Treatment of recurrent and resistant dermatomyositis and polymyositis in adults

INTRODUCTION — Dermatomyositis (DM) and polymyositis (PM) are two classic forms of inflammatory myopathy. Most patients respond to initial therapy, and some achieve sustained disease control either off all therapy or with low-dose maintenance therapy. There are two additional patterns of response:

●Recurrent disease – After achieving disease control with treatment, some patients experience disease recurrences (flares) during or after the period of medication tapering.

●Resistant disease – In other patients, the disease does not respond entirely to conventional initial approaches to remission induction, and other therapies must be considered after excluding alternative diagnoses.

Approaches to the treatment of recurrent and resistant disease in adults with DM and PM will be reviewed here. The initial therapy of and clinical manifestations of these disorders in adults, the management of the cutaneous manifestations of dermatomyositis, and issues related to DM and PM in children are discussed separately. (See "Initial treatment of dermatomyositis and polymyositis in adults" and "Clinical manifestations of dermatomyositis and polymyositis in adults" and "Cutaneous dermatomyositis in adults: Overview and initial management" and "Juvenile dermatomyositis and other idiopathic inflammatory myopathies: Epidemiology, pathogenesis, and clinical manifestations" and "Management of refractory cutaneous dermatomyositis in adults" and "Juvenile dermatomyositis and polymyositis: Treatment, complications, and prognosis".)

RECURRENT DISEASE — Complete discontinuation of treatment is unsuccessful in the majority of patients. For patients who experience disease flares after the achievement of disease control, a variety of clinical scenarios may occur. The following discussion, based primarily on the authors' experience, assumes that prednisone is tapered before attempts to discontinue either azathioprine or methotrexate.

●Flare at more than 10 mg/day of prednisone – Disease flares at such doses of prednisone require one of two actions:

•Addition of a glucocorticoid-sparing drug if neither azathioprine nor methotrexate has been used

•Treatment of the flare as a case of resistant disease if the patient is already taking either azathioprine or methotrexate (see 'Resistant disease' below)

With either action, a higher dose of prednisone, generally in the range of 1 mg/kg per day, will be required to reestablish disease control.

●Flare at 10 mg/day of prednisone or less – If a disease flare occurs at a prednisone dose of 10 mg/day or less, there are two options that are not mutually exclusive:

•Increase in prednisone to the lowest dose required to reestablish disease control. This dose is based upon the severity of the patient's clinical findings. If the disease flare is detected early, the dose required may be significantly lower than 1 mg/kg per day. The usual minimum dose is 20 mg/day.

•Increase in azathioprine or methotrexate to a higher dose, if the dose of the patient's glucocorticoid-sparing drug has not already been maximized.

Once disease control is restored, we suggest slower tapering than that which was used during the initial course. Some patients are maintained on low-dose prednisone (eg, 5 mg/day) for one year or more.

●Flare off prednisone but on a glucocorticoid-sparing drug – There are two options in such patients that are not mutually exclusive:

•Prednisone is reinstituted at the lowest dose required to reestablish disease control. The dose selected is based upon the severity of the patient's clinical findings and may be significantly lower than 1 mg/kg if the disease flare is detected early. The usual minimum dose is 20 mg/day.

•The glucocorticoid-sparing drug can be changed from azathioprine to methotrexate or vice versa.

If the patient has been treated previously with both azathioprine and methotrexate, the flare should be regarded as a manifestation of resistant disease.

●Flare off all immunosuppressive medications – Prednisone should be reinstituted with the daily dose varying with the severity of the relapse. The minimum starting dose of prednisone is 20 mg/day. In addition, a glucocorticoid-sparing drug should be resumed or started.

RESISTANT DISEASE — Before initiating alternative therapies in patients with resistant disease, consideration should be given to an alternative diagnosis, particularly inclusion body myositis (IBM). The picture of weakness and atrophy of the quadriceps in addition to wrist and finger flexion involvement raises the suspicion of IBM (see "Clinical manifestations and diagnosis of inclusion body myositis"). A repeat biopsy may be necessary to confirm the diagnosis [1]. In addition, the initial response to glucocorticoids in the patient with dermatomyositis (DM) and polymyositis (PM) typically takes four to six weeks for normalization of creatine kinase (CK) levels, or three to four months to regain muscle strength; thus, a patient should not be classified as having resistant disease without considering these time factors.

Multiple options exist for treating patients who do not respond adequately to glucocorticoids plus azathioprine or methotrexate. Evidence of clinically significant benefit is greatest with rituximab and intravenous immune globulin (IVIG). We suggest using rituximab first in this setting, and then trying IVIG if rituximab fails. Additional considerations that may influence the choice of therapies include the presence of interstitial lung disease (ILD), particularly if it has not responded to initial treatment measures. (See "Interstitial lung disease in dermatomyositis and polymyositis: Treatment".)

The reasons for favoring rituximab over IVIG include the following:

●Treatment with rituximab has been associated with substantial improvement in DM and PM in patients with previously refractory disease. (See 'Rituximab' below.)

●Rituximab appears to be effective in connective tissue disorders resembling DM and PM, such as systemic lupus erythematosus and rheumatoid arthritis (RA). (See "Rituximab: Principles of use and adverse effects in rheumatoid arthritis".)

●If effective, rituximab may be more likely to lead to a prolonged period of disease control. Many patients who respond to IVIG require continued treatments on a monthly basis.

●Rituximab is less costly than IVIG.

Other agents that may be of benefit include mycophenolate mofetil; calcineurin inhibitors, such as cyclosporine or tacrolimus; and cyclophosphamide. The choice of these other agents is often guided by comorbidities, insurance coverage, and cost, as comparative studies have not been performed.

Rituximab — Rituximab targets CD20-positive cells (ie, B-cell precursors), leading in most patients to the depletion of B cells in the blood within several weeks of administration. It is a promising agent for the treatment of both DM and PM. A variety of dosing regimens have been employed in a randomized trial and several small case series or case reports in patients with DM and PM [2-9]. In rheumatic disease (particularly RA), the trend with the use of rituximab is to employ two 1 gram doses two weeks apart.

Some data indicate that patients who suffer disease flares can be retreated effectively with rituximab, but a larger clinical experience with this agent and additional randomized trials are required before definitive conclusions can be drawn. Observations with rituximab include the following:

●The largest trial of rituximab in inflammatory myositis, the Rituximab in Myositis (RIM) trial, involved 195 patients, all of whom were treated with rituximab either at baseline or after an eight-week delay, including 76 patients with adult DM and PM and 48 patients with juvenile DM; all patients had disease refractory to glucocorticoids and at least one immunosuppressive or immunomodulatory agent (mean of 3.1 agents in addition to the glucocorticoid) [2]. The findings suggested that rituximab is potentially effective in these populations, but no differences in response to rituximab were seen between the two groups to which the patients were allocated.

Patients were randomly assigned to receive rituximab (750 mg/m² up to 1 gram, administered intravenously once weekly for two weeks) either on weeks zero and one ("early arm") or on weeks eight and nine ("late arm"), and were assigned to receive placebo at the time point during which they did not receive rituximab. There were no differences between the early and late treatment arms in the time from baseline to achieve the composite response criteria (both at about 20 weeks) or 20 percent improvement in strength, nor were there differences between the two arms in the frequency with which the response criteria or 20 percent improvement in strength were achieved or in the rate of glucocorticoid taper. The disease groups (DM, PM, and juvenile DM) did not differ in outcome.

Despite the failure to demonstrate differences based upon the eight-week treatment delay, the composite response criterion was achieved by 83 percent of the patients receiving rituximab during the 44-week trial, and the mean dose of prednisone in the 160 patients on it at baseline was significantly reduced, from 20.8 to 14.4 mg daily. Response criteria were also met after a second course of therapy by eight of nine patients eligible for retreatment after an initial response and later recurrence.

Only one patient withdrew due to an adverse effect, although 26 serious adverse effects attributed to the rituximab were observed, most of which were infections. These included pneumonia and cellulitis (six patients each), as well as urosepsis and herpes zoster (two patients each), and one patient each had septic arthritis, histoplasmosis, urinary tract infection, respiratory failure, heart failure, dysrhythmia, venous thrombosis, syncope, rash, and neurologic symptoms. One patient died during the trial from a suspected malignancy and stroke. Infusion reactions were more common with the administration of rituximab compared with placebo (15.4 versus 5.3 percent).

●Other smaller case series have also demonstrated benefit, some with longer follow-up than the RIM trial or with different treatment regimens [3-9]:

•In one study, 13 patients with refractory inflammatory myopathies were treated with rituximab (1 gram every other week for two treatments) and were followed for a mean of 27 months, showing a significant decrease in CK and improvement in strength by handheld dynamometry by 22 percent at 24 months [7].

•In another study, six patients with DM were treated with 375 mg/m² once weekly times four doses [3]. All showed major clinical improvement, with the gain over baseline strength being evident as early as four weeks after the initial infusion and ranging from 36 to 113 percent. Additionally, extramuscular signs of disease, including rash, alopecia, and reductions in forced vital capacity, improved within 12 weeks. Disease flares during the one-year follow-up were seen in four patients, all between 24 and 36 weeks after treatment.

•Several reports included patients with antisynthetase antibodies which remained elevated during therapy, despite good clinical responses to rituximab [3,4].

Intravenous immune globulin — For DM, immunoglobulin (IVIG) is a reasonable second-line therapy for patients with refractory disease. IVIG has received US Food and Drug Administration (FDA) approval for the treatment of adults with DM. Some physicians may use IVIG as a first-line therapy, particularly for patients at high risk of poor outcomes (eg, severe weakness, dysphagia). The expense of this treatment is an important consideration in its long-term use. (See "Overview of intravenous immune globulin (IVIG) therapy".)

The beneficial effects of IVIG for the treatment of DM have been supported by observational data and randomized trials [10-15]. The data supporting its use for the treatment of patients with PM are more limited [15,16]. In the largest randomized trial of 95 patients with DM, more patients achieved a response of at least minimal improvement based on a composite score of disease activity if they received IVIG compared with placebo (79 versus 44 percent) at 16 weeks [10]. At enrollment, patients were allowed to be on a maximum of prednisone 20 mg daily (or equivalent) as well as a maximum of two immunosuppressive drugs. When the outcome was defined as either a moderate or major improvement on the composite disease activity score, more patients in the IVIG group continued to have more favorable results. The trial was extended open-label to a total of 40 weeks, in which all participants received treatment with IVIG. The open-label phase was associated with a corresponding increase in treatment-related adverse events, including thromboembolic events.

The rate of IVIG infusion may influence the risk of thromboembolism in patients with DM. In this study, reduction of the maximum infusion rate from 0.12 mL/kg/minute to 0.04 mL/kg/minute led to a corresponding decline in thromboembolic events (1.54 per 100 patient-months versus 0.54 per 100 patient-months) [10]. Larger and longer-term trials are needed to further clarify the efficacy and safety of IVIG for the treatment of DM.

An alternative subcutaneous approach to the administration of immunoglobulin in patients with DM and PM has also been associated with clinical improvement in strength and quality of life measures [17]. In this small case series of seven patients, the usual monthly dose was divided into weekly doses given subcutaneously through a programmable pump, and the treatment appeared to be safe and well-tolerated.

Mycophenolate mofetil — We suggest using mycophenolate mofetil as a second-line agent in patients who have failed to respond to either methotrexate or azathioprine, or in patients with interstitial lung disease (ILD; for whom methotrexate may be contraindicated). Mycophenolate mofetil is less expensive and easier to administer than other agents used to treat patients with resistant disease (ie, IVIG or rituximab). Trials comparing the relative efficacy of these agents for the treatment of refractory myositis are not available.

Mycophenolate mofetil has been used with some success in retrospective series of patients with inflammatory myopathy [18-21]. These case series suggest a role for mycophenolate mofetil in the treatment of resistant myositis. The use of mycophenolate mofetil in patients with DM/PM-associated ILD is discussed in detail separately. (See "Interstitial lung disease in dermatomyositis and polymyositis: Treatment", section on 'Mycophenolate mofetil'.)

The following observations illustrate the range of findings:

●A retrospective series included 10 DM patients with a history of refractory disease [19]. After initiation of mycophenolate mofetil, manual muscle testing scores improved in five, and the glucocorticoid dose could be tapered in six. Serious opportunistic infections occurred in 3 of the 10 patients: a Mycobacterium xenopi abscess of the thigh; pulmonary blastomycosis; and Legionella pneumonia (fatal). However, it is likely that the patients' immunosuppressive regimens prior to the use of mycophenolate mofetil contributed to the development of opportunistic infections.

●In a second report, six patients with treatment-resistant myositis (two with DM, three with PM, one with overlap myositis) were treated for a mean of 22 months with mycophenolate mofetil (mean dose 1.6 g/day) [20]. Both muscle strength and serum CK levels improved in all patients, and the mean prednisone dose was tapered from 13.7 to 8.5 mg/day.

Clinicians prescribing mycophenolate mofetil for inflammatory myopathy must be alert to the possibility of opportunistic infection.

Calcineurin inhibitors — The calcineurin inhibitors, which include cyclosporine and tacrolimus, achieve their effects by interfering with T cell function. Data on the use of calcineurin inhibitors in DM and PM are limited to retrospective case series and to anecdotal reports; however, both appear to have some role in the treatment of resistant DM and PM. The limited evidence available suggests that tacrolimus offers some advantage over cyclosporine in efficacy, but larger studies are required before definitive conclusions are possible.

Cyclosporine — Efficacy for cyclosporine has been suggested for both primary therapy [22,23] and resistant disease, including ILD [24,25]. (See "Interstitial lung disease in dermatomyositis and polymyositis: Clinical manifestations and diagnosis".)

In one report, six patients previously resistant to methotrexate, azathioprine, cyclophosphamide, and/or IVIG underwent treatment with a mean daily cyclosporine dose of 3.5 mg/kg [24]. Over the median six-month course of treatment with cyclosporine, the mean daily prednisone dose was reduced by 75 percent. All six patients demonstrated improved strength in the shoulder girdle; four had stronger hip flexor muscles.

Tacrolimus — Tacrolimus has been used in a limited number of patients with inflammatory myopathy. The optimal dose for this indication is not certain.

It has been suggested that tacrolimus may be particularly effective in cases of inflammatory myopathy complicated by ILD. In one report, tacrolimus (0.075 mg/kg per day in two divided doses) was effective in a series of eight patients with refractory PM [26]. Strength normalized in five of six anti-Jo-1 antibody-positive patients and improved in the two anti-signal recognition particle (SRP) positive patients. The mean CK declined from 3114 to 87 international units/mL. Three of five patients with ILD also showed improvement in pulmonary function.

In a second series from the same authors with minor overlap, 13 patients with the antisynthetase syndrome and ILD were treated with tacrolimus for a mean duration of 51 months [27]. Twelve of the patients had antibodies to Jo-1 and one had antibodies to PL-12. The following benefits were noted:

●Serum CK levels improved by 75 percent.

●Manual testing of muscle strength improved or remained stable in 10 of 13 patients.

●The mean prednisone dose was tapered by 67 percent.

●There were substantial improvements in forced vital capacity (FVC), forced expiratory volume in one second (FEV1), and the diffusing capacity for carbon monoxide (DLCO).

In other small series of patients with ILD, tacrolimus appeared to be beneficial in patients who were not controlled with cyclosporine [28,29].

Cyclophosphamide — Cyclophosphamide and chlorambucil (which is infrequently used because of greater toxicity than cyclophosphamide) may be effective in treating myositis [30,31], but their utility is limited by their potential for toxicity, particularly the induction of malignancy. A more detailed discussion of dosing, dose adjustments, and adverse effects is presented separately. (See "General principles of the use of cyclophosphamide in rheumatic diseases" and "General toxicity of cyclophosphamide in rheumatic diseases".)

One study evaluated the use of intravenous cyclophosphamide (plus prednisone) for progressive ILD in 17 patients with DM or PM [32]. The patients were treated with intravenous cyclophosphamide at doses ranging from 300 to 800 mg/m² every four weeks. All patients received at least six courses.

The following findings were noted:

●Eleven of the 17 patients showed improvement in their dyspnea.

●Six of the seven patients who required supplemental oxygen were able to discontinue supplemental oxygen use.

●Twelve of the patients had improvements in FVC of at least 10 percent. For the group overall, the mean FVC improved by 15 percent over baseline, from 68 to 83 percent predicted.

In the absence of aggressive ILD or systemic vasculitis, cyclophosphamide should be considered only in patients who fail to respond to multiple other second-line agents.

Given the efficacy of alkylating agents in the treatment of vasculitides, cyclophosphamide may also be useful in patients with inflammatory myopathy who develop the complication of systemic vasculitis. (See "Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy".)

Corticotropin injection gel — A case series has suggested that corticotropin injection gel, a form of adrenocorticotropic hormone, may be beneficial in patients with exacerbations of DM or PM despite ongoing therapy with other immunosuppressive agents [33]. However, in the absence of proven benefit and the high cost of this drug, we do not recommend the use of corticotropin injection gel for resistant DM or PM.

Combination methotrexate and azathioprine — Combination therapy may be effective among those with resistant disease. This combination might be considered in the patient for whom mycophenolate mofetil or other options were unaffordable or ineffective. The only published study regarding combination treatment is a crossover study in which 30 patients with refractory myositis were randomly assigned to either a combination of weekly oral methotrexate and daily azathioprine or to intravenous methotrexate with leucovorin rescue every two weeks for six months [34]. The doses used in the study were methotrexate 7.5 mg per week and azathioprine 50 mg/day to start, with escalation to a maximum dose of 25 mg and 150 mg/day. Twenty-five of the patients had had inadequate responses to previous cytotoxic therapies.

The results were as follows:

●Among the 15 patients initially assigned to oral methotrexate/azathioprine, eight improved with oral therapy, and one improved with intravenous methotrexate during the crossover period.

●Of the 15 patients initially assigned to intravenous methotrexate therapy, three improved with intravenous therapy and four with oral combination therapy during the crossover period.

This study did not have sufficient power to compare the two treatment regimens. However, the data indicate that either the combination of oral methotrexate and azathioprine or high dose intravenous methotrexate with leucovorin rescue may benefit some patients with refractory disease.

Janus kinase inhibitors — There are case reports and small series suggesting that Janus kinase (JAK) inhibitors may be effective in DM. This effect may be mediated by preventing the observed upregulation of type 1 interferon [35].

A case report suggested that ruxolitinib, a JAK inhibitor developed to treat neoplastic diseases, may be effective for treating resistant DM [36]. The report describes a 72-year-old woman with severe DM that was only partially responsive to several different treatment regimens, including glucocorticoids, azathioprine, IVIG, and mycophenolate mofetil. Approximately one year later, she was diagnosed with a JAK2 mutation-associated myeloproliferative neoplasm for which she was given ruxolitinib. Her DM symptoms rapidly improved, and by 12 months her DM was in remission on monotherapy with ruxolitinib. Although the immunomodulatory effects of ruxolitinib in the treatment of DM appear to be promising, more data are needed to establish efficacy for this indication. The possibility that her DM may be paraneoplastic, and therefore that the treatment of the underlying disease was the cause for improvement, cannot be excluded. (See "Polycythemia vera and secondary polycythemia: Treatment and prognosis".)

In two small series of patients with multidrug-resistant cutaneous DM, the rash responded to tofacitinib [37,38]. In another report, two patients with rapidly progressive calcinosis cutis responded to tofacitinib, and in one of these patients, severe ILD also responded to tofacitinib [39].

EXTRAMUSCULAR DISEASE

Interstitial lung disease — The presence of interstitial lung disease (ILD) may influence the choice of therapeutic agents. The treatment of ILD resistant to initial therapies is described in detail separately. (See "Interstitial lung disease in dermatomyositis and polymyositis: Treatment".)

Refractory rash — In some cases of dermatomyositis (DM), the cutaneous manifestations are more refractory to treatment than the muscle disease. A variety of approaches to the problem of refractory cutaneous DM have been taken. The management of the cutaneous manifestations of DM, including initial management and the treatment of manifestations that are resistant to initial therapy, is discussed in detail separately. (See "Cutaneous dermatomyositis in adults: Overview and initial management" and "Management of refractory cutaneous dermatomyositis in adults".)

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: Dermatomyositis and polymyositis".)

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 5^th to 6^th 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 10^th to 12^th 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.)

●Basics topics (see "Patient education: Dermatomyositis (The Basics)" and "Patient education: Polymyositis (The Basics)")

SUMMARY AND RECOMMENDATIONS

Many patients with dermatomyositis (DM) or polymyositis (PM) require intermittent or even continuous therapy (see 'Recurrent disease' above and 'Resistant disease' above):

●Recurrent disease is defined as the occurrence of a disease flare following the achievement of disease control with treatment.

●Resistant disease does not respond sufficiently to the conventional approaches of glucocorticoids plus either azathioprine or methotrexate. In such cases, other therapies must be considered after excluding alternative diagnoses.

Recurrent disease

●For patients who experience disease flares after the achievement of disease control, there are several specific scenarios (see 'Recurrent disease' above):

•For disease flares at more than 10 mg/day of prednisone, we suggest the addition of either azathioprine or methotrexate (if not already used) or treatment of the patient as a case of resistant disease (Grade 2C). (See 'Resistant disease' above.)

•For disease flares at 10 mg/day of prednisone or less, we suggest increasing the prednisone to the lowest dose required to reestablish disease control and/or increasing the azathioprine or methotrexate dose, if this has not been maximized already (Grade 2C).

•For disease flares off prednisone but on a glucocorticoid-sparing drug, we suggest reinstituting prednisone at the lowest dose required to reestablish disease control and/or changing the glucocorticoid-sparing medication from azathioprine to methotrexate or vice versa (Grade 2C).

If the patient has already failed both azathioprine and methotrexate, treatment as a case of resistant disease is appropriate. (See 'Resistant disease' above.)

•For flares off all immunosuppressive medication, we suggest reinstituting prednisone with an initial daily dose that varies according to relapse severity (Grade 2C). The minimum starting dose of prednisone is 20 mg/day. In addition, a glucocorticoid-sparing drug should be resumed or started.

Resistant disease

●Multiple options exist for treating patients who do not respond adequately to glucocorticoids plus either azathioprine or methotrexate. Options for the treatment of resistant disease include (see 'Resistant disease' above):

•Rituximab

•Intravenous immunoglobulin (IVIG)

•Mycophenolate mofetil

•Cyclosporine

•Tacrolimus

•Cyclophosphamide

•Combination therapy with azathioprine and methotrexate

●We suggest using rituximab (two 1 gram doses two weeks apart) in the treatment of resistant disease (Grade 2B). (See 'Rituximab' above.)

●If rituximab is not effective, we suggest IVIG as the second-line agent for the treatment of resistant DM (Grade 2B). (See 'Intravenous immune globulin' above.)

●The presence of interstitial lung disease (ILD) may influence treatment choices. (See 'Interstitial lung disease' above and "Interstitial lung disease in dermatomyositis and polymyositis: Treatment".)

●In patients with inflammatory myopathy, mycophenolate mofetil (1 to 1.5 g twice daily) is a reasonable alternative if rituximab and IVIG have failed. (See 'Mycophenolate mofetil' above.)

●Because of their substantial side effect profiles, we suggest reserving alkylating agents (cyclophosphamide and chlorambucil) for patients whose disease has proven resistant to multiple other treatment options (Grade 1C). (See 'Cyclophosphamide' above.)

●Combination therapy with azathioprine (up to 200 mg/day) and methotrexate (up to 25 mg/week) hold some potential for efficacy in patients with resistant disease. However, the risk of treatment-related morbidity when using both of these medications together mandates the utmost care in monitoring patients for cytopenias and other adverse effects. (See 'Combination methotrexate and azathioprine' above.)

Refractory rash

●In some cases of DM, the cutaneous findings are more refractory to treatment than is the muscle disease, and additional management approaches are required. (See 'Refractory rash' above and "Cutaneous dermatomyositis in adults: Overview and initial management" and "Management of refractory cutaneous dermatomyositis in adults".)

ACKNOWLEDGMENTS — The UpToDate editorial staff acknowledges Stacy Rudnicki, MD and Marc L Miller, MD, who contributed to earlier versions of this topic review.