoglobulinemia is found in the absence of an underlying disease. Peripheral neuropathy develops in 25–90% of patients with cryoglobulinemia of any type.21,79–86 The neuropathy may manifest as a painful, distal, symmetric sensory or sensorimotor polyneuropathy; as multifocal/multiple mononeuropathies; or rarely as a pure small fiber neuropathy.21
The lack of local HCV replication in nerve biopsies suggests that that HCV-mixed cryoglobulinemia-associated neuropathy results from virus-triggered immune-mediated mechanisms rather than direct nerve infection and in situ replication.84,87 The neuropathy may arise due to ischemia from hyperviscosity or due to vasculitis related to immune complex deposition in small epineurial blood vessels. NCS are similar to PAN. Conduction block was appreciated on motor NCS in one report.21
Nearly 60% of vasculitis is restricted to peripheral nerves.1,3,6,7,25,30,88–91 This so-called nonsystemic vasculitis or isolated PNS vasculitis is usually seen in adults, but children can also be affected.6 The clinical, electrophysiological, and histopathological features of isolated PNS vasculitis are quite similar to PAN, except that there is no significant involvement of other organ systems. Individuals who are affected may present with multiple mononeuropathies or a generalized symmetric sensorimotor polyneuropathy. Laboratory testing may demonstrate elevated ESR or positive ANA titers. Vasculitis may be apparent on muscle biopsies,5 but the peripheral nerves are predominantly affected. The diagnostic yield of finding vasculitis is increased by biopsying both muscle and nerve.
The vasculitis typically involves small- and mediumsized arteries of the epineurium and perineurium, and immune complex deposition on these blood vessels may be appreciated on biopsy. MMPs, in particular MMP-2 and MMP-9 (gelatinase A and B), are upregulated in the peripheral nerves in patients with nonsystemic vasculitis.92 T cells are the predominant source of MMP-2 and MMP-9, although 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.
The prognosis for isolated PNS vasculitis is much better than that for systemic vasculitic disorders. Although some patients may be managed with corticosteroids alone, the combination of corticosteroid and cyclophosphamide has been reported to more likely result in remission and improves disability.25
Most neuropathies that occur following surgery are felt to be due to stretching or compression of nerves. However, a recent study has suggested that some of these neuropathies may be secondary to inflammation. In a study of 23 patients who developed neuropathies following a surgical procedure, 12 had no history of direct trauma to a nearby nerve and were suspected of having an autoimmune neuritis.93 A total of 21 patients had abnormal nerve biopsies that showed increased epineurial perivascular lymphocytic inflammation (9 small, 5 moderate, and 7 large), with 15 having findings suggestive of microvasculitis. Some of these patients apparently improved upon treatment with immunotherapy, but we do not know if the natural history might be gradual improvement. This entity seems similar to idiopathic brachial plexus and lumbosacral radiculoplexus neuropathy—some of which may occur after surgeries. Fibrinoid necrosis of vessel walls is not typical, but there is transmural or perivascular inflammation.
There is a lack of randomized therapeutic trials of corticosteroids and other immunosuppressive agent therapies in vasculitic neuropathy.1,11,30 Nonetheless, the mainstay of initial treatment of systemic vasculitis has been the combination of corticosteroids and cyclophosphamide.2,4,11,43,94–96 Since the use of corticosteroids to treat systemic vasculitis began in the 1950s, the 5-year survival rate increased from 10% to 55% by the mid-to-late 1970s.2 The addition of cyclophosphamide to corticosteroids further increased the 5-year survival rate to more than 80%.2,97 We tend to be aggressive in our treatment approach because treatment failure in a disease such as PAN may be lead to a catastrophic event, such as a bowel or myocardial infarction. Hypersensitivity vasculitis and sometimes isolated PNS vasculitis may be treated with only prednisone. However, a large retrospective series suggested that the combination of corticosteroids and cyclophosphamide was more effective than corticosteroids alone as mentioned previously.25 There is less experience with other immunotherapies in the treatment of vasculitis. Methotrexate (0.15–0.3 mg/kg per week) in combination with corticosteroids can be effective in GAN.54,98 Azathioprine, cyclosporine, tacrolimus, chlorambucil, and intravenous immunoglobulin have been tried in refractory cases with variable success.95,96,109–111 More recently, rituximab has gained popularity as it appears effective in ANCA-associated vasculitis and cryoglobulinemia. The current recommended treatment strategy is dependent on the type of vasculitis.
As mentioned, treatment of ANCA-associated vasculitis has been induction with corticosteroids and cyclophosphamide and then replacing cyclophosphamide with another second-line agent after 3–6 months as outlined in the previous section. However, there have been several reports suggesting rituximab may be beneficial11,99–106 and two randomized clinical trials107,108 showing that the combination of rituximab and corticosteroids is not inferior to cyclophosphamide and corticosteroids. Thus, the combination of corticosteroids (e.g., prednisone 1.0–1.5 mg/kg daily) and rituximab is increasingly recommended as the standard initial treatment of choice. Rituximab is typically given at a dosage of 375 mg per meter-squared weekly for 4 weeks.
Treatment of mixed cryoglobulinemia requires removal of the antigen. In patients with mixed cryoglobulinemia due to hepatitis C infection treatment with α-interferon appears to be effective.11,13,66,83,112–121 Combination of α-interferon and ribavirin also has yield positive results though no randomized, controlled trials have been performed.122–124 Use of high-dose corticosteroids and cyclophosphamide may allow the virus to persist and replicate, thus increasing the risk of liver failure. Methotrexate is avoided due to the risk of direct hepatotoxicity.
A short course of corticosteroids has been used to control the initial manifestations of the systemic vasculitis followed by plasma exchange and α-interferon.
Recently, there have been several reports suggesting rituximab may be beneficial in cryoglobulinemic vasculitis.125–135 Two randomized, open-label studies comparing rituximab to standard treatment with immunosuppressive agents demonstrated a greater response rate with rituximab.136,137 Two studies compared treatment with rituximab and antivirals (Peg-interferon-alpha/riboflavin) to antiviral alone and, again, the rituximab-treated patients seemed to do better.138,139 On this basis, we usually initiate treatment with plasma exchange followed by the combination of rituximab and antiviral therapy.
We typically treat with oral prednisone 1.5 mg/kg per day (up to 100 mg per day) as a single dose in the morning in addition to cyclophosphamide. After 2–4 weeks, we switch from daily to alternate-day prednisone (i.e., 100 mg every other day). However, if a patient is diabetic, we treat with daily corticosteroids (e.g., prednisone 50 mg daily) so as not to have wide fluctuations in blood glucose. In patients with severe vasculitis, we may initiate treatment with a pulse of intravenous methylprednisolone (1 g intravenously every day for 3 days), then switch to oral corticosteroids. Patients are concurrently started on calcium and vitamin D supplementation and sometimes on a bisphosphonate to prevent and treat steroid-induced osteoporosis.
In addition, oral or intravenous cyclophosphamide is started. Oral cyclophosphamide at a dose of 1.0–2.0 mg/kg is a more potent suppressor of the immune system but is associated with more adverse side effects (e.g., hemorrhagic cystitis) than intravenous doses. Thus, we usually treat patients with monthly intravenous pulses of cyclophosphamide at a dose of 500–1,000 mg/m2 of body surface area. Hydration is essential to minimize bladder toxicity. We also often premedicate patients with sodium 2-mercaptoethane sulfonate to reduce the incidence of bladder toxicity and with antiemetics to diminish nausea. Following intravenous pulses of cyclophosphamide, the leukocyte count drops. The nadir of the leukopenia occurs between 7 and 18 days, during which time the risk of infection is greatest. We check complete blood counts and urinalysis prior to each treatment. Urinalysis is obtained every 3–6 months after treatment because of the risk of future bladder cancer.
If patients do not respond to pulsed cyclophosphamide, oral dosing should be tried before concluding that the patient failed cyclophosphamide treatment. High-dose corticosteroids and cyclophosphamide are continued until the patient begins to improve or at least the deficit stabilizes. This usually occurs within 3–6 months. Subsequently, we discontinue cyclophosphamide and start methotrexate (7.5 mg per week). The methotrexate dose is gradually increased as necessary. At the same time, we begin to taper the prednisone by 5 mg every 2–3 weeks. In our experience, the disease may “burn itself out” and immunomodulating drugs may be successfully weaned after a year or more resulting in a prolonged drug-free remission in some cases.
Extrapolating to ANCA-associated vasculitis, rituximab might be beneficial in isolated PNS vasculitis, but we just do not have literature to support its use at this time. However, we certainly would use it in patients refractory to prednisone and cyclophosphamide and perhaps prior to cyclophosphamide use. In patients with hepatitis B–associated vasculitis, we usually treat with antiviral medications, plasma exchange, and a short course of corticosteroids. IVIG and rituximab have been used but the literature is scant; we also worry about increasing viral load with immunosuppressive agents and rituxan use.
SUMMARYThere are a number of causes of systemic vasculitis that can affect peripheral nerves, and many times the vasculitis may be isolated to the peripheral nerves. Individuals who are affected may manifest with mononeuropathy, multifocal neuropathy/multiple mononeuropathies, and overlapping mononeuropathies, or even as a generalized symmetric sensorimotor polyneuropathy. It is important to take a detailed medical history for disorders that may be associated with vasculitis (e.g., connective tissue diseases, viral hepatitis, and late-onset asthma). Useful laboratory tests include assessment for eosinophilia, ANAs, MPO/pANCA, PR3/cANCA, ESR, CRP, rheumatoid factor, cryoglobulins, hepatitis serology, and urinalysis. We like to have histological confirmation of vasculitis before initiating what can turn out to be long-term immunosuppressive therapy. The diagnostic yield of a combined superficial peroneal nerve and peroneus brevis muscle biopsy, when clinically affected, is high. Most patients improve with immunotherapy.
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