Clinics and Practice 2011; volume 1:e89

Systemic erythematosus- same patient. 1 ( PM or DM) identifies a group of Correspondence: Faten Frikha, Department of myositis : patients in whom the mascular is Internal Medicine, Hospital of Hedi Chaker, 3029 report of 6 cases the principle clinical feature often associated Sfax, Tunisia. with muscle , tenderness and wasting, or E-mail: [email protected] Fatma Maazoun, 1 Faten Frikha, 1 other form of connective tissue diseases; the Key words: overlap syndrome, systemic lupus ery - Mouna Snoussi, 1 Neila Kaddour, 1 muscle biopsy generally demonstrates areas of thematosus, myositis, classification criteria, cor - Hatem Masmoudi, 2 Zouhir Bahloul 1 muscle fibre necrosis accompanied by intersti - ticosteroid. tial and/or perivascular cellular infiltrates. 1Department of Internal Medicine, Received for publication: 22 September 2011. Myositis associated with overlap syndromes is Hospital of Hedi Chaker; 2Laboratory of Accepted for publication: 12 October 2011. usually of paroxysmal variety and has been immunology, Hospital Habib Bourguiba, associated with one or another of connective This work is licensed under a Creative Commons Sfax, Tunisia tissue disorders [Systemic Sclerosis (SSc), Attribution NonCommercial 3.0 License (CC BY- Rheumatoid arthritis (RA), Sjögren’s syn - NC 3.0). drome or systemic lupus erythematous (SLE)]. ©Copyright F. Maazoun et al., 2011 Pearson and Bohan found an incidence of 21% Licensee PAGEPress, Italy Abstract 2 of this type of myositis. Myositis is a rare com - Clinics and Practice 2011; 1:e89 plication of systemic lupus erythematous 3,4 doi:10.4081/cp.2011.e89 The incidence of myositis in patients with occurring in almost 4-16% of cases of SLE 3,5,6 systemic lupus erythematosus (SLE) is low and such association is considered to be an among different series. Here we attempt to heterogeneous condition, sometimes less describe the main features of SLE/myositis severe, 7 sometimes similar 2,3 or even worse 8 Other muscle’s investigations including overlap syndrome. We retrospectively reviewed than the primary disease. electromyography (EMG) and muscle biopsy the medical records of 174 patients with SLE Herein we report a survey of 6 patients who findings were also noted. seen over 15-year period. All the patients ful - developed overlap syndrome of systemic lupus Patients with an overlap syndrome were filled the revised American erythematosus and myositis. We attempt to subclassified into those who had a monophasic Association criteria for SLE. Patients who met analysis the epidemiological, clinical, illness (a single episode of active disease), The Bohan and Peter criteria for definite immunological features and therapeutic man - relapsing-remitting disease (disease flares myositis were included in this study. Among agement of this rare condition, which further associated with disease-free periods), chronic those patients, six patients had an associated elucidation. progressive disease (evidence of active dis - myositis (3.4% overall). They were 6 women ease despite treatment) and remission. with a mean age of 29 years (20-41 years). At the initial evaluation, 3 patients (50%) were complained from , and all patients had Materials and Methods symmetrical (proximal mus - Results cle weakness in 6 cases with distal muscle We retrospectively reviewed the medical weakness in 2 cases). The muscle disease was records of patients with SLE attending the Among a large cohort of 174 SLE patients severe in 1 case. Involvements of muscles of Department of internal medicine of The (whom 162 were females with a frequency of the pharynx and upper esophagus were noted University Hédi Chaker Hospital (Sfax, 93%) who had attended the Department of in 4 patients (66.6%). The Tunisia) between January 1996 and December internal medicine, 6 patients were found to (CK) levels were elevated in 4 cases with a 2010. All these patients fulfilled The revised have overlap of SLE and idiopathic myositis mean rate of 2153.5 UI/L. The electromyogram American Rheumatology Association criteria giving a frequency of 3.4%. Although myalgia (EMG) revealed signs of myositis in 5 cases. (ACR) for SLE. 9 Patients who had an associat - was found as a feature of SLE in 15.8% , a true Muscle biopsy, performed in 5 patients, ed myositis were included in this study. myositis defined by the Bohan and Peter crite - revealed an inflammatory changes For myositis diagnosis, we used the criteria ria was found in only 3.4% of our SLE patients. in 4 cases. Antinuclear (ANA) were proposed by Bohan and Peter for definite The mean age at presentation was 29 years positive in all cases. All our patients were myositis [dermatomyositis (DM) or polymyosi - (range between 20 and 41 years) all the treated with high doses of with tis (PM)], 10 including symmetrical muscle patients were females. SLE and myositis were favorable outcome. Relapse of SLE disease had weakness, increase in serum muscle enzymes, diagnosed at the same time in 5 cases (83.3%). occurred in 2 patients. The association SLE- characteristic electromyographic pattern, Myositis had occurred 9 months after SLE diag - myositis is rare with heterogeneous presenta - signs of myositis proven by muscle biopsy and nosis in one case. tion. Through our observations and literature in case of DM typical cutaneous rash. data we will specify the characteristics of this For each case, we studied the demographic Clinical features association. data (gender, age at onset, duration of symp - Four patients (66.6%) were symptomatic for toms), clinical features, investigations, treat - more than 2 months prior to presentation ment details, and the response to treatment. (range between 2 and 8 months). Constitu- Laboratory findings including levels of tional symptoms were the most common fea - Introduction serum creatine kinase (CK), hematological tures at disease onset. They were present in 5 details and renal function were obtained. For patients. Five patients (83.3%) had fever and 3 The term overlap syndrome includes a large immunological data, antinuclear antibodies patients (50%). had general fatigue. At the group of conditions characterized by the coex - (ANA) using HEp2 cells, antibodies directed time of SLE diagnosis, 4 of our patients istence of signs, symptoms and immunological against native double stranded (ds) DNA, (66.6%) had mucocutaneous involvements. features of 2 or more connective tissue dis - extractable antigens [Ro(SSA), La(SSB), RNP, They were photosensitivity in 4 cases (66.6%), eases and occurring simultaneously in the Sm.] were recorded. mild mucosal ulceration in 3 cases (50%),

[Clinics and Practice 2011; 1:e89] [page 189 ] Article malar rash in 2 cases (33.3%) and discoid SLE normal in one case. with SLE, true myositis is relatively rare as rash in 1 case (16.6%). Upon examination, 2 Renal biopsy was performed in 2 cases. It shown also by our study. 15 Myositis can occur patients (33.3%) had moderate arthritis (pain, disclosed aggressive diffuse proliferative lupus before, after SLE (case 2), or sporadically both swelling and tenderness in more than 2 joints nephritis (type IV) according to the World diseases can be present simultaneously (cases with some loss of function range of move - Health Organization WHO classification in one 1, 3, 4, 5 and 6 in our series). 14 ments), and 1 patient (16.6%) had pericardial case (case n°4), and showed type II lupus Several published studies had described the effusion. Neurological involvement was noted nephritis in the second case (case n°6). clinical characteristics of myositis in patients in 3 patients (50%): seizure in 2 patients and with SLE in some series 3,5,6,16 or in cases documented cerebral in 1 patient. Treatment and clinical course reports. 4,14,17,18 Our lupus myositis patients Two patients were found to have urine abnor - All of our patients had been treated with oral were all female which is concordant to the pre - malities (33.3%). prednisone (1 mg/kg/day) for 6 weeks. Then, vious studies. 3,7,14,17,19 The study reported by At the time of initial evaluation, 3 patients the dose was gradually tapered to 10 mg/day. Foot et al. 6 suggested that lupus myositis was (50%) were complained from myalgia, and all Three patients had received intravenous pulse very similar to primary disease, in contrast to patients had symmetrical muscle weakness of (1g per day for 3 days the milder descriptions of Fessel 16 and Tsokos (proximal muscle weakness in 6 cases with consecutively followed by high dose of oral et al. 5 were less than rigorous: all but one of distal muscle weakness in 2 cases). The mus - prednisone. The main indication being severe their patients with alleged myositis had a nor - cle disease was severe in 1 case with complete neurological involvement (cerebral vasculitis) mal serum CK, and only 5/18 subjects had a proximal and distal deficit in 1 case. in one case, severe myositis in one case and confirmatory muscle biopsy. Although it Involvements of muscles of the pharynx and proliferative lupus nephritis (type IV according remains unclear, some reports have indicated upper esophagus were noted in 4 patients to the WHO classification) in one case. The lat - that this overlap syndrome follows a benign (66.6%). It was a rapidly progressive ter has also been treated with monthly intra - course and that the prognosis of myositis asso - in 4 cases and a dysphonia in 1 case. One venous Cyclophosphamide pulses in associa - ciated with SLE is reputed to be better than pri - patient had typical DM skin changes tion with therapy. mary myositis in terms of morbidity and (heliotrope rash) leading to the diagnosis of Over a mean follow up of 6 years (6 months response to therapy. 20-22 However, there have DM. the other five patients were diagnosed as -9 years), the disease was monophasic illness been some controversies in the literature. having PM. in 3 cases with complete remission of both SLE Garton and Isenberg 3 have indicated, in a and myositis, relapsing–remitting SLE in 2 review of 30 cases that there is no significant Complementary investigations cases and chronic progressive SLE in 1 case. difference between patients with overlap Laboratory data Full remission of myositis had been obtained myositis /SLE and patients with primary myosi - Hematological examinations were abnormal for all cases. tis. There were no substantial deferences in in all cases. Five patients (83.3%) had lympho - The demographical, clinical characteristics, morbidity or mortality on prolonged follow-up, cytopenia, 3 patients (50%) had thrombocy - therapeutic management and outcomes of the and the clinical course was generally similar topenia and 2 patients (33.3%) had anemia. six patients are given in Table 1. for both groups. Antibodies to Jo-1 were of low Four patients (66.6%) had elevated creatine prevalence in this group, although anti-56 kDa phosphokinase at initial examination with a nRNP antibodies were seen with high frequen - mean serum CPK level at 2153.5 UI/L (range cy. Anti-56 kDa nRNP antibodies are associat - between 1003 and 3000 IU/L). Serum CPK level Discussion ed with myositis occurring together with SLE; was within normal limits in the other 2 cases. the presence of this can help to pre - Antinuclear antibodies were positive in all The existence of patients with signs and dict muscle involvement in this group of cases (range between 1/320 and 1/1280). Anti- laboratory tests results suggestive of a sys - patients. DNA native was positive in 3 cases. All patients temic but fulfilling more In other hand, in a recent study, the authors had other anti-nuclear antibodies (ANA) speci - than one classification criteria for well-defined had compared clinical and laboratory features ficities: 4 patients were positive for ribonucle - connective tissue disease is a more and more in 10 patients with SLE complicated by myosi - oprotein antibodies (anti-RNP), anti SSA frequent situation in clinical practice and tis with 290 patients with SLE without myosi - (n=4), anti-centromere (n=1), anti-Sm (n=3), define an overlap syndrome . In the literature, tis. The results suggested that patients with an anti-Scl70 (n=2), anti-histone (n=1), anti and because of the diversity of clinical symp - overlap of myositis and SLE are more likely to nucléosome (n=1), anti Ro52 (n=1), anti ECT toms, reliable data concerning the prevalence have alopecia, oral ulcers, erosive joint disease (n=1). Of the disease-specific antibodies, of overlap syndromes are not available. 11,12 and pulmonary disease but less likely to have anti-Jo-1 was detected in only one out of the 6 However, those patients appear to occur less renal disease. They found that those SLE/ patients tested. For patients who had positive frequent than patients with SLE, more fre - myositis patients were likely to die at a anti-RNP antibodies, none of them met the cri - quent than patients with systemic sclerosis younger age and that their overall disease evo - teria for mixed connective tissue disease (SSc) or idiopathic inflammatory myositis lution seems to be influenced by the presence (MCTD). (IIM). 12 In a longitudinal study of 100 patients of antiRNP autoantibodies. 23 Our lupus myosi - with IIM, Troyanov et al. found a frequency of tis patients are characterized by a frequent Electromyography and biopsy data 24% of myositis associated with connective tis - mild form of myositis with the presence on EMG was parformed in all patients. It was sue disease according to the original classifi - anti-RNP antibodies (66.6%), the frequency of suggestive of in 5 cation. 13 When using its novel classification of hematological (100%), mucocutanous (66.6%) cases, with spontaneous activity at rest, myositis, the author found that 60% of their and central neurological involvement (seizure including fibrillation potentials, positive sharp patients were classified as having overlap and cerebral vasculitis in 50%) for SLE with a waves, and complex repetitive discharges. myositis ,13 and that Systemic sclerosis was the good response to corticosteroid therapy in all Muscle biopsy, performed in 5 patients, most common disease associated with IIM. In cases. However, our study is small and poten - showed myopathy signs (necrosis and regen - the literature, SLE associated with myositis tial confounding influences must be consid - eration of muscle fibers with perivascular infil - occurs in 4-16% of cases. 14 In contrast to myal - ered. tration of mononuclear cells) in 4 cases. It was gia which can affect nearly half of patients In the primary autoimmune myositis, the

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Table 1. Summary of the demographical, clinical characteristics, therapeutic management and outcomes of our patients with systemic lupus erythematosus /myositis overlap syndrome. Case #1 Case #2 Case #3 Case #4 Case #5 Case #6 Age at onset (years)/gender 20/F 23/F 24/F 30/F 41/F 39/F SLE symptoms Hematological: Constitutional Constitutional Constitutional Constitutional Constitutional Anemia/lymphopénia symptoms: symptoms: symptoms: symptoms: symptoms: fever/ Arthritis/ fever/ Cuttaneous: fever/Oral ulcer/ fever/ fever/Oral ulcer/ Cutaneous: Pericarditis Malar rash/ Hematological: Cuttaneous: Hematological: discoid SLE rash/ photosensitivity/ Anemia/lymphopenia/ Malar rash/ Anemia Hematological: Hematological: thrombocytopenia/ photosensitivity Neurological Anemia/lymphopenia/ Anemia/lymphopenia Neurological Hematological: symptoms: thrombocytopenia/ Arthritis symptoms: seizure Anemia/ cerebral vasculitis Nephritis (II) lymphopenia/ thrombocytopenia/ Nephritis (type IV)/ Neurological symptoms: seizure/ Pericarditis Myositis symptoms PM: PM: PM: PM: DM: heliotrope PM: Proximal muscle Dysphagia/ Dysphagia/ Dysphagia/ rash/ / weakness Proximal and distal Myalgies/ Myalgias/ Dysphagia/ weakness Proximal muscle Proximal muscle Dysphonia/ weakness weakness Proximal muscle weakness Proximal and distal weakness Time of concomitant After 9 months concomitant concomitant concomitant concomitant onset of myosits/SLE symptoms Laboratory findings Baseline Baseline Baseline Baseline Baseline Baseline CK level (U/L): 19381 CK level (U/L): 54 CK level (U/l): 1003 CK level (U/L): 2673 CK level (U/L): 334 CK level (U/L): 3000 Immunological Positive ANA 1/1280 Positive ANA 1/320 Positive ANA 1/320 Positive ANA 1/1280 Positive ANA 1/1280 Positive ANA 1/1280 findings Positive anti-RNP Positive anti-RNP Positive anti-RNP Positive anti-DNA Positive anti-DNA Positive anti-DNA Positive anti-SSA Positive anti-SSA Positive anti-Sm Positive anti-SSA Positive anti-RNP Positive anti-JO1 Positive anti-Scl70 Positive anti-SSB Positive anti-Scl70 Positive anti-SSA Positive anti-Histones Positive anti-ECT Positive anti-Ro52 Initial treatment Prednisone Prednisone 1 Methylprednisolone Methylprednisolone Methylprednisolone Methylprednisolone 1mg/kg/day mg/kg/day for 6 pulses 1 g/day for pulses 1 g/day for pulses 1 g/day for 3 pulses 1 g/day for for 6 weeks then weeks then tapered 3 days 3 days days (neurological 3 days tapered to 30 mg/day to 10 mg/day Prednisone 1 mg/kg/ Prednisone 1 symptoms) Prednisone 1 day for 6 weeks then mg/kg/day Prednisone 1 mg/kg/day for 6 tapered to 10 mg/day for 6 weeks then mg/kg/day for 6 weeks then tapered tapered to 10 mg/day weeks to 10 mg/day Cyclophosphamide then tapered to pulses 10 mg/day (SLE nephritis) Outcomes (relapse) relapsing-remitting Improvement of - relapsing- chronic progressive monophasic illness monophasic illness disease/ Initial SLE and myositis remitting disease disease Improvement Improvement improvement/ symptoms - Initial improvement Complete remission with complete Relapse of SLE after infectious - 4 relapses of myositis with remission of both 2 months , under complications: of SLE symptoms normalization of diseases prednisone 30 mg/day Tuberculosis muscle function and (fever, anemia, levels serum CK pericarditis, Persistent fever myocarditi) and Anemia Mean duration of 3 years 9 years 8 years 6months 6 years 1 month 8 years and 9 months follow up SLE, systemic lupus erythematosus; F, female; PM, polymyositis; DM, dermatomyositis; anti-RNP, antibody to a ribonuclease-sensitive ribonuclear protein; ANA, antinuclear antibody.

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ANA were less commonly positive and the pres - association, the female predominance, and the 12. Gaubitz M. Epidemiology of connective tis - ence of a strongly positive ANA may lead to a variety of clinical presentation and the benign sue disorders. Rheumatology 2006;45:iii3- more diligent search for an associated autoim - course of myositis. Certainly, there are differ - iii4. mune rheumatic disease. 3 However, patients ences between overlap myositis/SLE and non- 13. Troyanov Y, Targoff IN, Tremblay JL, et al. can have a high frequency of specifically asso - overlap patients and SLE/ myositis should not Novel classification of idiopathic inflam - ciated autoantibodies to nuclear and cytoplas - be considered as a mild disease and should be matory based on overlap syn - mic antigens, termed myositis specific anti - treated as aggressively as primary myositis. drome features and autoantibodies: analy - bodies (MSA). 24 MSA are found almost in Many other questions need further study and sis of 100 French Canadian patients. patients with DM/PM and associated overlap investigations: what mechanisms induce and Medicine (Baltimore) 2005;84:231-49. syndromes. Autoantibodies detected in myosi - sustain myositis overlaps? What are the genet - 14. Rosti ć G, Pauni ć Z, Vojvodi ć D, et al. tis associated overlap syndromes also include ic and environmental risk factors that lead to Systemic lupus erythematosus and der - anti-U1 RNP, anti-Ro/SSA, anti-La/SSB, and myositis overlaps? And what new better thera - matomyositis-case Report. Srp Arh Celok anti-Sm. In general, the picture of overlap syn - pies can block these mechanisms? Lek 2005;133 Suppl 2:137-40. dromes is complex and heterogeneous. The 15. Isenberg DA, Snaith ML. Muscle disease in presence of specific autoantibody profiles is SLE: a study of its nature, frequency and certainly a useful tool in the diagnosis evalua - course. J Rheumatol 1981;8:917-24. tion of such patients. 20 References 16. Fessel WJ. Systemic lupus erythematosus Sometimes, it seems difficult to distinguish in the community. Arch Intern Med myositis associated with SLE from 1. Alarcon-Segovia D. 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