Patrick Cherin

Efficacy of intravenous gammaglobulin therapy in chronic refractory polymyositis and dermatomyositis: An open study with 20 adult patients

PURPOSE Polymyositis and dermatomyositis are inflammatory muscular diseases of unknown cause. Many interventions are available to treat patients with these conditions including corticosteroids, immunosuppressive drugs, plasmapheresis, and total body irradiation. However, these therapies are not always effective, and they may be associated with certain serious side effects. An attempt was made to evaluate the efficacy of polyvalent intravenous immunoglobulin (IVIG) in patients with polymyositis or dermatomyositis refractory to traditional treatment. PATIENTS AND METHODS Twenty patients (16 women and 4 men; mean age 43 [16 SD] years), 14 with chronic refractory polymyositis and six with dermatomyositis, received high doses of IVIG because of the failure of traditional treatments (prednisone [19], methotrexate [10], azathioprine [6], cyclophosphamide [3], cyclosporine [3], chlorambucil [1], plasmapheresis [8], lymphopheresis [1], and total body irradiation [1]). In one patient with positive results on picornavirus serologic testing, IVIG was the first treatment choice. IVIG therapy was given with prednisone in 15 patients, with methotrexate in six patients, and with plasmapheresis in one patient. There were no changes in treatment in the 2 months before the introduction of IVIG therapy and no increases in dose during this treatment. Preparations of polyvalent human intravenous gammaglobulins with increased intact immunoglobulin G were used. Thirteen patients received 1 g/kg daily for 2 days each month, and seven patients received 0.4 g/kg daily for 5 days each month. The mean duration of treatment was 4 months. RESULTS Clinical assessment, which consisted of the measurement of proximal muscle power, and biochemical studies were carried out before each treatment period. Significant clinical improvement was noted in 15 of the 20 patients. Mean muscle power estimated for the 20 patients before and after IVIG therapy was statistically significantly reduced (p less than 0.01). Eighteen patients showed biochemical improvement, and two patients with normal initial serum creatine kinase levels showed clinical improvement. Mean creatine kinase levels for the 20 patients during IVIG therapy showed a statistically significant decrease from the first IVIG perfusions (p less than 0.01). Side effects of IVIG therapy were noted in four patients; however, these effects were mild. During IVIG therapy, steroid doses were significantly reduced from the second or the third IVIG infusion (p less than 0.05). CONCLUSION IVIG is an efficacious new therapy for polymyositis and dermatomyositis and should play a role in the treatment of these diseases, replacing or reducing steroid and immunosuppressive medications.

Factors associated with underlying malignancy in a retrospective cohort of 121 patients with dermatomyositis.

Demographic, clinical, and laboratory features that predict underlying malignancy in patients with dermatomyositis (DM) are poorly known. We conducted a retrospective study in all adult patients with a definite (n = 75) or probable (n = 32) diagnosis of DM according to Bohan and Peter criteria or with amyopathic DM (n = 14) who were referred to 2 departments during a 13-year period. The diagnosis of malignancy-associated DM was retained if DM occurred in a context of recently diagnosed malignancy or if a malignancy was diagnosed during the 5 years following the diagnosis of DM. The Kaplan-Meier method was used to assess the cumulative incidence rates of underlying malignancy during the first 5 years of DM. Factors associated with malignancy in patients with DM were identified by Cox proportional hazards models. During the study period, 121 patients fulfilled the inclusion criteria (median age, 52 yr; range, 19-77 yr; women: 70%). For 29 of them, the diagnosis of malignancy-associated DM was retained. The cumulative incidence rate of malignancy was 21 ± 4% and 28 ± 5%, 1 year and 5 years after the diagnosis of DM, respectively. The median duration of follow-up of the 92 patients with no malignancy diagnosed was 36 months (range, 1-140 mo). In multivariate analysis, independent factors associated with an underlying malignancy in patients with DM were an age at diagnosis >52 years (hazard ratio [HR], 7.24; 95% confidence interval [CI], 2.35-22.31), a rapid onset of skin and/or muscular symptoms (HR, 3.11; 95% CI, 1.07-9.02), the presence of skin necrosis (HR, 3.84; 95% CI, 1.00-14.85) or periungual erythema (HR, 3.93; 95% CI, 1.16-13.24), and a low baseline level of complement factor C4 (HR, 2.74; 95% CI, 1.11-6.75). Lastly, low baseline lymphocyte count (<1500/mm3) was a protective factor of malignancy (HR, 0.33; 95% CI, 0.14-0.80). Taken together, these data may help physicians focus on a group of patients who might benefit from extensive evaluation for malignancy. Abbreviations: ALT = alanine aminotransferase, AST = aspartate aminotransferase, CI = confidence interval, CPK = creatine phosphokinase, DM = dermatomyositis, HR = hazard ratio, LDH = lactate dehydrogenase.

Severe Perturbations of the Blood T Cell Repertoire in Polymyositis, But Not Dermatomyositis Patients

Polymyositis and dermatomyositis are diseases characterized by muscle weakness and muscle inflammatory infiltrates. Their pathogenesis remains unclear. A central role for endomysial autoaggressive CD8+ T cells is suspected in polymyositis and for perivascular B cells in dermatomyositis. We compared the T cell repertoire of 10 polymyositis and 10 dermatomyositis patients by immunoscope, a method providing a global assessment of the T cell repertoire and a sensitive detection of clonal T cell expansions. Samples were analyzed qualitatively and quantitatively in the blood (unsorted cells and CD4+ and CD8+ cells) and in muscle infiltrates. Dramatic perturbations of the T cell repertoire were observed in the blood of polymyositis but not dermatomyositis patients (p < 0.0005), the latter being undistinguishable from controls. These perturbations were due to oligoclonal expansions of CD8+ T cells and most blood clonal expansions were also found in muscle. These results indicate that the pathogenesis of polymyositis and dermatomyositis is different and reinforce the view that polymyositis but not dermatomyositis is an autoimmune CD8+ T cell-mediated disease. Moreover, this method may be helpful for the differential diagnosis of polymyositis and dermatomyositis and for noninvasive follow-up of polymyositis patients.

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).

Infectious Complications in Polymyositis and Dermatomyositis: A Series of 279 Patients

OBJECTIVES To assess the prevalence and characteristics of severe pyogenic, nonpyogenic, and opportunistic infections in polymyositis and dermatomyositis (PM/DM) patients and to evaluate the predictive values for infections on clinical presentation and biochemical findings of PM/DM to detect patients at risk for such infections. METHODS The medical records of 279 consecutive PM/DM patients in 3 medical centers were reviewed. RESULTS One hundred four severe infections occurred in our patients (37.3%), ie, pyogenic (n = 71) and nonpyogenic/opportunistic infections (n = 33). Pyogenic infections were mainly due to aspiration pneumonia (n = 46) and calcinosis cutis infection. Thirty-three PM/DM patients developed nonpyogenic/opportunistic infections that were due to the following: Candida albicans, Pneumocystis jiroveci, Aspergillus fumigatus, Geotrichum capitatum, Mycobacterium (avium-intracellulare complex, xenopi, marinum, peregrinum, tuberculosis), Helicobacter heilmanii, cytomegalovirus, herpes simplex and zoster virus, hepatitis B and C, JC virus, Leishmania major, Strongyloides stercoralis. Esophageal dysfunction, ventilatory insufficiency, malignancy, and lymphopenia were significantly more frequent in the group of PM/DM patients with infections. CONCLUSION Our study underscores the high frequency of infections in PM/DM, resulting in an increased mortality rate. Our results suggest that prophylaxis against pyogenic infections should be routinely recommended for patients with PM/DM, including regular physical examination of lungs to depict aspiration pneumonia as well as risk factors of aspiration pneumonia. Finally, because a great variety of micro-organisms may be responsible for opportunistic infections, it seems difficult to initiate primary prophylaxis in PM/DM patients exhibiting risk factors for opportunistic infections.

Risk of syncope in the elderly and consumption of drugs: A case-control study

A multicenter case-control study (588 cases and 1807 controls) was performed to assess the risk of syncope in the elderly according to drug consumption within the three days before syncope, controlling the underlying cardiovascular diseases. Pair-matched and non-pair-matched analyses using logistic regression were performed, providing consistent results. After adjustment for age, sex, and cardiovascular disease, cases were shown to consume more often than non-cases drugs in classes of non-tricyclic antidepressants, neuroleptic drugs, and antiparkinsonians. A detailed analysis has shown that only four drugs were significantly associated with an excess risk of syncope: fluoxetine (OR = 2.6; 95% CI: [1.8-3.5]), aceprometazine (OR = 2.0; [1.5-2.5]), haloperidol (OR = 2.8; [2.0-3.6]), and L-dopa (OR = 2.8; [2.2-3.7]). This analysis shows that these drugs should be prescribed with special caution in the elderly.

Pneumomediastinum in interstitial lung disease associated with dermatomyositis and polymyositis

OBJECTIVE Spontaneous pneumomediastinum is a rare complication of dermatomyositis (DM) and polymyositis (PM). The aim of this study was to characterize this complication and determine its prognostic factors. METHODS We retrospectively collected a multicenter series of PM/DM cases complicated by pneumomediastinum. We analyzed all published cases and combined those that were exploitable with ours for an investigation of the factors associated with poor survival. RESULTS We collected 11 PM/DM cases complicated by interstitial lung disease and pneumomediastinum. Five of the 9 DM patients had clinically amyopathic DM without muscle weakness and high serum creatine kinase levels. The outcome was favorable in 7 of these patients and 6 had no sequelae. In total, approximately 25% of our patients of the 21 analyzable cases studied died within 1 month. With a median followup of 240 days, the cumulative estimated Kaplan-Meier survival rate was 64% at 1 year and 55% at 2 years. Poor survival was associated with absence of muscle weakness (P = 0.02), initial low vital capacity (P = 0.006), and initial low carbon monoxide diffusion capacity (P = 0.04). CONCLUSION In this first large series of patients with connective tissue disease complicated by pneumomediastinum to be reported, most patients had DM and half amyopathic DM, as in previous reports. Pneumomediastinum may occur before DM diagnosis and may thus reveal DM with minimal or no muscle involvement. Death was associated with an absence of muscle weakness and severe pulmonary involvement before the onset of pneumomediastinum. Corticosteroids and immunosuppressive therapy can result in complete recovery, as in half our cases.

Diaphragmatic dysfunction in patients with idiopathic inflammatory myopathies

Polymyositis, dermatopolymyositis, and inclusion body myositis imply chronic inflammation of skeletal muscles. Pulmonary complications include aspiration pneumonia, interstitial pneumonitis, or respiratory muscle myositis. This study aims at better describing their impact on respiratory muscle. Twenty-three consecutive patients (12 PM, 5 DM, 6 IBM) were studied (static inspiratory and expiratory pressures; diaphragm function in terms of the mouth and transdiaphragmatic pressure responses to bilateral phrenic stimulation). Pulmonary parenchymatous abnormalities were mild (6 cases) or absent. The mouth pressure produced by phrenic stimulation was 6.83+/-3.01 cm H2O, with 18 patients (78%) diagnosed with diaphragm weakness (<10 cm H2O) and lower values in DM (4.35+/-1.48 cm H2O) than in IBM and in PM (P<0.05). Diaphragm weakness is frequent and probably overlooked in inflammatory myopathies. Further studies are needed to delineate the clinical relevance of these results.

Interstitial Lung Disease in Anti–Jo‐1 Patients With Antisynthetase Syndrome

To assess the outcome of interstitial lung disease (ILD) in anti–Jo‐1 patients with antisynthetase syndrome, determine predictive variables of ILD deterioration in these patients, and compare features of anti–Jo‐1 patients with and without ILD.

Th1 and Th17 balance in inflammatory myopathies: Interaction with dendritic cells and possible link with response to high-dose immunoglobulins

To clarify the interactions between dendritic cells (DCs) and Th1 and Th17 T cell subsets and the mode of action of IVIG in inflammatory myopathies, Expression of CD4(+) and CD8(+) T cells, immature (CD1a) and mature (DC-LAMP) DCs, interleukin-17 (IL-17) and interferon-gamma (IFN-gamma), was quantified by immunohistochemistry in muscle biopsies from 13 patients (11 with polymyositis (PM) and 2 dermatomyositis (DM)) obtained before treatment with IVIG. The Th1/Th17 cytokine and the immature/mature DC ratio were studied according to the response to IVIG. Immature DCs were rarely detected compared to mature DCs, observed in all samples except one PM. IFN-gamma-producing cell count was higher than IL-17 count. Neither the expression of IFN-gamma nor IL-17 was correlated with that of DC subsets. Seven of the 13 patients (6 PM and 1 DM) responded to IVIG. T cells and DC subsets were not differentially expressed between responders and non-responders. The frequency of IFN-gamma-producing cells was significantly higher in non-responders with an increased IFN-gamma/IL-17-producing-cell ratio. In conclusion, mature rather than immature DC and IFN-gamma-rather than IL-17-producing cells accumulate in inflamed muscle. Increased IFN-gamma-producing cell count and IFN-gamma/IL-17-ratio were found in IVIG non-responders, suggesting a role for the Th17 mediated pathway in the response to IVIG.