Intravenous immunoglobulins for steroid-refractory esophageal involvement related to polymyositis and dermatomyositis: A series of 73 patients
To assess the long-term outcome of esophageal complications in the group of patients receiving intravenous immunoglobulins (IVIG) for the treatment of severe steroid-refractory esophageal involvement related to polymyositis/dermatomyositis (PM/DM).
We retrospectively reviewed the medical records of 73 patients (39 with PM, 34 with DM) with steroid-resistant esophageal involvement. Esophageal involvement was evaluated by clinical and manometric investigations.
Seventy-three patients with steroid-refractory esophageal involvement related to PM/DM received IVIG therapy (2 gm/kg monthly). The median interval between PM/DM diagnosis and the onset of esophageal complications was 6 months. The most common clinical manifestations revealing esophageal dysfunction were dysphagia (69.9%), coughing while eating (61.6%), and gastroesophageal reflux into the pharynx and/or mouth (34.2%). Twenty-five patients exhibited life-threatening esophageal complications requiring exclusive enteral feeding; 33 patients (45.2%) with esophageal impairment developed aspiration pneumonia. Sixty patients (82.2%) exhibited resolution of esophageal clinical manifestations, leading to a return to normal oral feeding and ablation of feeding enteral tubes. Four other patients (5.5%) improved, although they still experienced mild dysphagia intermittently. Because of impaired cricopharyngeal muscle relaxation, another patient successfully underwent cricopharyngeal myotomy. Eight patients died from aspiration pneumonia (n = 6) and cancer (n = 2). Muscle weakness, thoracic myopathy, and aspiration pneumonia were independent predictive factors of IVIG-treated esophageal complications in PM/DM patients.
Our findings indicate that IVIG should be considered in life-threatening esophageal impairment complicating steroid-resistant PM/DM. We also suggest that combined therapy of IVIG and high-dose steroids may be the first-line therapy in PM/DM patients with life-threatening esophageal manifestations.
Polymyositis (PM) and dermatomyositis (DM) are systemic inflammatory disorders affecting skeletal muscles and other organs, particularly the esophagus, where lesions have led to motor activity dysfunction (1–10). Esophageal disorders have been reported in 25–84% of PM/DM patients (7, 9, 11–15); they may result in life-threatening complications, particularly cachexia related to severe swallowing disorders and recurrent aspiration pneumonia (1, 3, 7, 9, 11–17). Both accurate diagnoses and management of esophageal impairment at an early stage are therefore required in PM/DM patients.
However, to date, only a few studies have been reported regarding therapy of esophageal complications in PM/DM patients, especially in the group with steroid-refractory esophageal involvement related to PM/DM. These data prompted us to conduct this retrospective multicenter study. Our aims were to 1) assess the prevalence of esophageal manifestations in PM/DM patients, 2) evaluate the outcome of esophageal complications in the group of patients receiving intravenous immunoglobulins (IVIG) for the treatment of severe steroid-refractory esophageal involvement related to PM/DM, and 3) determine predictive variables of PM/DM related to esophageal impairment, as well as of steroid-refractory esophageal involvement requiring IVIG therapy in PM/DM patients.
PATIENTS AND METHODS
This retrospective study began with a search of the institutional centers' medical record index, which provides access to the diagnoses of the centers' inpatients and outpatients. The first electronic search involved use of the codes PM and DM to identify patients with a diagnosis of PM/DM seen during the 13-year study period (January 1996 to July 1, 2009) in 3 academic centers (Lille, Paris, and Rouen). In essence, 301 consecutive patients were seen for evaluation of PM/DM. The criteria for diagnosis of PM/DM were based on the Bohan and Peter criteria: 1) symmetric muscle weakness, 2) increased serum muscle enzymes, 3) myopathic changes on electromyography, 4) typical histologic findings on muscle biopsy, and 5) characteristic dermatologic manifestations. PM and DM were considered definite in all of the patients who presented at least 4 manifestations (18, 19). No patient with PM/DM had inclusion of body myositis or other connective tissue disorders (especially systemic lupus erythematosus, systemic sclerosis, Sjögren's syndrome, or rheumatoid arthritis).
A second search was used to isolate the subset of PM/DM patients who exhibited esophageal impairment. The diagnosis of PM/DM-related esophageal involvement was determined by skilled physicians. It was based on the presence of the 3 following parameters: 1) clinical manifestations, e.g., dysphagia, gastroesophageal reflux into the pharynx and/or mouth, coughing while eating, both gastroesophageal reflux and new hoarseness of the voice, as well as aphagia for solids and liquids; 2) findings of esophageal manometry; esophageal motor impairment related to PM/DM was diagnosed by the presence of at least one of the following signs: low pressure in the upper esophageal sphincter (mean ± SD normal value 18 ± 11 mm Hg), decreased/absent peristalsis in the upper third of the esophageal body (esophageal contractile amplitude: mean ± SD normal value 99 ± 70 mm Hg, duration: mean ± SD normal value 3.8 ± 1.2 seconds), as well as decreased peristalsis within the lower two-thirds of the esophageal body; and 3) gastroscopy made to exclude esophageal mucosal involvement (esophagitis, ulcers, or cancer) that might be responsible for dysphagia; gastroscopy proved normal in all patients.
A third search was used to isolate the group of IVIG-treated patients exhibiting steroid-refractory esophageal involvement related to PM/DM. First, the medical records of these latter patients were reviewed for their characteristics at diagnosis of esophageal complications, including age and sex, extraesophageal manifestations related to PM/DM, and cancer. Extraesophageal manifestations related to PM/DM included: 1) muscle power gauged by 8 proximal muscles (neck extensors, trapezius, deltoid, biceps, psoas, maximus and medius gluteus, and quadriceps) by a modification of the British Medical Research Council grading system (20), resulting in scores ranging from 0–11 (theoretical maximum score 88 points); 2) Raynaud's phenomenon; 3) joint involvement; and 4) pulmonary involvement. The presence of interstitial lung disease (ILD) was confirmed if patients had abnormalities on a high-resolution computed tomography (CT) scan of the lungs (parenchymal nodules and micronodules, linear opacities, irregularity of the interfaces between peripheral pleura and aerated lung parenchyma, ground-glass opacities, honeycombing, and traction bronchiectases or bronchiolectases) and pulmonary function tests (PFTs; i.e., vital capacity <80% of predicted and diffusing capacity for carbon monoxide <70% of predicted). Ventilatory insufficiency due to respiratory striated muscle weakness was dichotomized as 1) severe hypoventilation determined by hypercapnic respiratory failure requiring intubation and mechanical ventilation, and 2) moderate hypoventilation characterized by a restrictive pattern on PFTs (i.e., decreased lung volumes with vital capacity <80%) without evidence of ILD.
Second, the medical records of these patients were checked for their characteristics at diagnosis of esophageal complications, including: 1) time of esophageal involvement onset in the course of PM/DM; 2) clinical manifestations revealing esophageal involvement; 3) findings of esophageal manometry at diagnosis of esophageal dysfunction; 4) biochemical characteristics at diagnosis of esophageal impairment, i.e., erythrocyte sedimentation rate (mm/hour), C-reactive protein level (mg/liter), hemoglobin level (gm/dl), leukocytosis (gm/liter), liver function tests (alanine aminotransferase and aspartate aminotransferase), serum total protein (gm/liter), albumin (gm/liter), and creatine phosphokinase (CPK); data of autoantibody screening were reviewed, including antinuclear antibodies and anti–Jo-1, anti-PL7, anti-PL12, anti-Mi2, anti-Ku, and anti–signal recognition particle (anti-SRP) antibodies; and 5) use of other drugs before IVIG therapy initiation, e.g., steroids and cytotoxic drugs. In all of these patients, esophageal manifestations had not responded to steroids and/or cytotoxic drugs given for at least 3 months before the evaluation; in turn, muscle weakness and esophageal clinical disorders were unimproved or deteriorated prior to IVIG therapy institution. Furthermore, there had been no changes in PM/DM therapy (i.e., steroids and cytotoxic drug regimens) in the 2 months before the initiation of IVIG therapy.
Third, the medical records of the patients were reviewed and checked for IVIG therapy and associated procedures. In regard to IVIG therapy, we used preparations of polyvalent human IVIG with an elevated proportion of intact plasma IgG, i.e., 2 gm/kg of body weight were administered monthly, and IVIG therapy was divided into 2 doses of 1 gm/kg of body weight given slowly (at a rate of <200 ml/hour), as described previously (20). In patients who exhibited no clinical response after the third IVIG therapy, IVIG was discontinued; on the other hand, the patients who responded to IVIG therapy were given IVIG infusions for at least 6 months. Particular attention was paid to data regarding the patients' associated therapy, as follows: swallowing rehabilitation measures (e.g., diet, feeding) and interventional procedures, i.e., percutaneous endoscopic gastrostomy (PEG), percutaneous endoscopic jejunostomy (PEJ), or a gastric tube.
Furthermore, IVIG-treated patients with esophageal involvement were followed up by clinical examination for at least 6 months after IVIG initiation. In these patients, the outcome of esophageal manifestations was assessed by reviewing clinical examination reports, with particular attention paid to dysphagia course, ablation of PEG/PEJ or a gastric tube, and need for additional procedures. Finally, in IVIG-treated patients, the outcome of esophageal manifestations was defined as resolution, improvement, and deterioration. Criteria for resolution of esophageal clinical complications consisted of the definite disappearance of the patients' clinical signs (dysphagia, aphagia, coughing while eating, gastroesophageal reflux, and new hoarseness of the voice). Criteria for deterioration of esophageal impairment consisted of worsening of the patients' esophageal clinical manifestations. Furthermore, the medical records were checked for the patients' survival statuses and causes of deaths.
Finally, we evaluated the predictive variables of PM/DM-related esophageal complications as well as of steroid-refractory esophageal involvement requiring IVIG therapy in PM/DM patients. Clinical features and biochemical findings were compared between 1) patients with and without esophageal dysfunction and 2) patients who received IVIG for PM/DM-related steroid-resistant esophageal involvement and patients who did not. For group comparison involving binary data, we used either the chi-square test or Fisher's exact test, depending on the sample size (n = >5 and n = ≤5, respectively). Comparisons involving continuous data were performed using the Mann-Whitney test. The results were regarded as significant when the P value was less than 0.05. In regard to variables with P values less than 0.1, we further proceeded with multiple logistic regression to calculate the multivariate odds ratio (OR; 95% confidence interval [95% CI]); the level of significance used was P values less than 0.05.
Prevalence of esophageal involvement related to PM/DM.
From 1996 to 2009, 301 consecutive patients were seen for PM/DM. Of these unselected patients, 118 patients who fulfilled the criteria for PM/DM-related esophageal involvement were identified. The prevalence of esophageal involvement was therefore 39.2% in our PM/DM patients.
Finally, among these 118 patients, 73 specifically were given IVIG therapy for steroid-refractory esophageal involvement related to PM/DM; these 73 patients exhibited concomitant deterioration of muscle symptoms.
General characteristics of IVIG-treated PM/DM patients with esophageal involvement.
The patients consisted of 32 men and 41 women, with a median age of 41 years (range 15–83 years). Thirty-nine patients were diagnosed as having PM, and 34 other patients were diagnosed as having DM (Table 1).
Table 1. General characteristics of the patient population (n = 73) at intravenous immunoglobulin therapy initiation
|Age, median (range) years||41 (15–83)|
|Clinical manifestations, no. (%)|| |
| Raynaud's phenomenon||8 (11)|
| Arthralgia/arthritis||22 (30.2)|
| Pulmonary involvement|| |
| Interstitial lung disease||20 (27.4)|
| Ventilatory insufficiency||32 (43.8)|
| Aspiration pneumonia||33 (45.2)|
| Malignancy||10 (13.7)|
PM/DM patients exhibited Raynaud's phenomenon (11%) and arthralgia/arthritis (30.2%). Ten patients (13.7%) had malignancy; none of these 10 latter patients with cancer had mediastinal compressive lymphadenopathy that might have been responsible for dysphagia.
PM/DM patients developed pulmonary involvement. Twelve patients (16.4%) had ILD and 32 patients (43.8%) had ventilatory insufficiency related to respiratory striated muscle weakness without underlying ILD. Twenty-nine patients had moderate ventilatory insufficiency (with decreased cough reflex and inability to take the maximum inspiration); the other patients (n = 3) had severe hypoventilation with hypercapnic respiratory failure requiring mechanical ventilation. Finally, 33 patients (45.2%) exhibited aspiration pneumonia.
At the beginning of IVIG therapy, laboratory studies disclosed the following median value for CPK: 707 IU/liter (range 23–13,460). Autoantibody screening showed antinuclear antibodies (n = 36); anti–Jo-1 (n = 6), anti-PL7 (n = 2), and anti-PL12 (n = 1) antibodies; and anti-SRP antibody (n = 2).
Before IVIG therapy initiation, PM/DM patients had unsuccessfully received steroids (n = 73), methotrexate (n = 40), azathioprine (n = 23), cyclosporine (n = 3), and mycofenolate mofetil (n = 1); moreover, there had been no changes in the regimens of steroids/cytotoxic drugs within the 2 months before IVIG institution.
Characteristics of esophageal involvement.
The median interval between PM/DM diagnosis and the onset of esophageal complications was 6 months (range 1–84 months). Esophageal involvement occurred at an early stage (≤3 months after PM/DM diagnosis in 30 patients [41.1%]); it was concurrently identified in association with PM/DM onset in 13 (17.8%) of these patients. In the 43 remaining patients (58.9%), esophageal impairment occurred at a later stage during the course of PM/DM.
At IVIG therapy institution, all 73 patients exhibited at least one of the esophageal clinical manifestations (Table 2). Clinical manifestations revealing esophageal dysfunction were as follows: odynophagia (n = 1 [1.4%]), dysphagia (n = 51 [69.9%]), gastroesophageal reflux into the pharynx and/or mouth (n = 25 [34.2%]), coughing while eating (n = 45 [61.6%]), new hoarseness of the voice associated with gastroesophageal reflux (n = 21 [28.8%]), and aphagia for solids and liquids (n = 22 [30.1%]). In addition, one PM patient exhibited dysphagia related to cricopharyngeal muscle obstruction. Regarding the severity of esophageal involvement at IVIG initiation, the median interval between PM/DM diagnosis and the onset of esophageal complications was 9 months (range 1–54 months) in patients with complete aphagia and 4 months (range 0–84 months) in patients with less severe esophageal clinical signs (P = 0.52).
Table 2. Clinical manifestations of esophageal involvement in the 73 polymyositis/dermatomyositis patients with IVIG-treated steroid-refractory esophageal disorders*
|Dysphagia (without aphagia)||51 (69.9)||6 (8.2)|
|Coughing while eating||45 (61.6)||4 (5.5)|
|Gastroesophageal reflux||25 (34.2)||2 (2.7)|
|Gastroesophageal reflux and new hoarseness of the voice||21 (28.8)||0 (0)|
|Odynophagia||1 (1.4)||0 (0)|
|Aphagia to both solids and liquids||22 (30.1)||1 (1.4)|
In our patients, esophageal manometry demonstrated low pressure in the upper esophageal sphincter (n = 73; median pressure in the upper esophageal sphincter 5.2 mm Hg), decreased peristalsis in the upper third of the esophageal body (n = 50), absence of peristalsis in the upper third of the esophageal body (n = 23), and decreased peristalsis within the lower two-thirds of the esophageal body (n = 8).
Therapy and followup of PM/DM patients with esophageal involvement.
The 73 patients received IVIG therapy as follows: 1 gm/kg daily for 2 days each month; the median IVIG therapy duration was 7 months (range 3–14 months).
At IVIG therapy institution, the patients also underwent concomitant dysphagia-associated rehabilitation, i.e., recommendations in feeding techniques (chew food well, swallow twice, small bites, alternate solids and liquids, sit upright during meal) and diet instructions (i.e., avoidance of foods that are chewy, that fall apart, or that are composed of mixed textures). Because of impossible oral feeding, the 22 patients with complete aphagia for solids and liquids required PEG (n = 5), JEG (n = 4), or a gastric tube (n = 16).
The median length of the patients' followup after institution of IVIG therapy was 32 months (range 1–92 months) (Table 3). Sixty patients (82.2%) exhibited resolution of their esophageal clinical manifestations. In the group of patients who had resolution of esophageal manifestations, a significant improvement of swallowing disorders occurred within 2 weeks after the first IVIG regimen; a complete disappearance of esophageal impairment was observed within 5–15 days after the second (n = 27) or the third (n = 33) IVIG regimen. This efficacy resulted in the return to normal oral feeding, with normal food consistency and ablation of feeding enteral tubes in all cases.
Table 3. Therapy and outcome in the 73 polymyositis/dermatomyositis patients with IVIG-treated steroid-refractory esophageal disorders*
|IVIG therapy|| |
| Regimen||2 gm/kg monthly|
| Duration of therapy, median (range) months||7 (3–14)|
|Additional measures|| |
| Rehabilitation measure|| |
| Diet instructions||73 (100)|
| Feeding techniques||73 (100)|
| Enteral feeding|| |
| Percutaneous endoscopic gastrostomy||5 (6.8)|
| Percutaneous endoscopic jejunostomy||4 (5.5)|
| Gastric tube||16 (21.9)|
| Cricopharyngeal myotomy||1 (1.4)|
|Outcome of esophageal complications|| |
| Resolution||60 (82.2)|
| Improvement||5 (6.8)|
| Deterioration and death related to:||8 (11)|
| Aspiration pneumonia due to swallowing disorders||6 (8.2)|
| Cancer||2 (2.7)|
Four other patients (5.5%) had improvement of esophageal clinical manifestations within 2 weeks after the first IVIG regimen, although they still experienced mild dysphagia intermittently. An additional patient with PM improved clinically under IVIG therapy, although she still exhibited moderate dysphagia. In this latter patient, videofluoroscopic examination showed impaired cricopharyngeal muscle relaxation. The patient successfully underwent cricopharyngeal myotomy and dilation, which resulted in complete disappearance of swallowing disorders.
Due to clinical resolution/improvement of esophageal clinical manifestations, steroid daily doses could be reduced in these 65 patients (median initial steroid dosage 32.2 mg/day before IVIG therapy versus median steroid dosage 25 mg/day after 3 IVIG infusions; P = 0.007). These 65 patients exhibited concomitant progressive improvement of muscle power; the median clinical muscle score before and after 3 IVIG infusions showed a significant improvement (median initial muscle score 47.5 points versus median muscle score 63.6 points after 3 IVIG infusions; P = 0.01). In these 65 latter patients, the median CPK value before and after 3 IVIG infusions also showed a marked decrease (median initial CPK level 913 IU/liter versus median CPK level 264 IU/liter after 3 IVIG infusions; P = 0.007).
Finally, 8 IVIG-treated patients (11%) had deterioration of esophageal clinical symptoms. Six of these patients died within 1 month after IVIG institution from aspiration pneumonia. The 2 other patients died from underlying malignancy (pancreas: n = 1, breast: n = 1).
Predictive factors of esophageal involvement in patients with PM/DM.
We compared both clinical and biochemical findings between patients with (n = 118) and without (n = 183) esophageal involvement. As shown in Table 4, we found no statistically significant difference between patients with and without esophageal impairment for the following factors: age, myositis subset, myalgia, joint involvement, CPK levels, and antinuclear antibodies. Interestingly, we observed that patients with esophageal impairment compared with those without more commonly exhibited muscle weakness (P = 0.002), ventilatory insufficiency (P < 10−6), and aspiration pneumonia (P < 10−6); on the other hand, patients with esophageal dysfunction less frequently developed Raynaud's phenomenon (P = 0.067), ILD (P = 0.007), and anti–Jo-1 antibody (P = 0.00007) (Table 4).
Table 4. Comparison of characteristics between PM/DM patients with and without esophageal involvement*
|General characteristics|| || || |
| Age, median years||50||51||0.882|
| PM/DM subset||47.5/52.5||54.6/45.4||0.724|
|Clinical characteristics|| || || |
| Muscle weakness||94.9||83.12||0.002|
| Raynaud's phenomenon||16.9||26.2||0.067|
| Joint manifestations||31.4||35||0.534|
| Interstitial lung disease||17.8||32.2||0.007|
| Ventilatory insufficiency||34.7||10.4||< 10−6|
| Aspiration pneumonia||35.6||9.3||< 10−6|
|Laboratory findings|| || || |
| CPK level, median IU/liter||749||679||0.227|
| Antinuclear antibodies||50||54.6||0.478|
| Anti–Jo-1 antibody||6.8||24||0.00007|
Under multivariate analysis, significant factors for esophageal manifestations were: muscle weakness (OR 2.9 [95% CI 1.2–4.7], P = 0.01), aspiration pneumonia (OR 4.2 [95% CI 1.4–8.3], P = 0.0005), and ventilatory insufficiency related to striated muscle weakness (OR 4.5 [95% CI 1.5–8.9], P = 0.0001); on the other hand, the significant factor for the absence of esophageal complications was anti–Jo-1 antibody (OR 0.3 [95% CI 0.13–0.91], P = 0.02).
Predictive factors of steroid-refractory esophageal involvement in IVIG-treated patients with PM/DM.
We compared both clinical and biochemical findings between patients with esophageal involvement who received (n = 73) or did not receive (n = 45) IVIG for esophageal manifestations.
As shown in Table 5, we found no statistically significant difference between patients who received or did not receive IVIG for esophageal complications in regard to age, myositis subset, myalgia, Raynaud's phenomenon, joint involvement, ILD, cancer, CPK levels, antinuclear antibodies, and anti–Jo-1 antibody. PM/DM patients who received IVIG for steroid-refractory esophageal involvement compared with patients who did not more often had muscle weakness (P = 0.02), aspiration pneumonia (P = 0.005), and ventilatory insufficiency (P = 0.002). In regard to therapy, patients with IVIG-treated esophageal manifestations more commonly received azathioprine (31.5% versus 6.7%; P = 0.001) and methotrexate (54.8% versus 24.4%; P = 0.002). Therapy was not different in patients who were given IVIG for esophageal involvement compared with other patients for cyclophosphamide (6.8% versus 11.1%; P = 0.502), combined therapy of azathioprine and methotrexate (6.8% versus 2.2%; P = 0.405), infliximab (4.1% versus 0%; P = 0.286), rituximab (1.4% versus 0%; P = 1), or mycofenolate mofetil (1.4% versus 0%; P = 1).
Table 5. Comparison of characteristics between PM/DM patients with esophageal involvement who received or did not receive IVIG for esophageal complications*
|General characteristics|| || || |
| Age, median years||50||53||0.184|
| PM/DM subset||53.3/46.6||50.4/49.6||0.867|
| Duration of PM/DM before onset of esophageal manifestations, median (range) months||6 (1–84)||7 (2–210)||0.792|
|Clinical characteristics|| || || |
| Muscle weakness||98.6||88.9||0.02|
| Raynaud's phenomenon||11||26.7||0.04|
| Joint manifestations||30.1||33.3||0.838|
| Interstitial lung disease||16.4||20||0.629|
| Ventilatory insufficiency||45.2||17.8||0.002|
| Aspiration pneumonia||45.2||20||0.005|
|Laboratory findings|| || || |
| CPK level, median IU/liter||726||768||0.603|
| Antinuclear antibodies||50||55.6||0.449|
| Anti–Jo-1 antibody||8.2||4.4||0.486|
Esophageal involvement is considered to be frequent in PM/DM, occurring in as many as 20–84% of patients (1, 4–9, 11–15). The current study confirms previous authors' data, as we observed esophageal disorders in 118 (39.2%) of 301 consecutive unselected patients with PM/DM. Interestingly, 24.3% (n = 73) of our overall PM/DM patients were given IVIG therapy for steroid-refractory esophageal involvement related to PM/DM. In our population, we suggest that the high prevalence of steroid-refractory esophageal complications may be explained, in part, because our patients were followed up in the Departments of Internal Medicine in 3 academic centers; in essence, our patients may have more severe PM/DM than other patients, e.g., PM/DM outpatients or PM/DM patients followed up in the Departments of Dermatology or in primary centers.
The time to onset of esophageal complications has been found to be variable in PM/DM patients (4–9, 11–15). Previous authors have found that the mean time from dysphagia onset to myositis diagnosis was 15–55 months (13, 15). In this instance, the median interval between PM/DM diagnosis to the onset of esophageal complications requiring IVIG therapy initiation was shorter (6 months). We have, in fact, observed that esophageal involvement occurred at an early phase of the disease (≤3 months after PM/DM diagnosis) in 41.1% of our patients. Our findings should encourage the search for esophageal involvement using physical examination and manometry during the initial evaluation of PM/DM patients. Interestingly, De Merieux et al (4) reported that patients with a short disease duration had milder clinical and radiologic esophageal impairment compared with patients with longstanding disorders. The present study does not confirm these data; in regard to the severity of esophageal involvement, we found that the median interval between PM/DM diagnosis and the onset of esophageal complications did not differ significantly between patients with life-threatening esophageal involvement compared with those without.
Esophageal motor activity disorders related to PM/DM may be responsible for swallowing disorders, including difficulty with solids and liquids, pain and preprandial discomfort in the sternal area, gastroesophageal reflux into the pharynx and/or mouth, or coughing while eating (1, 4, 5, 7, 11–17, 21–23). In our experience, dysphagia to solids and liquids, coughing while eating, and gastroesophageal reflux were the most common symptoms. Moreover, we observed that life-threatening complications (i.e., aphagia to solids and liquids) were not rare in our patients, occurring in 28.8% of cases. Because of complete aphagia for solids and liquids, oral feeding was impossible in these latter patients (30.1%), leading to total enteral feeding with PEG, JEG, or a gastric tube. In all of these patients, esophageal disorders could be attributed to PM/DM-related esophageal involvement because other causes of esophageal dysfunction could be excluded (i.e., cerebral vascular condition, motor neuron disease and myasthenia gravis, muscular dystrophies, or myopathies related to drugs, toxins, endocrine disease, and infections) and gastroscopy was always normal, which excluded dysphagia due to esophagitis, stricture formation, or cancer. Interestingly, we observed that 11 (50%) of these 22 patients with life-threatening esophageal disorders concomitantly exhibited muscle weakness involving both neck flexors and extensors; our findings are in accordance with the data of previous authors, who reported that muscle weakness of neck flexors and extensors was associated with the occurrence of swallowing disorders (4). Furthermore, swallowing difficulties may also be due to cricopharyngeal muscle obstruction (related to edema) and upper esophageal sphincter hypertrophy that may lead to achalasia (11, 16, 24, 25). In our experience, one patient with PM developed cricopharyngeal muscle obstruction and esophageal motor dysfunction, resulting in both severe swallowing disorders and recurrent aspiration pneumonia (via reflux of esophageal contents into the pharynx and lungs).
The diagnosis of esophageal complications at an early stage is crucial in PM/DM in order to improve the patients' management. Our series underlines that esophageal manometry is a relevant method to depict esophageal motor impairment in PM/DM (4, 5, 14, 16, 17). In our 73 IVIG-treated PM/DM patients with esophageal clinical involvement, esophageal manometry demonstrated characteristic motor activity disturbances in all cases, especially low pressure in the upper esophageal sphincter (100%), decreased peristalsis in the upper third of the esophageal body (68.5%), or absence of peristalsis in the upper third of the esophageal body (31.5%).
Oral steroids are the first line of therapy for patients with PM/DM at an initial dosage of 1 mg/kg daily, followed by progressive tapering (2, 7, 26–30). A favorable outcome to immunosuppressive therapy (i.e., azathioprine, methotrexate, and cyclosporine) in combination with steroids in patients who failed to respond to steroids alone has also been reported (2, 7, 26–30). However, these therapies are not always effective and may result in severe adverse effects, particularly in an increased risk of infection (10). The need for effective and safe therapy in PM/DM has prompted many authors to evaluate the efficacy of IVIG therapy in patients with PM/DM refractory to conventional therapies (26–32). In a double-blind placebo-controlled series of 15 patients with treatment-resistant DM treated with IVIG (1 gm/kg daily for 2 days each month over 3 months), Dalakas et al (30) reported both significant improvement of muscle strength score and decreased functional disability in 92% of cases. In our 73 patients with PM/DM, esophageal involvement continued to deteriorate gradually in spite of high doses of oral prednisone; we considered that immunosuppressive drugs were contraindicated in 13 of these patients because these patients were considered as having immunosuppression secondary to both high doses of steroids and denutrition due to major swallowing disorders, and all of the patients had a high risk of developing infectious aspiration pneumonia secondary to esophageal motor activity dysfunction and ventilatory insufficiency. These latter patients required a treatment with short-term efficacy. In our 73 patients, IVIG therapy resulted in a significant improvement of swallowing disorders in 89% of cases. Indeed, 60 patients had resolution of their esophageal manifestations and 5 other patients had marked improvement of swallowing disorders. In these patients, a significant improvement of swallowing disorders occurred rapidly (within 2 weeks after the first IVIG regimen). Interestingly, in the 60 patients who had resolution of esophageal manifestations, a complete disappearance of esophageal impairment was observed within 5–15 days after the second (n = 27) or the third (n = 33) IVIG regimen, which led to a return to normal oral feeding, ablation of feeding tubes, and rapid discharge from the hospital. Finally, among the 8 remaining patients (11%) who deteriorated, 6 died within one month after IVIG institution from aspiration pneumonia, and the 2 other patients died from underlying malignancy. In our study, a limitation was the concomitant continuation of steroids during the entire period of IVIG, making it difficult to be certain that improvement was only attributable to IVIG therapy. However, because all of the PM/DM patients had previously failed to respond to steroids and/or cytotoxic drugs (esophageal manifestations deteriorated persistently in spite of prednisone and/or cytotoxic drugs for at least 3 months before initiation of IVIG therapy), the improvement of esophageal manifestations may reasonably be related to IVIG infusions. Furthermore, it has been suggested that cricopharyngeal myotomy appears to be useful in PM/DM patients with swallowing disorders related to impaired cricopharyngeal muscle relaxation (4, 14, 16, 17, 23, 24). In our experience, one PM patient who improved under IVIG therapy still exhibited moderate dysphagia related to impaired cricopharyngeal muscle relaxation; she successfully underwent cricopharyngeal myotomy and dilation. Finally, botulinum injections of the upper esophageal sphincter are an intriguing option (17).
From a practical point of view, the knowledge of predictive factors of esophageal involvement seems essential to improve the management of PM/DM patients because that may result in decreased morbidity and mortality.
First, a main finding in our series is that muscle weakness, thoracic myopathy, and aspiration pneumonia were predictive factors of esophageal complications in PM/DM patients. Our findings underscore that these patients with esophageal involvement should be diagnosed at an early stage in order to decrease the risk of fatal aspiration pneumonia. We therefore suggest that PM/DM patients routinely should undergo esophageal and lung investigations during the initial evaluation of PM/DM patients; this evaluation may include esophageal manometry (which may reveal dysfunction of striated muscle motor activity and low pressure in the upper esophageal sphincter), PFTs (which may show a restrictive pattern and decreased maximal inspiratory and expiratory pressures), and chest radiograph/CT scan (which may reveal atelectasis, small lung volumes, and diaphragmatic elevation). Finally, we found interestingly that Raynaud's phenomenon, ILD, and anti–Jo-1 antibody occurred less commonly in PM/DM patients with esophageal complications; in essence, our series suggests that antisynthetase syndrome may be a protective factor of esophageal complications in PM/DM patients, although no definite conclusion can be drawn from our data.
Second, we observed interestingly that the group of patients who received IVIG for PM/DM-related steroid-resistant esophageal involvement compared with those who did not more commonly exhibited muscle weakness, thoracic myopathy, and aspiration pneumonia. Our findings underline that these latter patients had more severe PM/DM, requiring close monitoring and more aggressive therapy with short-term efficacy, especially IVIG. Finally, patients with PM/DM-related steroid-resistant esophageal involvement who received IVIG compared with those who did not more often received cytotoxic drugs (i.e., azathioprine, methotrexate), which also confirms that these PM/DM patients had more severe PM/DM.
In conclusion, our findings indicate that IVIG should be considered in life-threatening esophageal impairment complicating steroid-resistant PM/DM. We also suggest that combined therapy of IVIG and high-dose steroids may be the first-line therapy in PM/DM patients with life-threatening esophageal manifestations. Nevertheless, no definite conclusion can be drawn from our latter suggestion, and further investigations are warranted to confirm these data.
All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be submitted for publication. Dr. Marie had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study conception and design. Marie, Menard, Hatron, Hachulla, Mouthon, Tiev, Ducrotte, Cherin.
Acquisition of data. Marie, Menard, Hatron, Hachulla, Mouthon, Tiev, Ducrotte, Cherin.
Analysis and interpretation of data. Marie, Menard, Hatron, Hachulla, Mouthon, Tiev, Ducrotte, Cherin.