The idiopathic inflammatory myopathies (IIM) are systemic connective tissue diseases characterized by symmetrical, proximal muscle weakness and chronic inflammation in muscle tissue. They can be subclassified into dermatomyositis (DM), polymyositis (PM), and inclusion body myositis (IBM) according to differences in clinical as well as histopathological features, and they frequently involve other systems with interstitial lung disease, esophageal dis-motility, and heart failure being the most common [1-4].

The study of many reports suggests that the average age of diagnosis for adults is between 40 to 50 years, with a female to male ratio of 2:1. The most common presentation is proximal muscle weakness in almost all the patients [5-7]. The diagnostic criteria are based on the Bohnas and Peter criteria of 1975 [8,9].

Currently IIM is treated with cortico steroids, methotrexate, rituximab, and other immunosuppressants. Many reports proved the effectiveness of corticosteroids in most of the cases, with some patients requiring a combined therapy of corticosteroid with methotrexate or azathioprine [10,11].

Little is known about the pattern of IIM in Arabic countries. A limited number of studies have been conducted in Riyadh, Kingdom of Saudi Arabia, on juvenile dermatomyositis [12,13]. Al-Ballaa [14] studied the pattern of IIM and its association with malignancy, but there is still a lack of solid basic data on the clinical features, laboratory investigations, and effective management of patients with IIM.

Therefore, we conducted this study to explore the demographic characteristics, clinical features, and effective management of patients with IIM at 5 tertiary centers in Saudi Arabia.

Study design

We conducted this retrospective study in 5 tertiary medical centers in Saudi Arabia; King Abdulaziz University Hospital, King Abdulaziz Hospital, King Fahad Hospital in Jeddah, Prince Sultan Medical Military City, Riyadh, and Al-Hada Armed Hospital, Taif to analyze the records of patients with IIM from 1999 to 2014. Patients with the diagnosis of pure PM, pure DM, juvenile dermatomyositis (JDM), and PM/DM/JDM mixed with other connective tissue diseases; namely, rheumatoid arthritis (RA), scleroderma, and seronegative arthritis were included. The IIM diagnostic criteria were based on the Bohans and Peter criteria [8,9]. Selection at King Abdulaziz University hospital was based on ICD9 and ICD10 codes (710.3, 710.4, 729.1, M33.0, M33.2, and M60.90).

All patients fulfilling the above criteria were included from the other 4 centers attending the Rheumatology clinic. In total, the medical records of 28 patients (6 DM, 9 PM, 3 pure JDM, and 10 with overlap or mixed connective tissue disorder [MCTD]) were reviewed. The study excluded IBM, infectious myositis, unspecified myositis, myositis ossificans, myositis due to diabetes mellitus, drug induced myositis, myositis due to radiation, and myositis due to trauma or any myopathy related to general medical illness.

Data collection

Data were collected from the medical records using a questionnaire including: demographic data, family history of IIM, type of myositis, age of diagnosis, duration of the disease and association with malignancy or connective tissue diseases, clinical features recorded at the time of the diagnosis and during follow up, and other systemic involvement.

Laboratory tests comprised biochemical tests: creatinine kinase enzyme (CK) level, aspartate aminotransferase (AST)/alanine aminotransferase (ALT)/lactate dehydrogenase (LDH) levels, Creactive protein (CRP), erythrocyte sedimentation rate (ESR), and rheumatoid factor (RF); serology: anti-neutrophilic antibody (ANA), anti-transfer ribonucleic acid (anti-tRNA), anti-double strand deoxyribonucleic acid (anti-dsDNA), anticardiolipin G and anticardiolipin M (anti-CCP), anti-jo-1 and anti-ribonuclear protein (anti-RNP).

Electromyography (EMG) and muscle biopsy results were recorded at the time of diagnosis for each patient. Muscle biopsy was considere positive if showed: necrosis of myofibers, phagocytosis, regeneration with basophils, large vesicular sarcolernmal nuclei, and prominent nucleoli, atrophy in a perifascicular distribution, variation in fiber size and an inflammatory exudate, often perivascular according to Bohan's and Peter criteria [8,9].

Modalities of treatment used for IIM: steroids, methotrexate, azathioprine, cyclophosphamide, chlorambucil, intravenous immunoglobulin (IVIG), and rituximab as the approved treatment for IIM [10,11]. The course and outcome of the disease: the outcome of patients was classified into respondent and resistant.

Assessment of response was based on normalization of CK, muscle power, or improvement of clinical features. The number of relapses was reviewed and recorded. Relapse was defined as a return of the signs and symptoms after remission due to dose reduction or cessation of medication. The comorbidities were assessed as follows: systemic arterial hypertension (HTN), diabetes mellitus, and ischemic heart diseases (IHD).

The diagnosis of HTN was based on the eighth HTN report [15], and diabetes mellitus on the American Diabetes Association guidelines [16]. Finally, IHD was defined according to the American College of Cardiology [17]. Causes of mortality were recorded (respiratory failure from respiratory muscle weakness, IHD, malignancy, sepsis). Patients who died from other causes were categorized as others.

Statistical analysis

The Statistical Package for Social Sciences, version 20 (IBM SPSS Statistics for Windows, IBM Corp, Armonk, NY, USA) was used for data analysis any p-value below 0.05 was considered significant. Numerical results were expressed as mean and attribute results were expressed as frequencies and percentage.

Demographic and general background

A total of 28 patients with IIM were identified, 9 patients had PM, 6 had DM, 3 had JDM, and 10 patients had IIM mixed with connective tissue diseases (6 scleroderma, 3 ankylosing spondylitis, and one with RA). There were 21 females and 7 males patients giving a female to male ratio of 3:1. Twenty-four patients were Saudis (85.7%) and 4 were non-Saudi (14.3%). Their ages ranged from 14-83 years, with a mean age of 37.7 years with mean disease duration of 7.09 years. The most common clinical presentation was muscular weakness with predominance of proximal myopathy in (93.9%) of patients, followed by arthralgia/arthritis (82.1%), generalized rash (64.3%), facial/ heliotrope rash (60.7%), fever (50%), Gottorn sign (46.4%), and dysphagia (35.7%). Table 1 shows that the most commonly involved system was the musculoskeletal system (78.6%), manifesting as muscle pain and tenderness. Eleven patients (39.3%) exhibited gastrointestinal involvement with gastritis being the commonest cause. The respiratory system accounted for 28.6% of organ involvement, mostly with interstitial lung disease and aspiration pneumonia as clinical presentations.

Table 1: Demographic and clinical characteristics in patients with IIM.

The cardiovascular system was considered the least involved system as pericarditis was recorded in only 2 patients (17.9%). Three patients developed malignancies (10.7%). The first patient, a female diagnosed with DM at the age of 78 years, had breast cancer, and there were 2 male patients, one with nasopharyngeal carcinoma at the age of 49, and the other with non-hodgkin lymphoma at the age of 43 years.

Laboratory results showed the mean value of CK was 2995.12 Ug/l (22 Ug/l to 11998 Ug/l), ALT was 151.50 U/L (27 U/L to 373 U/L), AST was 152.33 U/L (26 U/L to 649 U/L), and LDH was high at 547.87 U/L (00.0 U/L to 1983 U/L) at the time of diagnosis. Inflammatory markers were documented; ESR results showed a mean of 67.84 mm/h (1 mm/h to 529 mm/h), and CRP was positively elevated in 15 patients at the time of diagnosis. For autoimmune markers, ANA was positive in 53.6%, anti-double strand DNA was positive in 10.7%, anti-cardiolipin was positive in 10.7%, RF was positive in 10.7%, and anti-jo-1 was positive in 7.1% of patients. The EMG findings were consistent with PM in 13 patients, 8 were positive for DM, and 5 patients for JDM. The EMG was positive in 26 (92.9%) patients, and muscle biopsy was positive in 12 patients (42.9%) which showed consistent features of inflammatory myopathies.

Treatment

Twenty-seven patients (96%) received oral corticosteroid (prednisolone), with normalization of CK enzymes in 57.1%, and muscle power in 71.4%. Other treatments included 16 (57.1%) patients that received methotrexate and hydroxychloroquine, 12 (42.9%) patients received IVIG in the emergency room setting, eight (28.6%) patients were on rituximab, and 2 (7.1%) patients received cyclophosphamide. There was no resistance detected in all patients. Seventeen (60.7%) patients showed total remission, and 11 (39.3%) patients relapsed.

The characteristics of patients who relapsed and those in remission are summarized in Table 2. Patients in remission showed lower percentages of DM (23.1%), JDM (15.4%), and both groups showed equal percentages of PM (53.85%), and malignancy association (7.7%).

Table 2: Factors affecting remission in patients with inflammatory muscle.

There were no significant differences in medical complaints recorded at the time of diagnosis for remissions and relapsing patients; however, patients in remission had lower presentation of proximal muscle myopathy (23.1%), fever (11.5%), dysphagia (7.7%), arthralgia/ arthritis (19.2%), and skin manifestations (38.5%).

As this study recorded the organ involvement of all IIM patients, there were slight differences between remission and relapsed patients as shown in Table 2.

For patients in remission, their lab results showed positive CRP (58.8%), anti dsDNA (11.7%), RF (11.7%), anti-jo-1 (5.9%), and ANA (64.7%).

Among all, 35.2% of the patients with positive muscle biopsy, and 100% with positive EMG results showed complete remission, 70.6% of patients who received methotrexate, hydroxychloroquine, and rituximab, 100% receiving prednisone, 5.9% receiving cyclophosphamide, and 35.3% receiving IVIG exhibited good clinical regression of the disease.

Involvement of the respiratory system (OR=3.89, 95% CI: 0.53-31.4, p=0.180), and positivity of ANA (OR=3.21, 95% CI: 0.52-10.53, p=0.092) was statistically significant.

Earlier studies describing the manifestations and clinical presentations of IIM published from the Western countries and East Asia include only vague characteristics of such diseases in Arab and Mediterranean populations.

In this study, we present the largest series of Arab IIM patients in the Eastern Mediterranean region reporting clinical and laboratory features as well as any association with malignancy, and also determining the patient and treatment related prognostic factors.

Our study comprised 28 consecutive patients without prior selection based on clinical presentation, which tends to be representative of IIM patients.

Determining a true age at onset of the disease is difficult to establish as many inflammatory myopathies have an insidious onset and early course.

In this study, we found a mean age at diagnosis of 37.70 ± 17.17 years, and the female:male ratio was 3:1. This is in accordance with Arabian Studis in Riyadh and Jordan where the mean age of onset was 37.3 ± 16.3, and the female:male ratio was 2.7:1 and 34.3 ± 9.2 years, and female:male ratio was 1.7:1 [14,18] and differing from data reported by Chinese [19] and Tunisian [20] studies showing higher ratio and mean age.

Our analysis showed a PM predominance of (32.14%), consistent with the American and European reports [21-24], and in contrast to a Chinese study [19], which showed a DM predominance.

Generally, our results as compared to previous reported studies show clinical feature similarities. The most common clinical presentation was muscular weakness with predominance of proximal myopathy in (93.9%) followed by arthralgia/arthritis (82.1%), both with a higher prevalence than other studies [14,19]. Several nonmuscular manifestations have been wildly described, and dysphagia is the most common among all [6,7,23,25,26], it is noted that we have lower prevalence of dysphagia (35.70%) than other studies [14,27] which could be contributed to early diagnosis and intervention.

The involvement of other organs with IIM has been well established, and we report consistent results [28]. Reinforcing the ideal comprehensive approach to patients with IIM, not only focusing on musculoskeletal involvement.

An association between IIM and malignancy has been widely reported in the literature [26,29-31] with a variety of types in different populations. It is suggested that malignancies usually associated with IIM in order are: ovarian cancer, lung cancer, and pancreatic cancer. The predominance of Nasopharengeal carcinoma (NPC) in the Asian population [32-35] could be because (NPC) is endemic to southeastern Asia, and is related to the chronic active infection of Epstein-Barr virus [36-39].

Our data showed 3 patients had malignancies (10.7%), a female with breast cancer and 2 male patients, one with nasopharyngeal carcinoma and one with non-hodgkin lymphoma. This low malignancy prevalence could be due to the lower mean age at presentation compared with other reports. Genetics or environmental differences may also have played a role.

Importantly, most of our patients had PM, and many studies have shown a strong association between DM and malignancy compared with lower malignancy prevalence in patients with PM [33-47].

Muscle enzyme, ESR, and EMG results were comparable with previous reports. The muscle biopsy results showed no significant difference, and were positive in (42.9%) and negative in (57.1%) in contract to other studies reporting a positive result in approximately (80%) of patients [6,48]. The ANA positivity varies from (40% to 60%) in the previous literature [6,49,50], and in our group ANA was positive in (53.6%) of patients. The anti-jo-1 antibody was positive in (7.1%) of patients, and this low percentage is not consistent with other reports of (16.1% to 23%) positivity [51,52], in our retrospective study (64.7%) with ANA went into remission can be explained with early diagnosis and initiation of treatment ,needs larger study to prove this observation.

Rheumatoid factor was positive in (10.7%) of patients and this percentage was closed to previous study [53]. Though anti ds DNA and anticardiolipin antibodies were not evaluated in previous studies, it was positive in (10.7%) of our patients may be due to high number of overlap syndrome we had in this study.

Regarding treatment, the number of patients treated with oral corticosteroids, hydroxychloroquine, and cyclophosphamide were comparable to a previous analysis of 109 patients with DM [54]. We identified that patients who received steroids exhibited an impressive improvement in their symptoms (71.4%; p=0.023) reinforcing the most favorable outcome achieved with steroid treatment [10,11]. The percentage of patients treated with methotrexate was higher than previous study (57% of our patients compared with 34% in other study [54]). A Brazilian study [54] reported clinical relapse in (53%) of patients, which differs to the (39.3%) found in our study.

On the basis of our results, patients who relapsed had other comorbid diseases such as hypertension (OR: 0.059; 95% CI: 0.006-0.628).

Previous studies did not explore improvement of muscle power as a prognostic factor for the disease, and our study revealed normalization of muscle power in (71.4%; p=0.023). This reliable prognostic factor may help physicians to assess the efficacy of their treatment and monitor progression of the disease.

Our study has several limitations due to its retrospective design and small sample size. A longer follow up would intensify the outcome. A low prevalence of IIM was an issue, which may have led to overstatement of the results. Mortality was not assessed. Different subgroup of IIM outcome is lacking primary IIM or IIM related to malignancy/associate with other connective tissue diseases.

We recommend conducting large multiregional prospective cohort studies with long follow up duration.

In conclusion, our results showed similar clinical features to previous reviews. We found lower malignancy prevalence compared with studies from America, Europe, and East Asia, and a strong relation between comorbid illnesses and remission. Normalization of muscle power is a reliable prognostic factor that may help to assess the efficacy of patient treatment and to monitor disease progression.