Epidemiological, clinical and immunological aspects of antisynthetase syndrome: a multicentre study in Dakar

Introduction

Idiopathic inflammatory myopathies (IIMs) or idiopathic-acquired myopathies represent a heterogeneous group of rare autoimmune diseases [1,2,3]. This group is made up of a set of acquired muscular disorders resulting from the dysregulation of the immune system. They can sometimes be associated with extramuscular autoimmune manifestations or cancer [1, 4]. The understanding of the pathophysiology of IIMs, their serological and histological specificity and above all the recent advent of myositis-specific autoantibodies (MSAs) have contributed to refining their classification. This classification, which is not unanimously accepted, includes dermatomyositis, inclusion myositis, autoimmune necrotising myositis and overlapping myositis and antisynthetase syndrome (ASS) and myositis associated with connective tissue disease [2, 4, 5]. ASS is characterised by muscle weakness, diffuse interstitial lung disease (ILD), polyarthritis, skin damage such as “mechanic’s hands” and, to a lesser extent, Raynaud’s phenomenon. Biologically, it is associated with autoantibodies of the antisynthetase family, the most frequent being the anti-Jo1 [6]. Studies on ASS are not numerous in sub-Saharan Africa. In Senegal, only two case-report studies have been published concerning this condition [7, 8]. In this context, we conducted a multicentric and descriptive study about epidemiological, diagnostic and immunological aspects of ASS.

Patients and methods

Patients

The aim of our study was to describe the epidemiological, clinical and immunological characteristics of patients with ASS followed in six major hospitals in Senegal. This was a retrospective, multicentre and descriptive study from 1 January 2014 to 30 June 2020 in four internal medicine departments, one pneumology department and one dermatology department of the following hospital centres: Aristide Le Dantec Hospital, Pikine National Hospital, Hospital Principal of Dakar, Dalal Jam National Hospital, Hygiène Social Institute and Regional Hospital of Thies. Our patients had been seen in the abovementioned departments. In this study, patients who met the diagnostic classification of Solomon et al. [9] were included, namely the presence of an anti-aminoacyl-tRNA (ribonucleic acid) synthetase antibody plus two major criteria or one major and two minor criteria. Patients with incomplete records were excluded from the study. An informed written consent has been obtained for all patients of the study.

Data

Data collection was done using a pre-established data collection form. The data included marital status, history, patient condition (cancer, connective tissue disease, infections, others) and treatment history. The physical examination was used to describe the characteristics of muscle involvement (topography, distribution, existence of amyotrophy) and to assess the characteristics of joint damage (topography, distribution, joint deformities, the presence of inflammatory signs such as synovitis). Pulmonary involvement was assessed by the existence of dyspnoea, oxygen saturation and the presence of crackling rales. Upon the dermatological examination, the existence of hyperkeratosis of the hands and feet and the existence of Raynaud’s syndrome were assessed. The physical examination was complete to look for other disorders. The biological data collected were as follows: haemoglobin level, sedimentation rate, C-reactive protein (CRP) level and creatine kinase (CK) level.

The following immunological markers were investigated: anti-amino acyl RNA synthetase antibodies (anti-Jo-1; anti-PL-7; anti-PL-12; anti-EJ; anti-OJ; anti-ZO; anti-KS; anti-YRS, anti-JS and anti-SC) by dot-myosite; anti-extractable nuclear antibodies (anti-Sm; anti-SSA; anti-SSB; anti- RNP; anti-Scl-70); anti-PM-Scl; anti-double-stranded deoxyribonucleic acid (anti-dsDNA) and antinuclear antibodies.

Chest computer tomography (CT) was used to assess pulmonary involvement such as ILD (interstitial lung disease), their type and extension. Other paraclinical investigations were about electromyogram (EMG), electrocardiogram (EKG), respiratory test function and cardiac ultrasound. The therapeutic data collected at the time of diagnosis concerned corticosteroid therapy, immunosuppressants, physiotherapy and patient education (PE).

Statistical analysis

The data were recorded and analysed using SPSS (Statistical Package for the Social Sciences) software version 26.0. The results were expressed as a mean (+ / − standard deviation) and median (with extremes) for the continuous variables and as percentages for the categorical variables. Means were compared using t Student, and comparisons between categorical measures were made using chi-square test. The comparison between categorical variables was made using the chi-square test. The p-value < 0.05 was considered statistically significant.

Results

From 1 January 2014 to 30 June 2020, 14 patients (3 males and 11 females) were included in the study, whose main clinical, biological and radiological manifestations are summarised in Table 1. The sex ratio was 0.27, and the mean age of our patients was 44.07 years (+ / − 10.43) with extremes between 24 and 58 years. The mean diagnostic delay was 22.71 months (+ / − 34.79 months) (Tables 2, 3 and 4).

Table 1 Clinical presentation of 14 ASS patients

Table 2 Different immunological tests of 14 AAS patients

Table 3 Chest CT of AAS patients

Table 4 Main characteristics of the patients

In our series, 2 of our patients (14.3%) had hypertension as a comorbidity. It should also be noted that 2 patients (14.3%) were initially classified as having dermatomyositis and polymyositis, without histological or immunological evidence. A family history of inflammatory arthritis was found in 2 patients (14.3%).

Muscle manifestations were present in all our patients with proximal and symmetrical weakness in 11 patients (78.6%). Distal and symmetrical weakness was present in 2 patients (14.3%); the last one had only myalgias. In our series, acute inflammatory arthritis concerned 5 patients (35.7%), while chronic polyarthritis constituted 7 patients (50%). Joint involvement concerned large and small joints in 12 patients (85.7%). Raynaud’s syndrome was a non-specific dermatological condition noted in 4 cases (28.5%), while specific dermatological (Figs. 1 and 2) manifestations were present in 7 patients (50%).

Fig. 1

Mechanic’s hand in our patient. Hyperkeratosis of the fingers associated with hyperpigmentation

Fig. 2

Plantar keratodermia. Plantar erythematous-squamous lesion

Laboratory tests showed non-specific inflammatory syndrome in 10 cases (71.42%). The mean CRP levels were 87.25 mg/l (+ / − 132.14 mg/l). We had 12 patients (85.7%) with elevated CK at the time of diagnosis of ASS; the mean CK level was 5259 U/l (+ / − 5885.65 UI/l). The immunological work-up showed anti-Jo1 autoantibodies in 10 patients (71.43%), anti-PL12 autoantibodies in 3 patients (21.4%) and anti-PL7 autoantibodies in 1 patient (7.1%). We did not find any statistically significant relationship between the clinical presentation and the distribution of antibodies.

EMG was described as myositis in 9 patients (64.3%). Muscle biopsy and muscle MRI were not performed in our series. Of the 8 patients (57.15%) who had a chest X-ray, five had interstitial syndrome. Chest CT scans were performed in 12 patients (85.72%) and showed non-specific ILD in 9 patients (64.3%), fibrosing ILD in 2 patients (14.3%) and unclassifiable ILD in 1 patient (7.1%) (Fig. 3).

Fig. 3

Chest computer tomography Interstitial Lung disease in our patient

Of the 2 patients (14.3%) who had an exploration of respiratory function, one case of obstructive syndrome and one case of mixed syndrome (obstructive and restrictive) were identified. Echocardiography of four patients showed circumferential pericardial detachment, septal hypertrophy with pericardial effusion, hyperkinetic heart with moderate arterial pulmonary hypertension or moderate tricuspid insufficiency. Corticosteroid therapy was used as first-line therapy for all patients. In our series, 13 patients (93%) of cases had received the combination of corticosteroid therapy and immunosuppressants such as azathioprine, methotrexate and hydroxychloroquine.

Discussion

We report here for the first time, to our knowledge, a multicentre study of ASS in sub-Saharan Africa. It identified 14 patients. Our series is relatively limited, it is consistent with the literature and the prevalence of this condition remains unknown in sub-Saharan Africa.

The preponderance of women in our series is similar to the literature. Although ASS is a condition that can occur at any age, the average age in our series was lower than that of Gusdorf et al. [10]. Compared to the literature [11], the patients in our series showed a delay in diagnosis. This could be explained by methodological differences or by a lack of knowledge of the disease in our region.

It should be noted that, as in most cohorts [6, 12] and our cohort, muscle involvement was present in all patients. This could be explained by various factors, such as the long delay in diagnosis or the immunological or ethnogenetic profile. We did not assess any correlation between anti-Jo titre and disease activity as reported by Stone et al. [13].

Joint manifestations were found in 85.7% of cases (n = 12). They consisted of acute polyarthritis in 5 patients (41.6%) and chronic polyarthritis in 7 patients (53.4%). These data are similar to those found in the literature [11, 14]. They are close to the data of Meyer et al., who in their study reported 88% of cases with polyarthralgia and/or polyarthritis in 17 cases of antisynthetase syndrome associated with rheumatoid arthritis and positive anti-citrullinated peptides antibodies.

Interstitial lung disease (ILD) was present in 12 of our patients and was dominated by non-specific lung disease (64.3%). This pattern had been found by other authors [15, 16] but in varying proportions. However, the evaluation of the degree of extension was not noted in our study, although this is an important parameter for monitoring the evolution of ILD in ASS patients with pulmonary involvement.

In the literature, mechanic’s hands are seen 19 to 56.5% of cases [6, 17]. Our data indicate that mechanic’s hands were seen in 50% of cases and hiker’s feet in 14% of cases. Gusdorf et al. study reported a lower frequency of mechanic’s hand among cases of ASS.

In our study, we noted that 28.6% of cases had Raynaud’s phenomenon, while incidence of Raynaud’ phenomenon ranged from 28 to 93% in other studies [14, 15]. The frequency of this vasculopathy can be explained pathophysiologically by the activation of endothelial cells by anti-Jo1 antibodies [18]. We noted anti-Jo1 antibodies in 10 patients (71.4%).

The presence of anti-SSA antibodies is considered a factor in the severity of lung parenchyma, muscle and joint involvement [15, 19]. They were found in 9 of our cases (64.3%). These results are higher than those of Dieval et al. who reported anti-SAA antibodies in50% of cases.

However, we did not find any statistically significant relationship between the clinical presentation and the distribution of antibodies.

The routine use of immunoblot for the detection of MSAs in IIMs has resulted in a significant number of multipositive cases [20]. We noted only one case (7.1%) of multipositivity of autoantibodies specific for myositis in our series. One patient had anti-NXP2 and anti-PL12. A reasoned prescription, collaboration between biologists and clinicians and a critical interpretation of the immunoblot seem essential.

The treatment of ASS is not yet codified [19, 21]. In general, treatment of ASS should be targeted according to the clinical phenotypes and symptom severity of the ASS [16, 22]. In our study, 13 patients were treated with corticosteroids at the time of diagnosis. The immunosuppressive drugs prescribed in association with corticosteroid therapy in our patients were azathioprine in seven cases, methotrexate in two cases and the combination of methotrexate and azathioprine in three cases. Methotrexate and azathioprine have similar efficacy in ASS [23], but methotrexate is often avoided in patients with severe ILD.

One of the limitations of our study is the retrospective nature of recruitment. This may have led to statistical biases due to missing data on parameters in some patient files. The second limitation is the relatively small size of our sample. However, it allowed us to highlight a clinical and immunological profile of ASS in our region.

Conclusion

ASS is a rare and heterogeneous connective tissue disease. Although retrospective, our multicentre study confirms the fact that ASS is a condition that predominates in young women with variable manifestations but dominated by muscular, articular and pulmonary involvement. It is often associated with the presence of antisynthetase antibodies, particularly against Jo1. Better knowledge of this syndrome by organ specialists would reduce the time taken to diagnose the disease, improve patient management and thus avoid the occurrence of the major complication of this syndrome, i.e. pulmonary fibrosis.