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Home , Lupus erythematosus, Scleroderma

CASE REPORT Ref: Ro J Rheumatol. 2018;27(2) DOI: 10.37897/RJR.2018.2.6 – : CASE REPORT Gabriela Ticu1, Marius Ioan Balea2, Camelia Badea1,3, Adelina Silvana Gheorghe1,4, Ruxandra Patrascu1,3 1Internal Medicine Department, Colentina Clinical Hospital, Bucharest 2Pneumology Department, Colentina Clinical Hospital, Bucharest 3Carol Davila University of Medicine and Pharmacy, Bucharest 4Prof. Dr. Alexandu Trestioreanu Institute of Oncology, Bucharest

Abstract The overlap syndromes are a diverse group of conditions that usually have characteristic features of at least two well-defined rheumatic diseases occurring together. We present the case of a 32-year-old patient who sequen- tially develops manifestations of systemic and systemic sclerosis. The first manifestation of the disease was the and, over time, the patient associated various other complications which influenced the diagnostic course. Digital ulcerations associated to scleroderma have evolved into ischemic necro- sis lesions, requiring amputation. This case is a clinically suggestive example of the complexity of autoimmune diseases, of associations between pathologies and unexpected evolutions, requiring constant and long-term follow-up of the patients.

Keywords: systemic lupus erythematosus, serositis, systemic sclerosis, digital ulcers, overlap syndrome

INTRODUCTION CASE PRESENTATION Clinicians are often challenged by the clinical is- We are presenting the case of a 32 years old sues when confronting with patients who either pres- woman, ex-smoker (10 pack-years, quit smoking 3 ent an undifferentiated rheumatic disease or an over- years ago), with class III obesity (body mass index lap syndrome. In the medical literature, it is 58.2 kg/m2) and a history of abortion on demand one appreciated that approximately 25 percent of pa- month prior to the admission at the hospital. She de- tients with rheumatic diseases cannot be definitely scribes left posterior thoracic pain, night rigors, fe- diagnosed with a single well-characterized systemic ver (38.5ºC), followed by decreased effort tolerance rheumatic disease (1,2). Moreover, some of them re- and dyspnea on minimal exertion, installed two main undiagnosed for a long period of time, despite weeks before presentation. The patient also com- plains of morning stiffness, especially in the periodical reassessments and expectant management wrists, which had intensified in the last month. (1,2). It happens due to the fact that this category of From the pathological personal history, it is worth patients exhibits several patterns, manifesting multi- mentioning that the patient followed 6 months of tu- ple nonspecific serologic or clinical abnormalities, berculostatic treatment, 9 years ago, for positive sometimes of more than one defined disorder. Some Mantoux tuberculin test, but without suggestive examples include rheumatoid – lupus (rhu- chest radiography or confirmation of tuberculosis pus), scleroderma – /, through sputum smear microscopy. scleroderma – lupus, scleroderma – rheumatoid ar- Physical examination on admission to the hospi- thritis, Sjögren‘s syndrome overlaps and others (1). tal revealed that the patient was afebrile, tachypneic

Correspondence address: Gabriela Ticu, Colentina Clinical Hospital, 19-21 Stefan cel Mare Road, Sector 2, Bucharest, Romania E-mail: [email protected]

84 ROMANIAN JOURNAL OF – VOLUME XXVII, NO. 2, 2018 ROMANIAN JOURNAL OF RHEUMATOLOGY – VOLUME XXVII, NO. 2, 2018 85 with a respiratory rate of 24 breaths per minute and diaphragmatic recess. The rest of the investigations tachycardic with a ventricular rate of 104 rhythmic (electrocardiogram, echocardiogram, abdominal and beats per minute (regular rhythm). The vesicu- pelvic ultrasound, lower extremity veins Doppler ul- lar murmur was abolished with dullness to percus- trasound) did not show any relevant particularities. sion over left base and decreased breath sounds The patient underwent thoracentesis of the left bilaterally. A bilateral could also be ob- pleural effusion. The fluid obtained had the charac- served. The blood pressure was normal, without pul- teristics of an exudate, with 2.400 cells/mm3, 46% monary crackles, cardiac murmurs or extra sounds neutrophils and 27% lymphocytes, but with negative and no evidence of arthritis or . bacterial cultures. Examination by Ziehl-Neelsen Since the onset of symptoms, prior to the admis- staining did not reveal acid-alcohol-resistant bacilli, sion in the hospital, the patient presented to the gen- the level of adenosine deaminase in the effusion liq- eral practitioner, who recommended chest radiogra- uid was normal and Mycobacterium tuberculosis phy, computed tomography (CT) scan of the thorax DNA was not detected by polymerase chain reac- and pleural ultrasound. At these investigations, a tion. Also, the histopathological examination of the pleural biopsy was normal. small pleural effusion was discovered in the left Despite having received antibiotic (ceftriaxone), lung, along with atelectasis aspect or pulmonary pa- anti-inflammatory and antialgic (celecoxib) treat- renchyma condensation (Fig. 1). No direct or indi- ment, subfebrility persisted, only with a minimal im- rect signs of pulmonary embolism have been detect- provement of the thoracic pain. ed. After 10 days, the patient was admitted again in The episode was interpreted as the an intercurrent the hospital for paroxysmal nocturnal dyspnea, per- respiratory infection, with secondary pleural reac- sistence of the thoracic pain and dyspnea on minimal tion and the patient received broad-spectrum empiric exertion. Clinical examination and several investiga- antibiotic therapy: 6 days of levofloxacin, followed tions (thoracic ultrasound, echocardiography and CT by 3 days of ciprofloxacin and 5 days of drug com- scan) led to the discovery of pericardial and bilateral bination (gentamicin, amoxicillin/clavulanic acid pleural effusions. During thoracic ultrasound, an im- and metronidazole). Under this treatment, she con- portant right diaphragmatic elevation with low mo- tinued to develop (38.2-38.5ºC). bility of the diaphragm was also noticed. We identified an important inflammatory pro- The serological tests revealed positive anti-nu- cess, based on the elevation of serum biomarkers: clear , C3 hypocomplementemia, pres- C-reactive protein (146.55 mg/L), erythrocyte sedi- ence of and high-titer anti-cardi- mentation rate (61 mm/1h) and fibrinogen (915 mg/ olipin IgM antibodies (antiphospholipid dL). The showed discrete ane- positivity). Anti-double stranded DNA (dsDNA) an- mia, thrombocytosis, without leukocytosis or leuko- tibodies, anti-Ro antibodies, anti-beta2-glycoprotein penia. Serum creatinine and microscopic urinalysis I IgG antibodies, anti-cardiolipin IgG antibodies were normal. were negative, as well as the rheumatoid factor and We also performed chest radiography after ad- direct Coombs test. mission, which revealed the same aspect of pleural These three immunological criteria, added to the effusion in small amounts, located in the left costo- forth clinical criterion (serositis, consisting in pleuri-

FIGURE 1. Chest radiography and computed tomography scan of the thorax showing small pleural effusion in the left lung (with a maximum of 2 centimeters in transversal diameter at the ultrasound examination) 86 ROMANIAN JOURNAL OF RHEUMATOLOGY – VOLUME XXVII, NO. 2, 2018 sy and pericarditis), led to the classification and then The switch in the patient’s dominant signs and diagnosis of systemic lupus erythematosus (SLE) symptoms guided us to discover a second autoim- with minimal articular involvement (based on the mune illness: systemic sclerosis (SSc) or scleroder- aforementioned morning joint stiffness) – according ma. Meeting the classification criteria for two sepa- to SLICC (Systemic Lupus International Collaborat- rate well-characterized rheumatic diseases, SLE and ing Clinics) classification criteria 2012. Due to the SSc, we came to the final diagnosis of overlap syn- presence of progressive dyspnea, accompanied by drome between the two diseases. pleuritic , diaphragmatic elevation and The patient received treatment with corticoster- lung volume reduction, we suspected a rare compli- oid, anti-malaric, sulodexide and pentoxifylline, as cation associated with lupus, the shrinking lung syn- well as topical dermatological preparations for the drome, but this has not been confirmed. ischemic lesions. She was advised to avoid cold ex- Under treatment with systemic posure and to quit smoking. No further actions were (Dexamethasone, followed by Methyl-prednisolone) taken for the next 5 months, as the patient did not and anti-malarial drug (), the present to the hospital for immunosuppressive thera- patient had a favorable evolution, both clinically and py and association of anticoagulation. During this biologically. time, she underwent gynecological assessments in Over the following two months, the patient did the private healthcare system. The cervical biopsy not experience fever, dyspnea or thoracic pain, so we showed the presence of an intraepithelial squamous advised her to continue the treatment with corticos- lesion, positive for Human papillomavirus DNA teroid and hydroxychloroquine as well as to lose (high-risk genotype). weight. At the following admission to the hospital, the The patient was admitted to the hospital again, physical examination showed that the lesions of is- after two and a half years when she presented acro- chemic necrosis had advanced. Using an endovagi- cyanosis with trophic changes and ulcerations in the nal ultrasound, pelvic intraperitoneal fluid and ovar- distal phalanges of the , persistent over the pre- ian inhomogeneous tumoral mass were detected, vious months. Meanwhile, she underwent gastric without a concrete diagnosis of the gynecological sleeve surgery and started smoking again. findings. Physical examination on this admission to the The previously suggested line of treatment was hospital found a normoponderal patient (body mass index 23.44 kg/m2) with puffy , applied: we added acenocoumarol for the ischemic of the fingers, digital tip ulcers, fingertip pitting necrosis lesions and started the intravenous cyclo- , severe acrocyanosis of the hands and telangi- phosphamide pulse therapy, at a dose calculated ac- ectasia. cording to the weight and body surface. Immunological markers showed low C3, normal By the time of administrating the second cyclo- levels of anti-centromere and anti-La antibodies, ab- phosphamide pulse therapy, the patient presented sence of lupus anticoagulant and absence of cryo- with extensive digital necrosis (first, second, third globulins. The other serological tests had resulted to fingers of the left hand and second, third, fourth of be the same as the ones from the previous admission. the right one). We considered that the clinical evolu- The electrocardiogram revealed a minor form of tion of peripheral ischemic lesions has dramatically right bundle branch block, while a slight interven- worsened, which is why we suggested it was appro- tricular septum hypokinesis had been seen on heart priate to amputate the necrotic lesions, discontinue ultrasound. There were no radiological changes on the pulse therapy and revalue the hand radiography, but nailfold capilloscopy brought patient’s status after surgery. She was then admitted to light a “late” scleroderma pattern. in the plastic surgery department for debridement Changes in pulmonary imaging were suggestive therapy of the wounds; systemic vasodilator treat- of (diffuse “ground-glass” opacification, ment and amputation of the distal phalanges of fin- pulmonary alveolar infiltrates and bronchiectasis). gers II and III (right hand) were necessary. In addition, alveolar-capillary membrane diffusing After 2 months, the patient presented for continu- capacity was normal. Pelvic ultrasound by transab- ation of cyclophosphamide pulse therapy, when cou- dominal evaluation showed abnormal uterus and pled repetitive monomorphic supraventricular and right ovarian masses, therefore we recommended a ventricular extrasystoles were observed for the first pelvis magnetic resonance imaging (MRI) scan. time on the electrocardiogram. ROMANIAN JOURNAL OF RHEUMATOLOGY – VOLUME XXVII, NO. 2, 2018 87

FIGURE 2. Raynaud‘s phenomenon (acrocyanosis), 3 months after the amputation of distal phalanges of fingers II and III from the right hand

Another month later, the evolution of the patient ver, the patient also underwent periodical ophthal- seemed to be favorable, without dyspnea, arthritis, mological monitoring and she did not manifest any , , but with severe and persistent changes. acrocyanosis in the hands and feet, along with After two months since the sixth cyclophospha- acroparesthesia at cold exposure (Fig. 2). mide pulse therapy, the patient was admitted again to The patient developed atrial flutter with variable the hospital for the seventh block, heart rate ranging from 60 to 90 beats per administration. On the electrocardiogram, sinus minute and value of the systolic blood pressure be- rhythm was maintained, with coupled supraventricu- tween 80 and 90 mmHg. On repeated electrocardio- lar extrasystoles and a heart rate of 70-80 beats per grams, atrial arrhythmia remained present and there- minute. fore we associated a non-dihydropyridine calcium We initiated dual receptor antagonist channel blocker to the treatment strategy. Be- () therapy for preventing further digital ul- ta-blocker was not added, due to the severe peripher- cers caused by SSc, and the patient would be reeval- al manifestations. uated in one month. On initiation, we performed an The following four cyclophosphamide pulse assessment of the digital tip ulcers and fingertip pit- therapies took place without any adverse reactions ting scars of the hands: ulcers were not present, only or supplementary findings, considering that the clin- scars without calcification in right IV (4 mm), ical progression was favorable. At the last admission right finger V (3 mm), left finger I (5 mm), left fin- to the hospital, there was no evidence of atrial flutter ger II (11 mm), left finger III (4 mm), left finger IV on the electrocardiogram, but several coupled su- (3 mm), left finger V (5 mm). We evaluated the praventricular extrasystoles were detected during HAQ-DI (Health Assessment Questionnaire Disabil- the Holter monitoring. ity Index) and VAS (Visual Analogue Scale) regard- During these admissions to the hospital, there ing the interference of Raynaud‘s phenomenon and were some constant findings: negative lupus antico- digital ulcers with daily activities. HAQ-DI score agulant, no inflammatory biological syndrome and was 0, while VAS for Raynaud‘s phenomenon was low C3 with normal C4 levels. The patient did not 10 mm and for digital ulcers 30 mm. Upon monitor- develop other complications of SSc or SLE, except ing the efficacy and toxicity response to the drug, we for Raynaud‘s phenomenon. We have been monitor- will decide whether the patient should continue the ing the possible development of pulmonary arterial treatment. , but there have not been signs of this We questioned the problem of differential diag- complication. After the last cyclophosphamide pulse nosis with mixed disease (MCTD), therapy, the SLEDAI severity score (Systemic Lu- for which some of the Alarcon-Segovia and Villareal pus Erythematosus Disease Activity Index) was 2, Diagnostic Clinical Criteria are met (edema of the which meant that the disease was inactive. Moreo- hands, Raynaud‘s syndrome and acrosclerosis). 88 ROMANIAN JOURNAL OF RHEUMATOLOGY – VOLUME XXVII, NO. 2, 2018

Consequently, we aimed to detect the presence of rospective analysis of pleural effusions, out of which anti-U1 ribonucleoprotein (RNP) antibodies (the se- 52% were associated to SLE, 9% to tuberculosis and rologic criteria for MCTD), which proved to be neg- 7% to parapneumonic processes (7). A cross-sec- ative. tional and prospective study including 2,390 SLE patients showed that fever, Raynaud’s syndrome and DISCUSSIONS anti-dsDNA antibodies were predictive factors of both pleurisy and pericarditis in SLE (6). Up to a third of patients with SLE might develop Besides pleuritis, there are also other pleuropul- another , which can have an im- monary manifestations which occur in 60-80% of portant impact on the development of damage and patients with SLE. Out of these, shrinking lung syn- mortality. (3) For example, it has been shown that drome has an estimated prevalence between 0.5% patients with SLE and other autoimmune disease and 1.1% in SLE population, more common in wom- have worse damage scores at 5 years after the lupus en (17:1 female:male ratio) (8). It is reported to be diagnosis, when compared to patients with SLE only much more frequent in advanced stages of the dis- (3). ease, but there are also rare cases of being the pre- Despite the fact that ample epidemiologic studies senting manifestation of SLE (8). There is literature on the incidence and prevalence of overlap syn- evidence of shrinking lung syndrome in patients dromes have not been done yet, there are some avail- with SLE-SSc overlap syndrome and therefore, this able data. One retrospective study which analyzed rare condition should be taken into consideration (9). 1,321 patients, demonstrated that an overlapping Rhythm and conduction disorders, along with second autoimmune illness (rheumatic or non-rheu- sudden cardiac death are important manifestations of matic) occurs in 30-52% of patients who already the cardiac involvement in autoimmune rheumatic have a diagnosis of SLE, rheumatoid arthritis, diseases. The main pathophysiological mechanisms Sjögren‘s syndrome or antiphospholipid syndrome. which leads to arrhythmias are the autoimmune pro- (4) In addition, the study shows that there is a differ- cess itself, atherosclerotic complications and even ence in terms of demographic aspects and treatment side-effects of the treatment (10). Sinus tachycardia, algorithms between patients with “pure” disease and atrial fibrillation and atrial ectopic beats are the ma- those with second autoimmune illness (4). jor cardiac arrhythmias described in SLE patients, In rheumatology, it is hard to establish criteria along with sick sinus syndrome and long QT syn- characteristic for each separate disease, due to the drome (10,11). Our patient presented with sinus lack of “gold standards”. Different criteria (of classi- tachycardia at the first admission to the hospital. In fication/diagnosis, response and remission) intend to some cases, sinus tachycardia may be the single guide clinicians in establishing diagnoses and choos- manifestation of cardiac involvement (11). Howev- ing the right treatment, but we sometimes have to er, in our case report, it was followed by a minor tolerate the uncertainty and avoid diagnostic labels if form of right bundle branch block and paroxysmal they are not clearly supported by established criteria atrial fibrillation. The most common heart rhythm (2). disorders in SSc are monomorphic, single premature From the beginning, the case was challenging in ventricular contractions, but also transient atrial fi- terms of differentiating between the infectious and brillation, atrial flutter or paroxysmal supraventricu- purely inflammatory process of the pleural effusion. lar tachycardia have been described in 20-30% of After ruling out the most frequent causes of exuda- these patients (11). Moreover, 25-75% of patients tive effusions (pneumonia, cancer, tuberculosis and with SSc develop conduction disturbances (bundle pulmonary embolism), an autoimmune disease was and fascicular blocks), due to fibrosis of the sinoatri- taken into consideration, as serositis is one of both al node (11). ACR (American College of Rheumatology) and There are studies that demonstrate the influence SLICC classification criteria for SLE (5). This man- of diet on SLE patients, based on the hypothesis of ifestation is not one of the most common ones in an existing molecular link between diet, gut com- SLE, but up to half of the patients (12-45%) present mensal germ populationm and immunity (12). It has with either pleurisy or pericarditis (6). Pleuritis as been shown that dietary changes can significantly the initial presentation to the hospital was found in affect the composition of gut microbiome and vi- more than one third of the patients included in a ret- rome, which possibly contributes to SLE pathogene- ROMANIAN JOURNAL OF RHEUMATOLOGY – VOLUME XXVII, NO. 2, 2018 89

sis (12). The patient from our case report has under- woman of young age, the development of paroxys- gone drastic changes in her diet, especially after the mal atrial flutter under the anticoagulant treatment gastric sleeve surgery. Caloric restriction was appre- received for peripheral ischemic necrosis and the as- ciated to have positive effects and prevent the pro- sociation of gynecological pathology, still of unde- gression of SLE, as well as other SLE associated termined etiology. The physical transformation of autoimmune diseases (12). the patient is spectacular and manifests a strong will in fighting with the disease, with a from CONCLUSIONS 149 kg to 56 kg at the present time. This case report emphasizes on the co-existence The intricate diagnostic course and the dynamic of multiple autoimmune diseases in individual pa- association of new elements have made this case to tients, a fact that clinicians should be aware of, in be a challenging one. In addition to this, the compli- order constantly to adapt the frequency and specifics cations that occurred are complex, notably the unfa- of the patient follow-up. vorable evolution of digital ulcers to amputation in a

REFERENCES

1. Panush R.S., Kramer N., Rosenstein E.D. Undifferentiated 8. Borrell H., Narváez J., Alegre J.J. et al. Shrinking lung syndrome systemic rheumatic (connective tissue) diseases and overlap in systemic lupus erythematosus: A case series and review of the syndromes. UpToDate. 2018 literature. Medicine. 2016;95(33):e4626. 2. Kelly A., Panush R.S. Diagnostic uncertainty and epistemologic 9. Guleria V.S., Singh P.K., Saxena P., Subramanian S. Shrinking humility. Clin Rheumatol. 2017;36(6):1211-1214. lung syndrome in systemic lupus erythematosus-scleroderma 3. Chambers S.A., Charman S.C., Rahman A., Isenberg D.A. overlap. Lung India. 2014;31(4):407-409. Development of additional autoimmune diseases in a multiethnic 10. Teixeira R.A., Borba E.F., Bonfá E., Martinelli Filho M. cohort of patients with systemic lupus erythematosus with reference Arrhythmias in systemic lupus erythematosus. Rev Bras Reumatol. to damage and mortality. Ann Rheum Dis. 2007;66(9):1173-1177. 2010 ;50(1):81-89. 4. Lockshin M.D., Levine A.B., Erkan D. Patients with overlap 11. Seferović P.M., Ristić A.D., Maksimović R. et al. Cardiac autoimmune disease differ from those with “pure” disease. Lupus arrhythmias and conduction disturbances in autoimmune rheumatic Sci Med. 2015;2(1):e000084. diseases. Rheumatology (Oxford). 2006;45(Suppl4):iv39-42. 5. Porcel J.M., Light R.W. Diagnostic approach to pleural effusion in 12. Vieira S.M., Pagovich O.E., Kriegel M.A. Diet, Microbiota and adults. Am Fam Physician. 2006;73(7):1211-1220. Autoimmune Diseases. Lupus. 2014;23(6):518-526. 6. Ryu S., Fu W., Petri M.A. Associates and predictors of pleurisy or pericarditis in SLE. Lupus Sci Med. 2017;4(1):e000221. 7. Palavutitotai N., Buppajarntham T., Katchamart W. Etiologies and outcomes of pleural effusions in patients with systemic lupus erythematosus. J Clin Rheumatol. 2014;20(8):418-421.