Approach

Management of CIDP should encompass a multi-modality approach, focusing on treating the underlying inflammatory disease process and maximising quality of life. Early detection and treatment minimises secondary axonal loss and prevents further impairment.[130]​ Multi-disciplinary care should include access to a neurologist, pain specialist, physiotherapist, occupational therapist, orthotist, prosthetist, and psychologist, as required.[1]​ As CIDP may co-exist with other conditions (e.g., diabetes mellitus, monoclonal gammopathy of undetermined significance [MGUS], HIV, or connective tissue diseases), checking for and treating such conditions is essential and may improve outcomes for CIDP.[19]

The treatment strategy for CIDP is dependent on disease course and severity. Patients with mild disease (weakness that does not interfere with daily activities) may be monitored for deterioration without treatment.​​​[131]​ Most other patients will respond to some form of immunosuppressive therapy. For patients with possible CIDP that does not fulfil clinical or electrodiagnostic criteria, a treatment trial with one of the first-line therapies, with objective measurement of response, may be used to establish a diagnosis.[1]

Initial therapy

Patients in whom the disease has a significant impact on function and quality of life should be treated with immunosuppressant or immunomodulatory therapy. Approximately 75% to 85% of patients will respond to monotherapy with intravenous immunoglobulin (IVIG), corticosteroids, or plasma exchange.[1][58][60]​​​[132][133][134]​​​[135]

Corticosteroids

Corticosteroids are effective for treating CIDP.[1][60][134]​​ High-dose pulsed methylprednisolone or dexamethasone are often tried first as they are easy to administer, have few adverse effects, have rapid onset of benefit, and are inexpensive.[1]​​[134][136]​ Efficacy and improvement in disability after treatment with pulsed high-dose dexamethasone or typical daily prednisolone regimens are equivalent; however, daily oral prednisolone may cause many more adverse effects, and may take longer to show benefit.[1][134][135]​​[136]

Intravenous immunoglobulin (IVIG)

IVIG is another effective option that is often used as first-line treatment because of its ease of use, rapid onset of benefit, and low incidence of adverse effects.[1][59][131][132][135]​​​[137]​​​​ There is no evidence for a difference in treatment efficacy between IVIG preparations.[1][138]​​​ If efficacious, IVIG can be repeated from every 2 to 6 weeks.[1] To optimise therapy, the dose should be reduced before the frequency of administration is lowered, to achieve maximal benefits with minimal amounts of IVIG. However, care must be taken to avoid deterioration before the next dose.[1]​​[131][132]

Plasma exchange

Plasma exchange is effective and relatively safe, resulting in significant short-term improvement in disability, clinical impairment, and motor nerve conduction velocity in patients with CIDP.[1][133] However, some patients who show improvement subsequently deteriorate.[133] Plasma exchange requires good vascular access and specialised equipment, which can make it less convenient than other treatments, especially in paediatric patients.[1][133][139]

Choice of initial therapy

Randomised controlled trials comparing efficacy between corticosteroids, IVIG, and plasma exchange do not show a significant benefit of any one over the others.[1][2][135]​ The final decision on which treatment to use is determined by availability, risks, contraindications, and disease severity; however, because corticosteroids and IVIG are easier to administer and are generally better tolerated, they are usually recommended ahead of plasma exchange.[1] If significant adverse effects occur with an initial therapy, an alternative should be substituted.

Corticosteroid therapy is not recommended as first-line treatment for patients with motor CIDP, due to evidence of deterioration after such therapy.[1]​​[68]​​​[69][135]

Partial or no response to initial therapy

It may take up to 3 months to determine treatment effectiveness. Lack of at least a partial response to one or two initial agents should lead to reconsideration of the diagnosis.[2]

If there is a partial but insufficient objective response to the initial agent (i.e., daily activities are still affected by distal weakness and paraesthesias), this agent should be continued and a second or third initial agent added to the regimen.[1]

If there is no objective response to the chosen initial agent within a few weeks to months (and the diagnosis of CIDP is confirmed), an alternative initial agent (corticosteroids, IVIG, or plasma exchange) should be tried before considering combination therapy.[1][2][140]

Refractory to combination therapy with initial agents

For patients whose condition does not improve sufficiently in response to a combination of two initial agents (i.e. two of corticosteroids, IVIG, and plasma exchange), re-evaluation of the diagnosis and referral to a specialist centre is appropriate. In one study, 32% of patients referred for CIDP had been incorrectly diagnosed.[16]​ In a study of patients referred to a tertiary care centre for refractory CIDP, reasons for therapeutic failure included an incorrect alternative diagnosis and inadequate immunotherapy. In patients who had a poor response to treatment, inadequate first-line therapy or failure to add a second or third agent were frequently observed. The authors also stressed the importance of electrodiagnostic studies to distinguish true CIDP from mimics.[42]

Alternative immunosuppressants

Once the diagnosis of CIDP is confirmed, an alternative immunosuppressant should be added. Although there is limited evidence, rituximab, cyclophosphamide, ciclosporin, azathioprine, or mycophenolate may be considered as an alternative agent after failure of initial treatments, or as add-on medication.[1][141][142]​​ Any combination of initial and alternative agents can be used, and decisions should be based on severity of disease and adverse-effect profile.[1]

Guidelines recommend against using interferon beta-1a, methotrexate, fingolimod, alemtuzumab, bortezomib, etanercept, fampridine, fludarabine, immunoadsorption, interferon alfa, abatacept, natalizumab, and tacrolimus.[1]

In one retrospective analysis, approximately 25% of patients refractory to standard therapy showed a response to an alternative immunosuppressant; the authors noted that adverse effects should be monitored closely.[142]

Ciclosporin is well tolerated, drug levels can be monitored to guide treatment, and it usually produces benefit within 3-6 months.[1][141]​ Combining ciclosporin with plasma exchange can make it difficult to achieve therapeutic levels of ciclosporin.

Cyclophosphamide (often in combination with a corticosteroid) may be used to treat refractory disease.[1] In one meta-analysis, cyclophosphamide yielded a response rate of 68% in patients with refractory CIDP; however, in practice, cyclophosphamide should be used with caution due to its toxicity, and patients must be monitored for adverse effects.[143]

Rituximab may be considered in refractory CIDP or CIDP associated with other autoimmune diseases or haematological diseases (e.g. monoclonal gammopathy).​[62][141]​​​​​[144][145]​​​​​ Rituximab may also be considered with nodal/paranodal antibodies (e.g. IgG4 anti-contactin-1 or anti-neurofascin-155 antibodies) after failure of corticosteroids or IVIG.[64][104][146][147]​​​ It is recommended for children instead of cyclophosphamide because of a better adverse-effect profile.[1]

Azathioprine is another good additional agent that is usually well tolerated.[1][141][148]​​ However, onset of action may take 6-18 months, so it is not recommended for initial treatment of relapse or active refractory cases unless combined with other agents.

Mycophenolate is used similarly to azathioprine as an additional agent when rapid improvement is not needed.[1] Some, but not all, studies have shown benefit.[149][150]​​

Maintenance therapy

Maintenance therapy may require long-term use of an initial agent, an alternative agent, or a combination of two or more initial or alternative agents, depending on which treatments have produced a response in the acute phase of treatment. IVIG and corticosteroids are the most common agents used. Plasma exchange is generally not recommended long term for patients in whom IVIG and corticosteroids are ineffective, because of the need for vascular access.[1]

Long-term therapeutic options must be chosen on an individual basis, taking into account adverse effects and response to treatment, because there are few clinical trial data to help guide the practitioner. With a good response to an initial agent, the patient usually has up to 1-2 years of therapy (depending on agent used) with a slow taper. If there is an exacerbation of the disease during taper, the dose should be increased to the initial dose that resulted in a good response.[1] Some patients may require 5-15 years of treatment, but eventual withdrawal should be considered, as approximately one-third of patients will go into remission and not require subsequent therapy. Thus, the need for continued maintenance therapy should be re-assessed every 6-12 months.[1]

IVIG

IVIG as maintenance treatment is associated with few adverse effects. The optimal dose and interval for IVIG maintenance treatment are not known. Once the patient is stable, treatment can be tapered based on clinical experience, by either reducing the dose or increasing treatment interval. The adjustment should be done every 6-12 months in the first 2-3 years of treatment.[1]

Subcutaneous immunoglobulin (SCIG) is approved for maintenance therapy in patients with CIDP who are receiving a stable dose of IVIG. There is insufficient evidence to recommend SCIG for initial therapy.[1] SCIG is typically given once weekly, but can be given over 2-3 days for larger doses. There is insufficient evidence that a higher dose of SCIG is superior to a lower dose, but the relapse rate was lower in the higher-dose group.[1][151][152]​​ When switching from IVIG to SCIG, it is advised to use the same mean dose per week.[1] SCIG may be beneficial for patients with adverse effects or treatment-related fluctuations from IVIG that are not resolved by premedication or dose adjustment.[153]​ SCIG can be administered at home by the patient, and eliminates problems associated with venous access. Some patients may, however, find it difficult to self-administer SCIG due to weakness; others may experience local infusion site reactions.[1]

Corticosteroids

Long-term corticosteroid treatment may induce significant adverse effects (e.g., osteoporosis, gastric ulceration, diabetes mellitus, cataracts, avascular necrosis of long bones, arterial hypertension). However, high-dose pulsed corticosteroids are associated with fewer adverse effects than daily oral dosing.[1]

Alternative agents

The most commonly used alternative medications during maintenance therapy are azathioprine, mycophenolate, and ciclosporin, although evidence of effectiveness is of low certainty. These alternative agents are used to decrease the dose or frequency of immunoglobulin or corticosteroids, or when patients experience adverse effects from those therapies.[1]

Ciclosporin usually shows benefit within 3-6 months, while azathioprine and mycophenolate may take up to 6-18 months. They may all increase the risk of malignancy when used for >10 years. Other alternatives should only be considered after these drugs have been shown to be ineffective.

Due to lack of evidence of efficacy and/or adverse safety profiles, guidelines recommend against using the following agents: methotrexate, tacrolimus, interferon beta-1a, interferon alfa, fingolimod, alemtuzumab, bortezomib, natalizumab, etanercept, abatacept, fampridine, fludarabine, and immunoadsorption.[1]

Stem cell transplantation

Several case reports and series have described the use of stem cell transplantation for treatment-resistant chronic CIDP, but evidence for efficacy is limited.[1][154][155][156]​​ This treatment may have life-threatening adverse effects, with significant morbidity and potential mortality. Therefore it should only be considered in specialised CIDP centres as a last resort for patients with severe chronic CIDP that is unresponsive to all other therapies or who have intolerable adverse effects with more conventional treatments.[1]

Symptomatic therapies

Pain associated with CIDP should be assessed and treated. It may be neuropathic or nociceptive, and a consequence of CIDP, or unrelated to it. Neuropathic pain may be more common in conditions that mimic CIDP (e.g., polyneuropathy-organomegaly-endocrinopathy-M-protein-skin changes [POEMS] syndrome, vasculitis, diabetes, amyloidosis, Charcot-Marie-Tooth disease 1B), so alternative diagnoses should be considered.[1]

All patients with neuropathic pain should be offered symptomatic therapy. Based on current guidelines, pregabalin, gabapentin, tricyclic antidepressants (e.g., amitriptyline), and serotonin-noradrenaline reuptake inhibitors (venlafaxine or duloxetine) are commonly used as first-line agents.[1][157][158]​​​ Tramadol and other opioid analgesics are recommended as second- and third-line agents, respectively.[157]​ Guidance from the US Centers for Disease Control and Prevention notes that evidence for efficacy of opioid therapy for neuropathic pain is limited, and that opioids should only be considered once other options have been tried, and if the expected benefits are anticipated to outweigh risks to the patient.[159]​ Slow upward dose titration may minimise adverse effects of pain medications, particularly those associated with sedation.

Fatigue is common in CIDP regardless of the disease activity state, and worsening fatigue over time is associated with poor quality of life and increased disability. However, fatigue should not be used as a diagnostic sign for CIDP. Reducing sedative use, better sleep hygiene, and treating depression may help with CIDP-related fatigue.[160][161]​​​

Depending on the severity of the weakness associated with CIDP, physiotherapy, occupational therapy, and orthotic evaluation may be needed. Referral to one or more of a physical medicine and rehabilitation physician, a psychiatrist or psychologist, a pain management consultant, and a podiatrist should be considered on an individual basis.[1]

A home exercise programme under the supervision of a physiotherapist may be of benefit, but this has not been adequately studied. Only one randomised controlled trial with a measure of functional ability as a primary outcome measure includes patients with CIDP.[162] Patients in the exercise group (home exercise programme consisting of strengthening, stretching, and aerobic conditioning exercises) had improved average muscle scores after 6 weeks, as well as improved scores on the role limitation (physical) scales of the SF-36, a measure of ability to do work or daily activities.

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