INTRODUCTION — Vasculitic neuropathy is usually only one feature of a systemic condition involving other organs. In a minority of patients with vasculitic neuropathy, peripheral nervous system vasculitis occurs in isolation and is called nonsystemic vasculitic neuropathy (NSVN) or isolated peripheral nervous system vasculitis.
NSVN can have a variable course ranging from an indolent and slowly progressive neuropathy to one associated with rapidly progressive disability.
This topic will review the treatment and prognosis of NSVN. The diagnosis and clinical manifestations of vasculitic neuropathy are presented separately. (See "Clinical manifestations and diagnosis of vasculitic neuropathies".)
GENERAL PRINCIPLES
Goals of therapy — The goals of therapy for nonsystemic vasculitic neuropathy (NSVN) are to minimize ongoing nerve injury and prevent involvement of additional nerves. Because the regeneration of nerves can take months to years and functional recovery may be incomplete, monitoring the response to therapy can be challenging. (See 'Monitoring response to therapy' below.)
Pretreatment assessment of disease severity — In general, the severity of the nerve involvement guides some of the therapeutic decisions. There are no universally agreed upon definitions of disease severity. However, we use the following descriptions as a guide:
●Mild disease – Patients with mild NSVN have a nondisabling indolent or slowly progressive course lasting weeks to months. Examples of more limited involvement include predominantly sensory symptoms or a sensorimotor neuropathy that is distally limited (such as numbness or weakness in a foot).
●Moderate to severe disease – Patients with moderate to severe disease have disability due to weakness and sensory loss that may involve multiple nerve distributions and accumulate rapidly, within weeks of initial symptoms.
INITIAL MANAGEMENT — When vasculitic neuropathy is associated with an identifiable systemic vasculitis or other systemic rheumatic disease, immunosuppressive therapy is directed at the underlying disease, as described elsewhere in the appropriate topic reviews. In such patients, only issues such as rehabilitation, orthoses, and pain control are specific for the neuropathy (see 'General measures' below). While diabetic radiculoplexus neuropathy is also considered a form of nonsystemic vasculitic neuropathy (NSVN), no specific treatment aside from symptomatic management is currently recommended. (See "Diabetic amyotrophy and idiopathic lumbosacral radiculoplexus neuropathy".)
The following discussion will focus on the treatment of nonsystemic (ie, isolated) vasculitic neuropathy. Because of the lack of treatment trials in NSVN, treatment recommendations are based primarily on clinical experience, observational data, and cautious extrapolation from trials using immunosuppressive agents for the treatment of systemic vasculitides.
Systemic glucocorticoids plus glucocorticoid-sparing agent — For most patients with vasculitic neuropathy, we suggest initial treatment with high-dose systemic glucocorticoids in combination with a glucocorticoid-sparing agent rather than glucocorticoids alone. Exceptions to this recommendation might include patients for whom the diagnosis is unclear, and situations in which glucocorticoids are initially prescribed alone to assess for "steroid-responsive disease." There are no randomized trials evaluating the role of glucocorticoids or any other immunosuppressive therapy for the treatment of NSVN. In addition to presumed improved efficacy with combination therapy, the rationale for additional immunosuppressive therapy is also based on the potential for these medications to reduce the cumulative dose of prednisone and diminish the adverse effects associated with glucocorticoids.
Treatment regimens with glucocorticoids vary widely among practitioners, with regional and interdisciplinary variation. For severe disease, some clinicians use high-dose pulse glucocorticoid therapy such as 1000 mg of intravenous methylprednisolone given for three days followed by daily oral prednisone. For less severe disease, oral prednisone is typically used initially. A widely used oral regimen begins with a prednisone equivalent of 1 mg/kg per day, up to a maximum daily dose of 80 mg. This regimen is continued for two to four weeks with ongoing assessment of the clinical response. The prednisone dose should be tapered steadily. Notably, there is the potential for glucocorticoid-related morbidity, including muscle weakness, which may interfere with interpretation of the clinical response. (See "Major side effects of systemic glucocorticoids".)
Observational data supporting this approach come from small cohort studies [1-3]. In the largest retrospective cohort, which included data from 60 patients with biopsy-proven NSVN, overall clinical improvement as determined by the treating clinician occurred in all patients after they received high doses of intravenous glucocorticoids [2]. Among 46 patients with over one year of follow-up (median six years), 43 of whom received severity-adjusted immunosuppressive therapy in addition to glucocorticoids, all demonstrated improvement from baseline over the follow-up period. Another retrospective cohort with 48 patients with NSVN found that combination therapy (20 patients) was associated with a greater likelihood of remission compared with glucocorticoid monotherapy (95 versus 61 percent), improved disability, and a trend towards reduced relapse rates and improvement in chronic pain after a median follow-up period of 63 months [1]. Combination therapy consisted of glucocorticoid plus oral cyclophosphamide in 18 patients, azathioprine in 1 patient, and intravenous immune globulin in 1 patient. Clinical experience suggests that rituximab is likely effective in this role as well [4].
Our recommendation to use combination therapy as initial treatment differs from the 2010 Peripheral Nerve Society guideline in which glucocorticoid monotherapy is the preferred initial treatment unless the neuropathy is "rapidly progressive," which is defined as new motor or sensory deficits within four weeks of presentation [5]. Combination therapy is otherwise reserved for patients whose disease progresses on glucocorticoid monotherapy. These guidelines do not include subsequent data from observational studies as well as new information regarding the management of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis [4].
Choice of glucocorticoid-sparing agents — The choice of glucocorticoid-sparing agents is generally based on disease severity at presentation, side effect profiles, and patient comorbidities.
Mild disease — For patients with mild NSVN, we suggest using a combination of high-dose glucocorticoids with either azathioprine or methotrexate. Azathioprine and methotrexate have not been compared directly in clinical trials and the decision to use one over another is partly based on the side effect profile of each drug and other patient factors (eg, methotrexate is contraindicated during pregnancy).
Rituximab, an anti-CD20 monoclonal antibody, may also be a reasonable option for patients with mild disease, although we have limited experience in this setting and generally reserve it for more severe disease or in patients who progress or cannot tolerate other first-line therapies. (See 'Moderate to severe disease' below.)
●Azathioprine – Azathioprine is typically initiated at a dose of 50 mg/day and gradually increased. If this dose is tolerated well at one week, the daily dose can be increased over several weeks to the range of 1.5 to 3.0 mg/kg per day. The maximum dose should typically not exceed 200 mg/day.
Azathioprine metabolism and toxicity is predominantly related to thiopurine methyltransferase (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'.)
Although azathioprine is generally well tolerated by patients, observational data suggest limited efficacy. In an observational cohort study in which 19 of 43 patients with biopsy-proven NSVN were treated with 150 mg azathioprine daily after initial treatment with glucocorticoids, only 46 percent of patients on azathioprine showed improved disability, while the remaining patients had progression of disease or only slight improvement during the median seven-year follow-up [2].
Other available evidence comes from the use of azathioprine for other systemic vasculitides. (See "Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy", section on 'Dosing of azathioprine'.)
●Methotrexate – Methotrexate is typically initiated at a dose of 15 mg/week, with increases in dose every week 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".)
The efficacy of methotrexate for NSVN is based on expert opinion, our clinical experience, and its use in treating other vasculitides such as granulomatosis with polyangiitis and microscopic polyangiitis. (See "Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy", section on 'Non-organ- and non-life-threatening disease'.)
Moderate to severe disease — For patients with moderate to severe NSVN, particularly those with motor nerve involvement, we suggest using the combination of high-dose glucocorticoids with cyclophosphamide. Rituximab, an anti-CD20 monoclonal antibody, is a reasonable alternative first-line therapy in patients who are intolerant of or resistant to cyclophosphamide. The general approach to using cyclophosphamide is to establish disease control as quickly as possible through combination therapy with prednisone and then to discontinue cyclophosphamide after three to six months. Cyclophosphamide is replaced by a medication with a lower risk of toxicity, usually azathioprine, methotrexate, or rituximab. (See 'Maintenance therapy and glucocorticoid tapering' below.)
The choice of oral versus intravenous cyclophosphamide is dictated primarily by practice style. We prefer intravenous cyclophosphamide given the lower cumulative dose associated with this administration and subsequent lower risk of toxicity. A regimen recommended by Peripheral Nerve Society guidelines is pulse intravenous cyclophosphamide at 0.6 g/m2 every two weeks for three doses followed by 0.7 g/m2 every three weeks for three to six doses. A more detailed discussion of dosing, dose adjustments, and adverse effects is presented elsewhere. The induction of remission appears equally likely regardless of whether oral (daily) or intravenous (intermittent) cyclophosphamide is used. (See "General principles of the use of cyclophosphamide in rheumatic diseases" and "General toxicity of cyclophosphamide in rheumatic diseases".)
If rituximab is selected, we typically use the dose regimen used for rheumatoid arthritis, administering 1 g of rituximab initially followed 14 days later by another 1 g dose. (See "Rituximab: Principles of use and adverse effects in rheumatoid arthritis", section on 'Initial dose'.)
Other than observational data and clinical experience in NSVN, cyclophosphamide is known to be efficacious in the treatment of ANCA-associated vasculitis. In an observational cohort of 48 patients with NSVN, combination therapy with glucocorticoids and cyclophosphamide was associated with greater likelihood of remission and improved disability compared with glucocorticoid monotherapy [1]. For patients treated with cyclophosphamide for less than six months, the relapse rate was 54 percent compared with no relapses in patients treated for greater than six months. There was also a trend towards a reduced number of relapses and improvements in chronic pain. The use of cyclophosphamide in the management of granulomatosis with polyangiitis and microscopic polyangiitis is discussed in detail separately. (See "Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy", section on 'Cyclophosphamide-based regimen'.)
While there are no data for the use of rituximab in patients with NSVN, rituximab has demonstrated efficacy in the treatment of ANCA-associated vasculitis. Based on clinical experience, rituximab is likely effective for NSVN and has been recommended by some professional groups as first-line therapy for NSVN [4,6]. (See "Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy", section on 'Rituximab-based regimen'.)
Monitoring response to therapy — One of the more challenging aspects of the treatment of NSVN is monitoring the response to therapy. It is important to recognize that new nerve infarctions can occur in distributions of extensive vascular compromise up to several weeks after the institution of therapy. Thus, the development of a new nerve infarction shortly after starting immunosuppression does not necessarily signal the need to intensify treatment, particularly if other indicators of disease activity suggest disease control.
The disease is primarily monitored clinically by serial neurologic examinations. Patients are typically assessed at least monthly (or sooner initially) to monitor for disease activity. Features to focus on include the anatomic distributions of weakness and sensory loss. Since nerve regeneration starts proximally and moves distally, strength and sensation are generally recovered in proximal aspects sooner than distal regions. Pain is an unreliable indicator of disease activity since pain worsens not only with nerve injury but can also occur in a delayed fashion after nerve injury. If the erythrocyte sedimentation rate or C-reactive protein were initially elevated, they should be repeated to help assess the clinical response.
SUBSEQUENT MANAGEMENT
Maintenance therapy and glucocorticoid tapering — Because of the toxicity of long-term cyclophosphamide therapy, patients who receive cyclophosphamide for severe disease should be transitioned to a less toxic maintenance therapy after disease control has been attained with cyclophosphamide. Azathioprine or methotrexate are often used in this setting. Rituximab is being used increasingly in this context, as well, primarily based on clinical experience. (See "Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy", section on 'Maintenance therapy'.)
Most patients and clinicians prefer to discontinue glucocorticoids before stopping the other maintenance immunosuppressive medicine. The timing of a taper should be individualized and generally may begin once the disease appears to be stabilized and glucocorticoid-sparing therapy has been established.
There is no standard tapering regimen for vasculitic neuropathy, but regimens similar to the one outlined below are often used. Assuming that a patient begins prednisone at 60 mg/day and remains on this dose for four weeks, the following taper will require a total of 24 weeks to reach a daily dose of 5 mg:
●The prednisone dose is tapered by 10 mg each week until a dose of 40 mg/day is reached.
●After one week on 40 mg/day, the prednisone dose is tapered by 5 mg each week until the dose reaches 20 mg/day.
●After one week on 20 mg/day, the prednisone dose is tapered by 2.5 mg each week until the dose reaches 10 mg/day.
●After one week on 10 mg/day, the prednisone dose is tapered by 1 mg every two weeks until the dose reaches 5 mg/day.
There is large variation to the taper suggested above. The Peripheral Nerve Society, for example, suggests tapering prednisone to 10 mg daily at six months [5]. The most important principles are slow taper (over weeks) and close monitoring for signs of recurrent nerve dysfunction or the development of inflammatory disease in other organ systems. (See 'Monitoring response to therapy' above.)
Discontinuation of the prednisone taper should be attempted if the patient has achieved and maintained good disease control. Tapering off prednisone completely should not proceed faster than 1 mg/day decreases every two weeks. Deviations from this regimen may be necessary if patients develop glucocorticoid myopathy or experience disease flares. (See "Glucocorticoid-induced myopathy".)
Relapsing or resistant disease — Disease relapses present clinically as new areas of weakness and numbness. Treatment selection depends on the stage of therapy and severity of relapses. Mild relapses, such as involvement of one new nerve during initial glucocorticoid taper, are treated by increasing the glucocorticoid dose and prolonging the taper. On the other hand, repeated relapses or severe relapses (such as multiple new nerves being affected) are handled by escalation of therapy. For example, if methotrexate or azathioprine were used in conjunction with glucocorticoids, then cyclophosphamide or rituximab is substituted for methotrexate or azathioprine.
For refractory disease such that glucocorticoids cannot be tapered, there is limited evidence to suggest that adjunctive intravenous immune globulin may be helpful [7,8]. Plasma exchange has been used in this context as well, though substantive data to support use are lacking.
Duration of therapy — The optimal duration of therapy is unclear, and is largely based on expert consensus and clinical experience. The Peripheral Nerve Society guidelines recommend treating for 18 to 24 months, extrapolating from clinical experience in systemic vasculitis. This duration of therapy can be tailored further individually if there is, for example, toxicity to therapy. On the other hand, based on our clinical experience, relapses have occurred after the 24-month time point. In general, our approach is to treat for at least two years of clinical remission and then taper or discontinue therapy. The overall relapse rate is estimated to be approximately 30 percent [4].
GENERAL MEASURES
Routine follow-up — Patients are generally followed at least monthly initially and then every three to four months after sustained remission is achieved. During visits, patients should be queried for symptoms suggestive of systemic vasculitis, such as rash, dyspnea, or sinus discharge, and screened for systemic involvement as indicated. Whether all patients should be routinely screened by laboratories or imaging for emergence of systemic vasculitis is unclear, and practice varies, but there is agreement that there should be a low threshold to investigate any new clinical findings suggestive of vasculitis.
Rehabilitation and orthoses — Rehabilitation efforts, including physical and occupational therapy consultation, should begin as early as possible. An ankle foot orthosis or wrist splint may be helpful in allowing patients to reestablish useful function in an affected extremity while awaiting neurologic recovery. (See "Basic techniques for splinting of musculoskeletal injuries".)
Pain control — The pain associated with the vasculitic neuropathy may be severe. A number of pain-modifying agents may be considered, including amitriptyline/nortriptyline, duloxetine, gabapentin, or pregabalin. We strongly prefer avoiding the use of opioid analgesics for neuropathic pain.
Absent direct data in patients with nonsystemic vasculitic neuropathy (NSVN), we generally approach pharmacologic pain management in NSVN similarly to other painful neuropathies, such as postherpetic neuralgia or painful diabetic neuropathy. (See "Postherpetic neuralgia", section on 'Treatment' and "Management of diabetic neuropathy", section on 'Pain management'.)
Osteoporosis prevention — All patients treated with high-dose glucocorticoids are at risk for glucocorticoid-induced osteoporosis. Thus, all patients embarking upon treatment courses for inflammatory myopathy are potential candidates for antiresorptive therapy designed to prevent bone loss.
The prevention and treatment of glucocorticoid-induced osteoporosis are discussed separately. (See "Prevention and treatment of glucocorticoid-induced osteoporosis".)
Prevention of opportunistic infections — Patients treated with the combination of high-dose prednisone and/or other immunosuppressive agents should receive Pneumocystis pneumonia prophylaxis. (See "Treatment and prevention of Pneumocystis pneumonia in patients without HIV", section on 'Prophylaxis'.)
A common prophylactic strategy for patients with normal renal function is the use of trimethoprim-sulfamethoxazole (TMP/SMZ), which may be given as one double-strength tablet daily or three times per week or as one single-strength tablet daily. Prophylactic regimens for Pneumocystis pneumonia are discussed in detail separately. (See "Treatment and prevention of Pneumocystis pneumonia in patients without HIV", section on 'Regimens'.)
PROGNOSIS — The long-term outcomes in patients with vasculitic neuropathy are primarily available from single-center studies based in academic hospitals. In the best-characterized cohort of 48 patients with nonsystemic vasculitic neuropathy (NSVN) followed for a median of 63 months, the disease-related mortality was 10 percent [1]. Pulmonary embolism secondary to immobility was the most common cause of death. Most patients were either asymptomatic (12.5 percent) or only mildly to moderately symptomatic (67.5 percent, able to walk without assistance) at final follow-up. The most common disability was chronic pain. Only 6 percent of patients had spread of vasculitis to other tissues, all of which was to the skin.
Similar outcomes have been captured in other studies. In a retrospective review of 106 patients (only 11 nonsystemic) collected over 28 years, remission was achieved in all but six patients, and the one-year survival was 90 percent [9]. Younger age (less than 64 years) is associated with better outcomes [2]. In a small retrospective study, foot drop and peroneal nerve involvement appeared to be prognostic of a poorer outcome [10].
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: Neuropathy".)
SUMMARY AND RECOMMENDATIONS
●Goals of therapy – The goals of therapy for nonsystemic vasculitic neuropathy (NSVN) are to control vascular inflammation as quickly as possible in order to minimize ongoing nerve damage and prevent the involvement of additional nerves. (See 'General principles' above.)
●Initial management – NSVN is uncommon, and prospective studies have not been performed. Treatment recommendations for NSVN are based primarily on clinical experience, retrospective case series, and extrapolation from trials using immunosuppressive agents for the treatment of systemic vasculitides. (See 'Initial management' above.)
●High-dose glucocorticoids plus glucocorticoid-sparing agent – For most patients with NSVN, we suggest initial treatment with high-dose systemic glucocorticoids in combination with a glucocorticoid-sparing agent rather than glucocorticoids alone (Grade 2C). In addition to presumed improved efficacy with combination therapy, the rationale for a concurrent glucocorticoid-sparing agent is also based on the potential to reduce the cumulative dose of prednisone and diminish the adverse effects associated with glucocorticoids. (See 'Systemic glucocorticoids plus glucocorticoid-sparing agent' above.)
The selection of a glucocorticoid-sparing agent is guided by disease severity and side effect profiles.
•Mild disease – For most patients with mild NSVN, we suggest either azathioprine or methotrexate rather than cyclophosphamide (Grade 2C). While comparative efficacy data are limited, azathioprine and methotrexate generally have a more favorable toxicity profile than cyclophosphamide. Rituximab may be a reasonable option for initial therapy even in mild disease, although our experience with it in this setting is limited. (See 'Mild disease' above.)
•Moderate to severe disease – For patients with moderate or severe NSVN, we suggest initial therapy with cyclophosphamide (Grade 2C). Some clinicians may choose rituximab as a reasonable alternative to cyclophosphamide based on experience with the antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides. Patients who receive cyclophosphamide are typically transitioned to a less toxic agent such as azathioprine, methotrexate, or rituximab after three to six months. (See 'Moderate to severe disease' above.)
●Disease monitoring – Monitoring the response to therapy is primarily clinical and can be challenging in NSVN, and clinical improvement typically takes months. Pain alone is not a reliable marker of disease activity, and it can sometimes worsen with resolution of nerve ischemia. (See 'Monitoring response to therapy' above.)
●Maintenance therapy – Most patients and clinicians prefer to discontinue glucocorticoids before stopping the other maintenance immunosuppressive medicine. The timing of a taper should be individualized and generally may begin once the disease appears to be stabilized and glucocorticoid-sparing therapy has been established. (See 'Maintenance therapy and glucocorticoid tapering' above.)
●Prognosis – Treated NSVN rarely involves other organs, but approximately 30 percent of patients experience a relapse of neuropathy. Though the long-term neurologic outcome is favorable, the development of chronic pain is common. (See 'Duration of therapy' above and 'Prognosis' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Steven David Brass, MD, MPH, MBA, who contributed to an earlier version of this topic review.
