Cancer can occur in patients with inflammatory myopathies. This association is mainly observed in dermatomyositis, and myositis-specific antibodies have allowed us to delineate patients at an ...increased risk. Malignancy is also reported in patients with necrotizing autoimmune myopathies, but the risk remains elusive. Anti-signal recognition particle or anti-HMGCR antibodies have been specifically associated with necrotizing autoimmune myopathies. We aimed at screening the incidence of cancer in necrotizing autoimmune myopathies. A group of patients (n = 115) with necrotizing autoimmune myopathies with or without myositis-specific antibodies was analysed. Malignancy occurred more frequently in seronegative necrotizing autoimmune myopathies patients and in HMGCR-positive patients compared to anti-signal recognition particle positive patients. Synchronous malignancy was diagnosed in 21.4% and 11.5% of cases, respectively, and incidence of cancer was higher compared to the general population in both groups. No specific type of cancer was predominant. Patients suffering from a synchronous cancer had a decreased median survival time. Cancer screening is necessary in seronegative necrotizing autoimmune myopathies and in HMGCR-positive patients but not in anti-signal recognition particle-positive patients.
Anti-synthetase syndrome (anti-SS) is frequently associated with myositis and interstitial lung disease (ILD). We evaluated prospectively, in a multicenter, open-label, phase II study, the efficacy ...of rituximab on muscle and lung outcomes.
Patients were enrolled if they were refractory to conventional treatments (prednisone and at least 2 immunosuppressants). They received 1 g of rituximab at D0, D15, and M6. The primary endpoint was muscular improvement based on manual muscular testing (MMT10, Kendall score in 10 muscles) at M12. Secondary endpoints were normalization of creatine kinase (CK) level, ILD improvement based on forced vital capacity and/or diffuse capacity for carbon monoxide, and number and/or doses of associated immunosuppressants.
Twelve patients were enrolled, and 10 completed the study. Only 2 patients presented an improvement of at least 4 points on at least two muscle groups (primary end-point). Overall, seven patients had an increase of at least 4 points on MMT10. CK level decreased from 399 IU/L (range, 48-11,718) to 74.5 IU/L (range, 40-47,857). Corticosteroid doses decreased from 52.5 mg/d (range, 10-70) to 9 mg/d (range, 7-65) and six patients had a decrease in the burden of their associated immunosuppressants. At baseline, all 10 patients presented with ILD. At M12, improvement of ILD was observed in 5 out of the 10 patients, stabilization in 4, and worsening in 1.
This pilot study of rituximab treatment in patients with refractory anti-SS provided data on evolution of muscular and pulmonary parameters. Rituximab should now be evaluated in a larger, controlled study for this homogenous group of patients.
Clinicaltrials.gov NCT00774462.
Aims: Edema of the limbs is uncommon in idiopathic inflammatory myopathies (IIM). The few reported cases have been associated with severe and refractory dermatomyositis (DM), sometimes in association ...with cancers. We aimed to determine if edematous myositis is a homogeneous subtype based on clinical, serological and pathological features. Methods: This is a retrospective observational study performed between 2008 and 2015 in the French national referral center for myositis. All adult patients with an inflammatory muscle biopsy and upper limbs edema were included as well as IIM cases without limb edema as controls. Clinical, biological and pathological features were collected. Results: Seventeen edematous myositis were included and compared to 174 IIM without edema, including 50 DM controls. Edema was the first manifestation in 23% of patients. Muscle weakness was severe and symmetric, 71% of patients presented dysphagia and a restrictive ventilatory pattern was found in 40%. Fifty‐two percent of patients had a typical DM skin rash and 23% had cancer within 3 years of diagnosing myositis. Fifty‐three percent of patients presented a myositis specific antibody and only DM‐specific antibodies were detected. Classic pathological DM features (perifascicular atrophy, perifascicular/perimysial perivascular inflammation) were uncommon but capillary C5b‐9 deposition and MxA expression were seen in 79% and 73% of cases, respectively. A perimysial edema was found in 82% of cases. Seventeen percent of patients died (median follow up of 18 months). Edematous myositis demonstrated more marked capillary C5b‐9 deposition compared to IIM controls. There was no clinical, biological or pathological difference with DM controls except for limb edema. Conclusion: Our study underlines that limb edema could be a symptom of IIM and that edematous myositis are mostly DM. The vasculopathy seems to play a key role in its pathophysiology. Limb edema associated with muscle impairment should suggest the diagnosis of DM in clinical settings.
Idiopathic inflammatory myopathies are heterogeneous in their pathophysiologic features and prognosis. The emergence of myositis-specific autoantibodies suggests that subgroups of patients exist.
To ...develop a new classification scheme for idiopathic inflammatory myopathies based on phenotypic, biological, and immunologic criteria.
An observational, retrospective cohort study was performed using a database of the French myositis network. Patients identified from referral centers for neuromuscular diseases were included from January 1, 2003, to February 1, 2016. Of 445 initial patients, 185 patients were excluded and 260 adult patients with myositis who had complete data and defined historical classifications for polymyositis, dermatomyositis, and inclusion body myositis were enrolled. All patients were tested for anti-histidyl-ARN-t- synthetase (Jo1), anti-threonine-ARN-t-synthetase (PL7), anti-alanine-ARN-t-synthetase (PL12), anti-complex nucleosome remodeling histone deacetylase (Mi2), anti-Ku, anti-polymyositis/systemic scleroderma (PMScl), anti-topoisomerase 1 (Scl70), and anti-signal recognition particle (SRP) antibodies. A total of 708 variables were collected per patient (eg, cancer, lung involvement, and myositis-specific antibodies).
Unsupervised multiple correspondence analysis and hierarchical clustering analysis to aggregate patients in subgroups.
Among 260 participants (163 62.7% women; mean age, 59.7 years; median age range, 61.5 years 48-71 years), 4 clusters of patients emerged. Cluster 1 (n = 77) included patients who were male, white, and older than 60 years and had finger flexor and quadriceps weakness and findings of vacuolated fibers and mitochondrial abnormalities. Cluster 1 regrouped patients who had inclusion body myositis (72 of 77 patients 93.5%; 95% CI, 85.5%-97.8%; P < .001). Cluster 2 (n = 91) regrouped patients who were women and had high creatine phosphokinase levels, necrosis without inflammation, and anti-SRP or anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) antibodies corresponding to immune-mediated necrotizing myopathy (53 of 91 58.2%; 95% CI, 47.4%-68.5%; P < .001). Cluster 3 (n = 52) regrouped patients who had dermatomyositis rash and anti-Mi2, anti-melanoma differentiation-associated protein 5 (MDA5), or anti-transcription intermediary factor-1γ (TIF1γ) antibodies, mainly corresponding with patients who had dermatomyositis (43 of 52 82.7%; 95% CI, 69.7%-91.8%; P < .001). Cluster 4 (n = 40) was defined by the presence of anti-Jo1 or anti-PL7 antibodies corresponding to antisynthetase syndrome (36 of 40 90.0%; 95% CI, 76.3%-97.2%; P < .001). The classification of an independent cohort (n = 50) confirmed the 4 clusters (Cohen κ light, 0.8; 95% CI, 0.6-0.9).
These findings suggest a classification of idiopathic inflammatory myopathies with 4 subgroups: dermatomyositis, inclusion body myositis, immune-mediated necrotizing myopathy, and antisynthetase syndrome. This classification system suggests that a targeted clinical-serologic approach for identifying idiopathic inflammatory myopathies may be warranted.
Abstract Natural history studies in sporadic inclusion body myositis are of fundamental interest for future therapeutic trials. Previous works have demonstrated the particular relevance of knee ...extension strength in the follow-up of this disease. This work aimed to extend a preceding natural history over 9 months to a four year period. Thirteen patients were assessed using clinical and functional scales and dynamometry. Except wrist extension torque and manual muscle testing composite score, all the measurements presented a significant decline. The most important changes were observed for knee extension and ankle flexion and extension. The relative change in knee extension strength correlated with the level of strength at baseline. A non-linear correlation was found between 6-minute walk distance and knee extension strength. This study confirms that knee extension strength is particularly relevant to follow patients with sporadic inclusion body myositis. It also shows that a strength loss does not have linear consequences on motor ability. Finally strength and motor ability are complementing each other in the understanding of disease progression.
The predominance of extramuscular manifestations (e.g., skin rash, arthralgia, interstitial lung disease ILD) as well as the low frequency of muscle signs in anti-melanoma differentiation-associated ...gene 5 antibody-positive (anti-MDA5+) dermatomyositis caused us to question the term myositis-specific antibody for the anti-MDA5 antibody, as well as the homogeneity of the disease.
To characterize the anti-MDA5+ phenotype, an unsupervised analysis was performed on anti-MDA5+ patients (n = 83/121) and compared to a group of patients with myositis without anti-MDA5 antibody (anti-MDA5-; n = 190/201) based on selected variables, collected retrospectively, without any missing data.
Within anti-MDA5+ patients (n = 83), 3 subgroups were identified. One group (18.1%) corresponded to patients with a rapidly progressive ILD (93.3%;
< 0.0001 across all) and a very high mortality rate. The second subgroup (55.4%) corresponded to patients with pure dermato-rheumatologic symptoms (arthralgia; 82.6%;
< 0.01) and a good prognosis. The third corresponded to patients, mainly male (72.7%;
< 0.0001), with severe skin vasculopathy, frequent signs of myositis (proximal weakness: 68.2%;
< 0.0001), and an intermediate prognosis. Raynaud phenomenon, arthralgia/arthritis, and sex permit the cluster appurtenance (83.3% correct estimation). Nevertheless, an unsupervised analysis confirmed that anti-MDA5 antibody delineates an independent group of patients (e.g., dermatomyositis skin rash, skin ulcers, calcinosis, mechanic's hands, ILD, arthralgia/arthritis, and high mortality rate) distinct from anti-MDA5- patients with myositis.
Anti-MDA5+ patients have a systemic syndrome distinct from other patients with myositis. Three subgroups with different prognosis exist.
Objectives
Interstitial lung disease (ILD), one of the most common extramuscular manifestations of idiopathic inflammatory myopathies (IIMs), carries a poor prognosis. Myositis-specific autoantibody ...(MSA)-positivity is a key finding for IIM diagnosis. We aimed to identify IIM-associated lung patterns, evaluate potential CT–ILD finding–MSA relationships, and assess intra- and interobserver reproducibility in a large IIM population.
Methods
All consecutive IIM patients (2003–2019) were included. Two chest radiologists retrospectively assessed all chest CT scans. Multiple correspondence and hierarchical cluster analyses of CT findings identified and characterized ILD-patient subgroups. Classification and regression-tree analyses highlighted CT-scan variables predicting three patterns. Three independent radiologists read CT scans twice to assign patients according to CT–ILD-pattern clusters.
Results
Among 257 IIM patients, 94 (36.6%) had ILDs; 87 (93%) of them were MSA-positive. ILD–IIM distribution was 54 (57%) ASyS, 21 (22%) DM, 15 (16%) IMNM, and 4 (4%) IBM. Cluster analysis identified three ILD-patient subgroups. Consolidation characterized cluster 1, with significantly (
p
< 0.05) more frequent anti-MDA5–autoantibody-positivity. Significantly more cluster-2 patients had a reticular pattern, without cysts and with few consolidations. All cluster-3 patients had cysts and anti-PL12 autoantibodies. Clusters 2 and 3 included significantly more ASyS patients. Intraobserver concordances to classify patients into those three clusters were good-to-excellent (Cohen
κ
0.64–0.81), with good interobserver reliability (Fleiss’s
κ
0.56).
Conclusion
Despite the observed IIM heterogeneity, CT-scan criteria enabled ILD assignment to the three clusters, which were associated with MSAs. Radiologist identification of those clusters could facilitate diagnostic screening and therapeutics.
Summary statement
Interstitial lung disease in patients with idiopathic inflammatory myopathy could be classified into three clusters according to CT-scan criteria, and these clusters were significantly associated with myositis-specific autoantibodies.
Key Points
•
Cluster analysis discerned three homogeneous groups of interstitial lung disease (ILD) for which cysts, consolidations, and reticular pattern were discriminatory, and associated with myositis-specific autoantibodies.
•
Like muscle- and extramuscular-specific phenotypes, myositis-specific autoantibodies are also associated with specific ILD patterns in patients with idiopathic inflammatory myopathies.
Systemic lupus erythematosus (SLE) is a T and B cell-dependent autoimmune disease characterized by the appearance of autoantibodies, a global regulatory T cells (Tregs) depletion and an increase in ...Th17 cells. Recent studies have shown the multifaceted immunomodulatory effects of vitamin D, notably the expansion of Tregs and the decrease of Th1 and Th17 cells. A significant correlation between higher disease activity and lower serum 25-hydroxyvitamin D levels 25(OH)D was also shown.
In this prospective study, we evaluated the safety and the immunological effects of vitamin D supplementation (100,000 IU of cholecalciferol per week for 4 weeks, followed by 100,000 IU of cholecalciferol per month for 6 months.) in 20 SLE patients with hypovitaminosis D.
Serum 25(OH)D levels dramatically increased under vitamin D supplementation from 18.7±6.7 at day 0 to 51.4±14.1 (p<0.001) at 2 months and 41.5±10.1 ng/mL (p<0.001) at 6 months. Vitamin D was well tolerated and induced a preferential increase of naïve CD4+ T cells, an increase of regulatory T cells and a decrease of effector Th1 and Th17 cells. Vitamin D also induced a decrease of memory B cells and anti-DNA antibodies. No modification of the prednisone dosage or initiation of new immunosuppressant agents was needed in all patients. We did not observe SLE flare during the 6 months follow-up period.
This preliminary study suggests the beneficial role of vitamin D in SLE patients and needs to be confirmed in randomized controlled trials.
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