In inflammatory myopathies, dropped head/bent spine syndrome is associated with scleromyositis: an international case–control study
IM patients with DH/BS have a delayed diagnosis, older age, severe atrophying muscle involvement prevailing in the upper limbs, loss of walking ability, dysphagia, systemic signs of systemic sclerosis and mortality. 

DH/BS is a marker of IM severity associated with scleromyositis diagnosis that has important consequences for patient management. 

Inflammatory myopathies (IM) are rare systemic diseases characterised by myopathy with evidence of inflammation-driven muscle lesions. They encompass a heterogeneous group of diseases, some of which have been identified based on clinical, serological and pathological features. The 2017 European Alliance of Associations for Rheumatology/American College of Rheumatology (EULAR/ACR) classification criteria recognise dermatomyositis (DM), sporadic inclusion body myositis (sIBM) and polymyositis (PM). There is evidence that IM can be further divided into immune-mediated necrotising myopathies (IMNM) and IM overlapping with other connective tissue diseases, especially antisynthetase syndrome (ASS) and systemic sclerosis (SSc). Identification of these different conditions is fundamental since each of these distinct disorders requires different management. Distribution of muscle weakness is an important clinical feature that differentiates IM subgroups. The preferential involvement of the quadriceps and the finger flexors is the hallmark of sIBM. It has recently been reported that muscle weakness is also differentially distributed among muscles in the other IM subgroups. For instance, muscle weakness is more pronounced in the lower limbs in patients with IMNM while it is more pronounced in the upper limbs in patients with overlap IM and anti-PM/Scl antibodies. Dropped head or bent spine (also referred to as ‘camptocormia’) syndrome (DH/BS) is defined as an involuntary flexion of the neck or trunk, respectively, when standing, and resolving in recumbent position. IM has been found in about 15%–17% of patients with myopathic DH/BS. No studies have compared IM patients with and without DH/BS. Thus, the significance of this peculiar distribution of muscle weakness is currently unknown in this setting. In the present study, we conducted an international case–control study of IM patients with or without DH/BS. 

Study design An international multicentre retrospective case–control study was performed: all practitioners registered on MyositEst (a network for IM in Eastern France), the Club Rhumatisme et Inflammation (a national network for rare autoimmune diseases in France), the French myositis network, the American and European NEtwork of Antisynthetase Syndrome collaborative group and the Canadian Inflammatory Myopathy Study Group were contacted (totallising ≈2000 physicians). These physicians were reached by electronic letters and invited to report patients suffering from IM with axial muscle impairment responsible for a DH/BS (DH/BS-IM patients). For each DH/BS-IM patient reported, physicians were asked to randomly select two IM patients without DH/BS to be included and reported as controls (control-IM patients). Patients Patients were included if diagnosed with IM according to the 2017 EULAR/ACR criteria for IM. Patients with DH/BS and without other causes than IM were included as case patients (DH/BS-IM patients). Other causes of DH/BS, such as extrapyramidal syndrome, myasthenic syndrome, motor neuron disorder and a history of radiotherapy involving the paravertebral area were exclusion criteria. IM patients without DH/BS at the IM diagnosis and during follow-up were included as controls (control-IM patients). Data assessment and definitions All data were collected using a standardised form, completed by the main practitioner in charge of the patient. All the recorded variables were defined. Dysphagia was defined as pharyngeal and/or oesophageal signs when eating and/or drinking (eg, difficulty swallowing solid and/or liquids, food sticking in throat, coughing while eating). Arthralgia was defined by inflammatory joint pain with or without arthritis. Pulmonary involvement was defined by interstitial lung disease on high resolution CT scan of the chest. Echocardiography was used to screen for pulmonary hypertension. Renal crisis was defined as decrease in renal function and (1) new onset of blood pressure >150/85 mm Hg or (2) when normal blood pressure (normotensive renal crisis) either microangiopathic haemolytic anaemia or consistent findings on kidney biopsy. Cutaneous involvement was diagnosed and categorised as skin thickening, puffy fingers, telangiectasia, DM rash and/or mechanic’s hand ascertained by experienced physicians. Abnormal nailfold capillaroscopy corresponded to enlarged capillaries and/or capillary loss with or without pericapillary haemorrhages at the nailfold. Improvement of the myopathy was defined as a ≥15% improvement in strength and a ≥30% decrease in creatine kinase level according to International Myositis Assessment and Clinical Studies Group criteria. IM autoantibodies identification was performed according to the local protocol of each centre. At the time of the study, no guideline was available for the set of autoantibodies to test in myositis patients. The set of autoantibodies tested in each patient was chosen by the physicians depending on the clinical phenotypes. All participants were expert in the field. Immunodot was used in all the centres for testing myositis-specific and associated autoantibodies (Euroimmun, D-tek). Luminex technology was used to test antisignal recognition particle and anti-3-hydroxy-3-methylglutaryl-CoA reductase autoantibodies only in a centre. IM patients were first classified according to 2017 EULAR/ACR criteria. Patients were further classified as follows: IMNM and DM were diagnosed using ENMC criteria, ASS was diagnosed using Connors et al ’s criteria, SSc overlapping with IM was diagnosed using the 2013 ACR/EULAR criteria for SSc, IBM was diagnosed using Lloyd et al ’s criteria. Statistical analysis Data statistical analyses were performed using JMP software (V.7.0). Categorical variables were compared between groups using Fisher’s exact test or χ 2 test. Quantitative variables were compared using t-test (normal distribution) or Mann-Whitney test (non-normal distribution). The normality of the distributions was verified with the Shapiro-Wilk test. Parameters independently associated with DH/BS were determined by multivariate analysis (logistic regression). To this aim, features displaying an association with DH/BS with a p<0.05 in the univariate analysis were included in a multivariable logistic regression analysis. The Kaplan-Meier method was used to produce survival curves, compared with the log-rank test. The interdependence of the parameters associated with survival was assessed using the Cox (proportional hazards) model. 

An international multicentre retrospective case–control study was performed: all practitioners registered on MyositEst (a network for IM in Eastern France), the Club Rhumatisme et Inflammation (a national network for rare autoimmune diseases in France), the French myositis network, the American and European NEtwork of Antisynthetase Syndrome collaborative group and the Canadian Inflammatory Myopathy Study Group were contacted (totallising ≈2000 physicians). These physicians were reached by electronic letters and invited to report patients suffering from IM with axial muscle impairment responsible for a DH/BS (DH/BS-IM patients). For each DH/BS-IM patient reported, physicians were asked to randomly select two IM patients without DH/BS to be included and reported as controls (control-IM patients). 

Patients were included if diagnosed with IM according to the 2017 EULAR/ACR criteria for IM. Patients with DH/BS and without other causes than IM were included as case patients (DH/BS-IM patients). Other causes of DH/BS, such as extrapyramidal syndrome, myasthenic syndrome, motor neuron disorder and a history of radiotherapy involving the paravertebral area were exclusion criteria. IM patients without DH/BS at the IM diagnosis and during follow-up were included as controls (control-IM patients). 

All data were collected using a standardised form, completed by the main practitioner in charge of the patient. All the recorded variables were defined. Dysphagia was defined as pharyngeal and/or oesophageal signs when eating and/or drinking (eg, difficulty swallowing solid and/or liquids, food sticking in throat, coughing while eating). Arthralgia was defined by inflammatory joint pain with or without arthritis. Pulmonary involvement was defined by interstitial lung disease on high resolution CT scan of the chest. Echocardiography was used to screen for pulmonary hypertension. Renal crisis was defined as decrease in renal function and (1) new onset of blood pressure >150/85 mm Hg or (2) when normal blood pressure (normotensive renal crisis) either microangiopathic haemolytic anaemia or consistent findings on kidney biopsy. Cutaneous involvement was diagnosed and categorised as skin thickening, puffy fingers, telangiectasia, DM rash and/or mechanic’s hand ascertained by experienced physicians. Abnormal nailfold capillaroscopy corresponded to enlarged capillaries and/or capillary loss with or without pericapillary haemorrhages at the nailfold. Improvement of the myopathy was defined as a ≥15% improvement in strength and a ≥30% decrease in creatine kinase level according to International Myositis Assessment and Clinical Studies Group criteria. IM autoantibodies identification was performed according to the local protocol of each centre. At the time of the study, no guideline was available for the set of autoantibodies to test in myositis patients. The set of autoantibodies tested in each patient was chosen by the physicians depending on the clinical phenotypes. All participants were expert in the field. Immunodot was used in all the centres for testing myositis-specific and associated autoantibodies (Euroimmun, D-tek). Luminex technology was used to test antisignal recognition particle and anti-3-hydroxy-3-methylglutaryl-CoA reductase autoantibodies only in a centre. IM patients were first classified according to 2017 EULAR/ACR criteria. Patients were further classified as follows: IMNM and DM were diagnosed using ENMC criteria, ASS was diagnosed using Connors et al ’s criteria, SSc overlapping with IM was diagnosed using the 2013 ACR/EULAR criteria for SSc, IBM was diagnosed using Lloyd et al ’s criteria. 

Data statistical analyses were performed using JMP software (V.7.0). Categorical variables were compared between groups using Fisher’s exact test or χ 2 test. Quantitative variables were compared using t-test (normal distribution) or Mann-Whitney test (non-normal distribution). The normality of the distributions was verified with the Shapiro-Wilk test. Parameters independently associated with DH/BS were determined by multivariate analysis (logistic regression). To this aim, features displaying an association with DH/BS with a p<0.05 in the univariate analysis were included in a multivariable logistic regression analysis. The Kaplan-Meier method was used to produce survival curves, compared with the log-rank test. The interdependence of the parameters associated with survival was assessed using the Cox (proportional hazards) model. 

The flowchart is shown in . Sixty-three DH/BS patients were reported, excluding 14 patients because of myasthenia gravis (n=3), a history of cervical radiotherapy (n=2), immune checkpoint inhibitor-related myositis (n=1), non-inflammatory myopathy (n=3) or insufficient data to confirm IM (n=5). Thus, 49 DH/BS-IM patients (DH: n=28; BS: n=21) and 98 control-IM (two per one case, randomly selected from the same centre) were finally included . Comparison of the DH/BS-IM patients with the control-IM patients is shown in . DH/BS is associated with older age and delayed diagnosis of IM DH/BS-IM patients were 12 years older at the IM diagnosis (65.0 years (55.0–74.2) vs 53.0 (42.7–63.0), p<0.0001). In addition, the delay before IM diagnosis (interval between first muscular signs reported and diagnosis of IM) was twice as long in the DH/BS group (6 months (IQR: 3–11) vs 3 months (IQR: 1–9), p=0.009). In both groups, the female/male ratio was about 2.5 and median follow-up was more than 3 years. DH/BS is associated with severe myopathy All DH/BS-IM patients had weakness of the limbs. Hallmarks of the myopathy in the DH/BS-IM patients were weakness prevailing in the upper limbs as compared with the lower limbs (42.9% vs 15.3%, p=0.0003), dysphagia (57.1% vs 25.5%, p=0.0001), muscle atrophy (65.3% vs 34.7% p=0.0004) and loss of the ability to walk (24.5% vs 5.1%, p=0.0005). Weight loss was reported in the majority of the DH/BS-IM patients (61.2% vs 23.5% in the control-IM group, p<0.0001) and reached nearly 10 kg (−9.5 kg (95% CI −5.3 to −12)). This pattern of muscle weakness and its severity were associated with DH/BS independently of other factors, especially age (p<0.05). Consistently with the severe muscle involvement, intravenous immunoglobulins were used in the majority of the DH/BS-IM patients (65.3% vs 34.7%, p=0.0004). Yet, improvement of the myopathy was less frequent than in the control group (69.4% vs 85.7 %, p=0.02), although DH/BS had improved (as judged by the patient and the clinician) in 61.2% of the patients at the last follow-up. DH/BS is frequently associated with SSc overlapping with IM (scleromyositis) Raynaud’s phenomenon was more often featured in DH/BS-IM patients (51.0% vs 30.6%, p=0.02), as well as abnormal nailfold capillaroscopy (64.5% vs 38.3%, p=0.02), telangiectasia (38.8% vs 7.1%, p<0.0001), sclerodactyly (36.7% vs 6.1%, p<0.0001), puffy fingers (22.5% vs 3.1%, p=0.0004), scleroderma (12.2% vs 2.0%, p=0.02), digital ulcers and/or pitting scars (12.2% vs 5.1%, p=0.2). In addition, other frequent systemic manifestations of SSc (but not included in ACR/EULAR 2013 criteria), such as pericarditis (18.4% vs 2.0%, p=0.0009), myocarditis (6.1% vs 3.1%, p=0.4), calcinosis (12.2%, vs 5.1%, p=0.2) and renal crisis (4.0% vs 0%, p=0.049) were all more frequent in DH/BS-IM patients. Moreover, 36.6% of DH/BS-IM had auto-antibodies associated with SSc (vs 11.1% in control-IM, p=0.002), the most frequently reported being anti-PM/Scl (28.6%). Finally, 40.8% of the DH/BS-IM patients fulfilled the 2013 ACR/EULAR criteria for SSc (vs only 5.1% in the control-IM group, p<0.0001). This association was maintained in the multivariate analysis (p<0.0001). DH/BS is associated with increased mortality Ten patients died in DH/BS group (20.4%) versus nine in the control group (9.2%). The main cause of death was cardiovascular events in the DH/BS-IM (n=5, 50%) versus cancer in the control group (n=5, 55%). Survival analysis, as shown in , showed a higher mortality in the DH/BS-IM patients (p=0.002). To further explore the link between DH/BS and mortality, we studied the survival of patients with and without the six features independently associated with DH/BS identified in . Loss of walking ability was associated with mortality independently of the other factors in the Cox multivariate model (risk ratio 5.8 (95% CI 1.6 to 20.8)). 

DH/BS-IM patients were 12 years older at the IM diagnosis (65.0 years (55.0–74.2) vs 53.0 (42.7–63.0), p<0.0001). In addition, the delay before IM diagnosis (interval between first muscular signs reported and diagnosis of IM) was twice as long in the DH/BS group (6 months (IQR: 3–11) vs 3 months (IQR: 1–9), p=0.009). In both groups, the female/male ratio was about 2.5 and median follow-up was more than 3 years. 

All DH/BS-IM patients had weakness of the limbs. Hallmarks of the myopathy in the DH/BS-IM patients were weakness prevailing in the upper limbs as compared with the lower limbs (42.9% vs 15.3%, p=0.0003), dysphagia (57.1% vs 25.5%, p=0.0001), muscle atrophy (65.3% vs 34.7% p=0.0004) and loss of the ability to walk (24.5% vs 5.1%, p=0.0005). Weight loss was reported in the majority of the DH/BS-IM patients (61.2% vs 23.5% in the control-IM group, p<0.0001) and reached nearly 10 kg (−9.5 kg (95% CI −5.3 to −12)). This pattern of muscle weakness and its severity were associated with DH/BS independently of other factors, especially age (p<0.05). Consistently with the severe muscle involvement, intravenous immunoglobulins were used in the majority of the DH/BS-IM patients (65.3% vs 34.7%, p=0.0004). Yet, improvement of the myopathy was less frequent than in the control group (69.4% vs 85.7 %, p=0.02), although DH/BS had improved (as judged by the patient and the clinician) in 61.2% of the patients at the last follow-up. 

Raynaud’s phenomenon was more often featured in DH/BS-IM patients (51.0% vs 30.6%, p=0.02), as well as abnormal nailfold capillaroscopy (64.5% vs 38.3%, p=0.02), telangiectasia (38.8% vs 7.1%, p<0.0001), sclerodactyly (36.7% vs 6.1%, p<0.0001), puffy fingers (22.5% vs 3.1%, p=0.0004), scleroderma (12.2% vs 2.0%, p=0.02), digital ulcers and/or pitting scars (12.2% vs 5.1%, p=0.2). In addition, other frequent systemic manifestations of SSc (but not included in ACR/EULAR 2013 criteria), such as pericarditis (18.4% vs 2.0%, p=0.0009), myocarditis (6.1% vs 3.1%, p=0.4), calcinosis (12.2%, vs 5.1%, p=0.2) and renal crisis (4.0% vs 0%, p=0.049) were all more frequent in DH/BS-IM patients. Moreover, 36.6% of DH/BS-IM had auto-antibodies associated with SSc (vs 11.1% in control-IM, p=0.002), the most frequently reported being anti-PM/Scl (28.6%). Finally, 40.8% of the DH/BS-IM patients fulfilled the 2013 ACR/EULAR criteria for SSc (vs only 5.1% in the control-IM group, p<0.0001). This association was maintained in the multivariate analysis (p<0.0001). 

Ten patients died in DH/BS group (20.4%) versus nine in the control group (9.2%). The main cause of death was cardiovascular events in the DH/BS-IM (n=5, 50%) versus cancer in the control group (n=5, 55%). Survival analysis, as shown in , showed a higher mortality in the DH/BS-IM patients (p=0.002). To further explore the link between DH/BS and mortality, we studied the survival of patients with and without the six features independently associated with DH/BS identified in . Loss of walking ability was associated with mortality independently of the other factors in the Cox multivariate model (risk ratio 5.8 (95% CI 1.6 to 20.8)). 

This is the first study to assess the significance of DH/BS in IM. This study benefited from a multicentre international recruitment from tertiary hospitals and different specialties, with a case–control design, suited to obtain an accurate overview of this peculiar muscle involvement in IM. We show that IM patients with DH/BS have a delayed diagnosis, older age, severe atrophying muscle involvement prevailing in the upper limbs, dysphagia and systemic signs of SSc, fulfilling the ACR/EULAR 2013 criteria for this disease in barely half of the cases. Scleromyositis is not recognised as a current classification of IM. Yet, this diagnosis has important consequences for patient management. Notably, myopericarditis and renal crisis were over-represented in DH/BS IM patients. Despite high specificity, ACR/EULAR 2013 criteria for SSc have poor sensitivity for scleromyositis, notably because they do not take into account the autoantibodies most frequently associated with this disease. In this regard, four of the nine DH/BS IM patients with unclassified IM  had scleromyositis according to the clinician’s opinion (3/9 with anti-Ku antibodies) consistently with a high (≥7) yet insufficient (<9) ACR/EULAR 2013 score for SSc (in the absence of anti-Scl-70, anticentromere and anti-RNA polymerase III). This points to the need for scleromyositis criteria and indicates that DH/BS might be a sign of this disease. IM patients with DH/BS had loss of walking ability contributing to lower survival independently of older age. Mortality in this group was mainly due to cardiovascular events, as opposed to cancer in the control group. Low muscle mass and strength have been shown to be independently associated with increased all-cause mortality in different settings under the term ‘sarcopenia’. Myopericarditis and aggressive treatment, more frequent in DH/BS patients, might also have played a role in this result. This highlights the severity of myopathy as a prognosis factor in IM and indicates that DH/BS might be a marker of this severity. 

