Clinical Aspects of Overlap Syndrome-Case Report and Literature Review

We report a patient with overlap syndrome (systemic sclerosis (SSc) and polymyositis (PM)). The heterogeneous nature of systemic sclerosis may lead to a great diversity in the clinical presentation of the disease. With this case report we aim to demonstrate clinical manifestations of systemic sclerosis and polymyositis in an overlap-syndrome, with support from antibody profile and laboratory data.

A 51-year old female patient came to the Pulmonology Ward in 2015 complaining of shortness of breath and reduced exercise tolerance for approximately 1 year.Clinical examination revealed a rash on the neck that spread throughout the upper part of thorax, in addition to swollen, reddish fingers with skin stiffness on the hands.The patient also suffered from a swollen face and swollen eyelids.On auscultation, crackles were heard in the lower lung fields.On X-ray, changes in the interstitium were seen, and computer tomography confirmed fibrotic areas located peripherally in the lower lobes.In HRCT (high definition computer tomography) fibrosis was found in both lungs peripherally in the lower posterior lobes.The most exacerbated patches of fibrosis were present in the eighth segment of the lung and the lung uvula.These changes drew upwards in the distal segments of the subsegmental bronchi and the diaphragm.Small lymph nodes were present in the aortopulmonary window, in the front of the mediastinum, in recesses and under the carina (Figure 1).However, tests of respiratory functions were normal.An echocardiography revealed some features, which suggest pulmonary arterial hypertension (PAH), but a right heart

Discussion with A Review of the Literature
In this study, characteristic skin, muscle and organ changes as well as characteristic laboratory and imaging data allowed us to diagnose systemic sclerosis (SSc) with polymyositis (PM).Initially only skin stiffness was present, while muscle involvement presented 12 months later.Typical skin changes (stiffness of the hands and face, including microstomia, microhelia and telangiectasia) are often observed in the course of SSc [1].The skin is characterized by vascular obliteration and fibrosis of the skin, giving it a firm and taut character [2,3].The scale used in the assessment of skin involvement is the modified Rodnan skin score (MRSS).Skin thickness is assessed at 17 different anatomical locations by palpation, and is then rated on a scale from 0-3 (where 0 represents normal skin, 1-mild, 2 -moderate, and 3 -severe skin thickening) [4].Total amount of individual scores from each location is correlated with disease progression over time [4,5].In this case, the MRSS was low ( which can expand to hands and forearms [1,2].It is associated with a more benign course than the diffuse type, with organ involvement occurring only late in the disease [2,3].The type of dcSSc has skin sclerosis extending proximal to the wrists, characteristically to the trunk and proximal limbs [3].It is characterized by skin thickening developing over the first 3-12 months [2] and severe internal organ involvement early in the disease, leading to a high mortality rate [3]. In this case, the patient had a clinically apparent decrease in muscle function with elevated levels of creatine kinase and aldolase.The elevated muscle enzymes and clinically evident muscle involvement (weakness estimated using the Lovet scale) as well as PM-Scl antibodies enabled us to diagnose an overlap syndrome consisting of SSc with an inflammatory myopathy.Increased creatine kinase and aldolase levels in the clinical picture of systemic sclerosis is strongly suggestive of muscle involvement [6]; however, the absence of increased creatine kinase and aldolase levels does not exclude myositis [7].There is no general consensus of how to classify the different types of myopathies associated with systemic sclerosis, as they can be analyzed based on histological findings, degree of clinical severity, response to corticosteroid therapy, electromyographic (EMG) patterns or MRI findings [6,7].
Skeletal muscle involvement influences the quality of life and debilitates daily functioning [8].However, muscle weakness without cardiac muscle changes has not been shown to increase mortality rate [9].Conversely, muscle involvement in SSc is associated with a higher risk of myocardial complications [10], and an involvement of the heart would lead to a dramatic increase in 5 year mortality rates of up to 70% [11].
In SSc, the course of disease may be predicted when evaluating the specific antibody profile.Several antibodies has been linked to a certain type of disease progression.The more general antibodies that suggests SSc are mainly antitopoisomerase -anti-Scl-70 or ATA; anti-centromere antibodies and anti-RNA polymerase III antibody -ARA [5,12].Our patient was found to be ANA positive with a titer of 1:5120 (the patterns of nuclear staining was patchy and nucleolar), which is positive in up to 88% of patients with scleroderma [12].The systemic sclerosis antibody profile also revealed the presence of the antibodies anti-Scl-70 and anti-PM-Scl.The anti Scl-70 autoantibody, also called the anti-topoisomerase 1-autoantibody after the type 1 topoisomerase target [13], is highly characteristic for SSc.The specificity of this marker is over 98% but the sensitivity is generally low (26-28%) [5].In addition, it has been observed that anti-topoisomerase 1 antibody is associated with severe pulmonary fibrosis [14,15].
Other antibodies which have been detected in this patient are the anti-PM-Scl antibodies.These antibodies are found in polymyositis, dermatomyositis and systemic sclerosis, usually in overlap syndromes with varying predominating symptoms [16][17][18].They are present only in 3% of patients with SSc and up to 25% in patients with overlap syndromes (SSc with PM or Ssc with dermatomyositis -DM) [16,19].The anti-PM-Scl antibodies can be further subdivided into two major subgroups, the anti-PM-Scl-75 [20] and the anti-PM-Scl-100 [21].Anti-PM-Scl-75 antibodies are more common in patients with dcSSc and are associated with a higher prevalence of lung involvement, joint contractures and muscular atrophy than anti-PM-Scl-75 negative patients.Besides, anti-PM-Scl-75 antibodies reveal greater association with digital ulcers [22].The anti-PM-Scl-100 positive patients have a higher diarrhea, regular emesis or constipation [22].The most common symptoms reported by patients with the anti-PM-Scl antibody are muscle weakness, Raynaud's phenomenon and arthritis [23].
Nailfold capillaroscopy (NFC) is a helpful method used in the diagnosis of SSc and later in the course of the disease as an indicator of disease activity [24,25].This method is a non-invasive and useful technique used in the detection and follow-up of autoimmune rheumatic diseases [24].Usually this method is used to differentiate primary Raynaud's phenomenon from secondary Raynaud's phenomenon [25].In this case, NFC has been done to analyze the vascular pattern of the patient.We found a disorganized distribution of the normal distribution of capillaries, twisted enlarged capillaries and capillary hemorrhages (extravasates), enlargement of capillary loops, and 'budding' ('bushy') capillaries.Such changes are observed in systemic sclerosis as well as in polymyositis [26].NFC is one of the examinations recommended as a part of the screening and monitoring of progression in SSc [27], and such a regiment has also been planned in this patient.
In this case, the patient reported a decreased exercise tolerance with dyspnea and chest pain a year before imaging studies.Factors affecting the outcome of an exercise tolerance test in patients with SSc and ILD needs further investigation.However, early identification of pulmonary involvement is essential, especially considering how insidious and heterogenous SSc-ILD can be.When a patient suspected of SSc presents with pulmonary findings on examination, several measures can be done to investigate the pulmonary involvement.One of them includes the pulmonary function tests (PFT), which on spirometry usually demonstrates a restrictive pattern representing the parenchymal involvement.Changes in the pulmonary function test can occur even before onset of significant clinical symptoms, therefore it should be frequently used as a screening measure [39].In our patient, spirometry revealed a FEV1 of 85% and the Tiffeneau test (the ratio of FEV% to FVC) was within normal ranges (values lower that 70% suggest obstruction).FVC is found to be reduced in 40-75% of patients with SSc [40].There is no clear correlation between a decreased FVC (which is the gold standard test to evaluate ILD) and a decreased exercise tolerance test [41].The pathophysiologic background of a reduced exercise tolerance test in patients with SSc and ILD is thought to be multifactorial, with a constellation of variables such as reduced oxygen diffusion across the alveolar membrane [42], vasodilatory failure in response to exercise [49] and diagnosed PAH [51].However, simple measurement such as the 6 minute walk test (6MWT) is a reliable prognostic factor for patients with SSc and PAH, but not in patients with SSc and concomitant PAH and ILD [34].The 6MWT is a viable test as a marker of disability in patients with SSc-ILD.Although nonspecific, it might be used to monitor endurance and stamina as a general indicator of disease progression [35].However, some authors considered that this test has limited use.Many variables can influence the results, ranging from muscle function, pulmonary function, neuromuscular junction functioning to technician skill and patient motivation [36].The 6MWT of this patients was within the recommended values [37].
The screening spirometry should include diffusing lung capacity of carbon monoxide (DLCO), a parameter shown to have a negative correlation with parenchymal inflammation which results in thickening of the interstitium and poor diffusion capacity.In fact, a decreasing DLCO has been shown to be the single most important marker for poor outcome, which elucidates disease progression [38].Fortunately, in this case, the DLCO was only slightly decreased (lower than 80%).
In this patient, evident changes of interstitial lung disease (ILD) were present (Figure 1).The occurrence of ILD in the course of systemic sclerosis (SSc) is fairly common, with evidence of interstitial changes in the lungs being reported in up to 91% of patients with scleroderma who had undergone a HRCT [39].Degree of fibrosis detected on HRCT has been proven to predict future forced vital capacity (FVC%) decline in the absence of effective treatment [40].ILD secondary to systemic sclerosis is throughout literature regarded as the leading cause of morbidity and mortality in SSc.During the last 30 years a paradigm change has occurred regarding the leading cause of death in SSc.Previously, SRC (scleroderma renal crisis) was the leading cause of death in patients with SSc.However, now as SRC is effectively treated with ACE-I, pulmonary fibrosis has emerged as the leading cause of mortality with pulmonary arterial hypertension (PAH) coming second [41].
Pulmonary involvement in systemic sclerosis can be divided into two subtypes, SSc-ILD and PAH.There are some evidence showing that the specific subtype of pulmonary involvement can be linked with subtypes of systemic sclerosis.Pulmonary fibrosis were found to be more common in patients suffering from dcSSc with a prevalence of 53.4% compared to lcSSc with 34, 7%.On the other hand, isolated PAH (in the absence of lung fibrosis) was found in 45% of patients with lcSSc and only 26% of patients with dcSSc [42].Interestingly, pulmonary disease may even occur in the absence of skin involvement as an entity known as scleroderma sine scleroderma (ssSSc).In such cases idiopathic ILD is usually diagnosed; however, the presence of Raynaud's phenomenon, telangiectasias and positive antinuclear antibodies supports the possibility of ssSSc [49].It has to be pointed out that SSc-ILD is a very heterogeneous disease.It may affect any aspect of the respiratory tract, and it may present itself at any time during the course of systemic sclerosis [51].Occasionally, ILD may even be the initial manifestation of SSc, but in the course of the disease mucocutaneous telangiectasia, Raynaud's phenomenon and abnormal nailfold capillaries may be observed [43,44]).
It is of importance that the concurrent appearance of PAH with evidence of pulmonary fibrosis is common in SSc and overlap syndrome associated with SSc.In a study conducted by Demir et al., the reported incidence of PAH in SSc patients were reported in 24.1% patients; however only one-fifth from this group had only PAH, while the rest of patients had PAH associated with ILD [48].Data was reported by Lefèvre et al., who found that the pooled 3 year survival rates in patients with SSc and only PAH were 59%, while the same survival rate in SSc patients and concomitant PAH and ILD were only 35% [48].Authors of this review pointed that a greater score in the NYHA classification were associated with a worse prognosis in patients with SSc and only PAH.Nevertheless, NYHA classification were not a prognostic factor in patients with SSc associated with pulmonary hypertension and ILD [48].
In conclusion, patients with SSc with associated PAH and ILD are characterized by a higher mortality rate than patients with SSc or single PAH [34,45].In this case, HRCT showed bilateral reticular abnormalities and honeycombing with peripheral distribution in lower lobes.HRCT is an essential part of routine evaluation of SSc-ILD.Abnormalities on HRCT was found in 55-65% of all patients with SSc, and as high as 96% in patients with abnormalities on PFT.SSc-ILD presents typically on HRCT as ground-glass opacities (GGO) mixed with a pattern of pulmonary fibrosis, compatible with the nonspecific interstitial pneumonia (NSIP) pattern [49].However, 11-37% of patients with SSc-ILD was reported to have honeycomb cystic changes, which a pattern more consistent with usual interstitial pneumonia (UIP) [51], so overlapping of the patterns may be seen.
One might argue that HRCT should be done as soon as possible after an initial diagnosis of SSC, even in the absence of pulmonary symptoms.As previously mentioned, SSc-ILD may be present on HRCT long before clinical symptoms.In a serial study done on 90 patients with SSc, 40 was found to be clear of pulmonary fibrosis on the initial scan, while 35 (88%) continued to be free of pulmonary fibrosis on HRCT on follow-up for an average of five years [48].HRCT may be used as a predictor of long-term prognosis with regard to SSc-ILD.
Other diagnostic tools worth mentioning are bronchoalveolar lavage fluid (BAL-fluid).BAL-fluid analysis has been an issue of debate.Even though the procedure is relatively safe, the findings seem to be nonspecific.Nonetheless, significant BAL lymphocytosis or eosinophilia may provide good support for a clinical diagnosis when combined with other diagnostic and clinical findings [49].In 2012, The Official American Thoracic Society Practice Guideline released a report concluding that a BAL-fluid analysis frequently provides clinically useful information when the BAL-fluid is gathered under guidance from a HRCT, and the data obtained is used in conjunction with clinical information [51].
Echocardiography revealed a low TAPSE value and a thickened free wall of the right ventricle.This led to a suspicion of pulmonary hypertension (Table 1).Thus, the patient was admitted to the department of cardiac surgery, where a right heart catheterization (RHC) was performed.A slightly elevated systolic right ventricular pressure (RVP) was observed; however, mean pulmonary arterial pressure (mPAP), cardiac index (CI) and pulmonary vascular resistance (PVR) were within recommended values.

Patient Result Normal Range
Biochemical Analysis WBC [10 hypertension disorders and is the diagnostic gold standard for pulmonary hypertension [51].After an analysis of above mentioned data, pulmonary hypertension was excluded; however, the patients is under regular cardiologic control (Graph 1 and 2).Graph 2: Organ specific approach for diagnosis and management of scleroderma and polymyositis overlapsyndrome.

Prognosis and Treatment
A prognostic algorithm has been suggested by Goh et al. that measures baseline PFT and HRCT, with the purpose of differentiating patients with extensive and limited disease.Patients with >20% abnormalities on HRCT are considered to have extensive lung disease, while HRCT abnormalities <20% are considered limited.If the HRCT is inconclusive, FVC <70% is regarded as extensive lung disease while >70% is regarded as limited.Patients with extensive lung disease have been found to have a much higher mortality rate and more progressive lung deterioration [51].The five-year survival rate for SSc-ILD is estimated to be 85%, and early death is relatively uncommon [52].In contrast to idiopathic interstitial pneumonia, survival rates does not differ between the pathological patterns of NSIP and UIP [30].It is of great importance to recognize patients who are at risk to develop extensive SSc-ILD due to the fact that mortality rates are so much higher and treatment should be initiated as early as possible.Risk factors such as sex, race and antibodies such as anti-topoisomerase-1 which have been discussed previously has to be taken into account [53].Besides, it has been suggested that patients with SSc-PM overlap-syndrome have an increased risk of mortality due to ILD and cardiac disease when compared to the single entities of either systemic sclerosis or polymyositis [54].
The patient was treated with cyclophosphamide (CYC) and low dose glucocorticosteroids, which is considered as the current mainstay of treatment in SSc-associated ILD.The effect of cyclophosphamide on forced vital capacity (FVC) in patients with SSc and ILD was significant but modest [55,56] with an observed reduction of dyspnea but without effect on DLCO rates [57].There is no treatment that can reverse lung fibrosis, therefore the viable treatment used in SSc-ILD is focused on the preceding inflammation that is thought to lead to fibrosis.In this case, and Biomedical Research-http://archclinbiomedres.com/ -Vol. 2 No. 4 -Aug 2018.[ISSN 2572-5017] 118 catheterisation did not confirm the PAH.Diffusing capacity of lung carbon monoxide (DLCO) was measured, with a result of 6.47 mmol/min/KPa.

Figure 1 :
Figure 1: Chest HRCT showing bilateral reticular abnormalities and honeycombing with peripheral distribution in lower lobes.

Table 1 :
[44,45]ica4 parameters and echocardiography measurements of analysed patient.Besides, a ratio of PVR to SVR was low and ranged at 0.017 (the value PVR/SVR over >0.75 indicates significant pulmonary vascular disease).The amount of mPAP over 25 mmHg, elevated pulmonary vascular resistance over 3 Wood Units and decreased cardiac output are characteristic for PAH[3 Hoeper,4Galiè][44,45].Fortunately, such changes were not present in this case.It has to be underlined that RHC plays a central role in identifying pulmonary