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Autoimmunity Reviews 15 (2016) 558–563

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Autoimmunity Reviews journal homepage: www.elsevier.com/locate/autrev

Review

Epidemiological, clinical and laboratory profiles of cutaneous polyarteritis nodosa patients: Report of 22 cases and literature review Paulo Ricardo Criado a,⁎, Gabriela Franco Marques a, Thamara Cristiane Alves Batista Morita a, Jozélio Freire de Carvalho b a b

Dermatology Division, Hospital das Clínicas da Faculdade de Medicina de São Paulo (HC-FMUSP), São Paulo, São Paulo, Brazil Rheumatology Division, Aliança Medical Center, Salvador, Bahia, Brazil

a r t i c l e

i n f o

a b s t r a c t

Article history: Received 1 February 2016 Accepted 8 February 2016 Available online 11 February 2016

Cutaneous polyarteritis nodosa (CPAN) is a rare disease that affects small and middle caliber vessels of the deep dermis and subcutaneous tissue and its etiopathology remains yet to be understood. Methods: Retrospective review of twenty two cases diagnosed as CPAN and confirmed by skin biopsy over the last 11 years was evaluated in our department. Results: We found predominance in white woman, mean age of 39.4 years, showing no comorbidities in most of our sample. Mean follow-up time was 58 months. The most frequent cutaneous manifestations were ulcers, livedo racemosa, subcutaneous nodules, atrophie blanche lesions and purpuras; with lower limb involvement in all cases, however other areas were also involved. The main regional symptoms were pain and paresthesia, while systemic complaints were absent in the majority of cases. Mononeuritis multiplex was identified in a quarter of our sample. Most of the laboratory findings were non-specific. There was evidence for previous contact with Mycobacterium tuberculosis in 46.1% of cases which were tested for purified protein derivative (PPD) test. In our patients the disease course was benign and without complications, and systemic polyarteritis nodosa did not develop in any patient. Conclusions: An extensive work-up including laboratory tests on autoimmunity and thrombophilic factors and investigation of infectious diseases, especially previous contact with tuberculosis agent, should be part of the CPAN investigation. © 2016 Elsevier B.V. All rights reserved.

Keywords: Polyarteritis nodosa Livedo reticularis Ulcer Systemic vasculitis

Contents 1. 2. 3.

Introduction . . . . . . . . . . . . . Patients and methods . . . . . . . . . Results . . . . . . . . . . . . . . . . 3.1. Distribution by gender and age . 3.2. Skin color . . . . . . . . . . . 3.3. Profession . . . . . . . . . . . 3.4. Follow-up beginning and duration 3.5. Comorbidities . . . . . . . . . 3.6. Clinical manifestations . . . . . 3.7. Laboratory examination . . . . . 4. Discussion . . . . . . . . . . . . . . 5. Conclusion . . . . . . . . . . . . . . References. . . . . . . . . . . . . . . . .

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1. Introduction

⁎ Corresponding author at: Rua Carneiro Leão 33, 09050-430, Vila Scarpelli, Santo André, SP, Brazil. E-mail address: [email protected] (P.R. Criado).

http://dx.doi.org/10.1016/j.autrev.2016.02.010 1568-9972/© 2016 Elsevier B.V. All rights reserved.

Classic polyarteritis nodosa (PAN) was the first systemic vasculitis described. In 1866, Kussmaul and Maier characterized this fatal condition, originally named “periarteritis nodosa”. In 1903, Ferrari pointed out the transmural nature of the arterial inflammation involving medium caliber vessels, leading him to propose the term “polyarteritis

P.R. Criado et al. / Autoimmunity Reviews 15 (2016) 558–563

nodosa”. However, it was only in 1931 that Lindberg recognized the existence of a limited cutaneous form of PAN [1,2]. Multi-organ involvement in systemic PAN is pervasive, particularly in the kidneys, heart and liver; although in most cases cutaneous findings are the first evidence of the disease. On the other hand, the cutaneous polyarteritis nodosa (CPAN), which affects predominantly the skin, could also be associated with extracutaneous findings and includes fever, malaise, myalgias, arthralgias and neuropathy. The distinction between the systemic and the cutaneous form is essential. The clinical course of CPAN is chronic, varying the number of remissions and relapses [3–7]. Its true incidence is to be yet accurately identified, affecting subjects that could be placed in all ages, ranging from infants to elderly individuals and affects predominantly women [1,3,4,8]. The etiology involved in CPAN lingers in an uncertain ground, but current knowledge advocates that it is a disorder mediated by immune complexes. Direct immunofluorescence often shows IgM and C3 deposits within affected arterial walls [1,8,9]. Furthermore, a 77.8% prevalence of IgM antibodies against the phosphatidylserine– prothrombin complex among patients with CPAN helps to embed the theory that prothrombin bound for apoptotic endothelial cells induces an immune response. This process would, then, lead to the development of anti-phosphatidylserine–prothrombin complex antibodies, which, by its turn, presumably activates the classical complement pathway to cause CPAN [9]. A large number of infectious and non-infectious entities have been associated both to the beginning and the recurrence of CPAN. Among infectious agents, the one that plays the most frequent role is group A beta-hemolytic streptococcus, especially in children [10–12]. With its relation to hepatitis B and C, HIV, B19 parvovirus and Mycobacterium tuberculosis have been pointed out, among others [13–19]. In the context of non-infectious diseases, an association with autoimmune diseases has been pointed out, such as myasthenia gravis, Chron's disease, ulcerative retocolitis and auto-immune hepatitis [20– 23]. Still, other categories are listed apart like neoplasms, vena cava thrombosis and immunization against diphtheria, tetanus and hepatitis B [24–27]. Drugs such as penicillin and tetracycline are also related to CPAN, minocyclin being the main one involved. In these cases, withdrawal of medication tends to be followed by improvement of the skin lesions [28–30]. Until present time, and to our knowledge, there are no studies concerning epidemiological data of CPAN in Brazil, making available in the literature only anecdotal case reports. Hence, our study aims to establish a database on epidemiological, clinical and laboratory information of CPAN patients admitted to the vasculitis clinics of our tertiary hospital. 2. Patients and methods This is a cross-sectional, retrospective and descriptive study; with data collection from files comprehending the period between January of 2003 and December of 2014. All files with a clinical diagnosis of CPAN were selected from the vasculitis clinics of the Dermatology Department Hospital das Clinicas da Faculdade de Medicina da Universidade de Sao Paulo (HCFMUSP), previously confirmed by histopathological study. A total of 22 cases were obtained. The histopathological findings considered had to gather the criteria described ahead: necrosis of small-sized arteries at the dermosubcutaneous junction, muscular arteries in the subcutis or arterioles in the deep dermis and/or fibrin thrombi in the vascular lumen; fibrinoid necrosis in the intima and infiltration of lymphocytes and neutrophils around the vessel walls, without leukocytoclasia. Cases that did not fulfill these criteria, or lacked clinical information, were excluded. Information that originated from medical records included age onset of the disease, gender, clinical manifestations, relevant medical history, histopathologic diagnosis and laboratory test results either from our chronic ulcers or vasculitis protocol available at our institution

559

then. These ancillary tests included complete blood count and general exams as biochemical and research for autoimmune conditions, prothrombotic states and infectious disease. The epidemiological, clinical and laboratory data were registered in a structured form, originating a database featuring the characteristics of each patient individually. From that assembling of information an analysis was conducted by one of the authors as a fail-safe mechanism to avoid bias in data collection and registration. Microsoft Excel® was used as the datasheet template, allowing analysis for descriptive statistics. Continuous data were represented as mean and standard deviation (mean ± SD), and categorical variables as percentages.

3. Results 3.1. Distribution by gender and age The study group consisted of 17 female (77.3%) and 5 male (22.7%) patients. The male to female ratio was 1:3.4. Age ranged from 9 to 61 years, with a mean age at the time of diagnosis of 39.4 years (SD 15.2 years). Female mean age ± standard deviation was 41.7 ± 14.5 years, while male mean age ± standard deviation was 31.6 ± 16.6 years (Table 1).

3.2. Skin color Patients were classified according to race/skin color. Sixteen patients were white (72.7%), 4 patients were mullato (18.2%) and 2 patients were black (9.1%).

3.3. Profession The occupational attributions of the 5 male subjects were airplane pilot, carpenter, delivery motorcycle pilot, doorman and student. Among women, 6 were housemaids, 3 were nurse technicians, 3 were school teachers and the remainder were declared as a secretary, cook, student and accountant.

3.4. Follow-up beginning and duration The patient that has been in regular follow-up for the longest time in our department had his admittance in 2003. From that point on, 2 new CPAN cases were identified in 2004, 1 other in 2006, 3 in 2008, 2 in 2009, 4 in 2010, 2 in 2011, 5 in 2013 and 2 in 2014. In a total of 22 patients, 18 of them remained associated to our institution and 4 dropped out. The timeframe concerning follow-up from admittance varied from 7 to 132 months, with mean disease duration of 58.36 months and SD 38.97 months.

Table 1 Distribution by gender and age. Age 0–10 11–20 21–30 31–40 41–50 N50 Total

Male 1 0 1 2 0 1 5

Mean age ± standard deviation (SD) 39.4 ± 15.2 years. Female's mean age ± standard deviation (SD) 41.7 ± 14.5 years. Male's mean age ± standard deviation (SD) 31.6 ± 16.6 years.

Female 0 1 2 5 3 6 17

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P.R. Criado et al. / Autoimmunity Reviews 15 (2016) 558–563

3.5. Comorbidities

Table 3 Clinical features of the studied sample.

Among the 22 patients, 14 (63.6%) did not present other associated diseases, while 8 (36.4%) had at least one co-morbidity (Table 2). These conditions were composed by 6 cases of systemic arterial hypertension and 3 cases of type 2 diabetes. All patients with systemic arterial hypertension were submitted to a Doppler ultrasound of the renal arteries and no signs of stenosis were identified, excluding renovascular hypertension. Interestingly, one of the diseases identified was of a patient with a past diagnosis of subacute cutaneous lupus erythematous, Sjögren syndrome and multiple sclerosis; not to mention a female patient that developed cutaneous lesions that were compatible with granulomatous interstitial disease and, also, a case of a patient that was diagnosed with ductal breast carcinoma during the treatment of CPAN. Investigation of social habits revealed 3 cases of tobacco smoking, one patient with alcohol abuse history and, to the rest of the subjects, no other data was registered.

Characteristic

Cutaneous lesions

Site affected by lesions Regional symptoms associated with the lesions

Groups

N° (%)

Ulcers Livedo racemosa Subcutaneous nodules Atrophie blanche lesions Purpura Lower limbs Upper limbs Trunk None Pain Paresthesia

14 (63.7%) 12 (54.5%) 11 (50.0%) 10 (45.4%) 06 (27.3%) 22 (100%) 06 (27.3%) 06 (27.3%) 07 (31.8%) 14 (63.7%) 08 (36.3%) 05 (22.7%) 18 (81.8%) 02 (9.1%) 02 (9.1%) 01 (4.5%) 01 (4.5%) 0 (0%)

Mononeuritis multiplex

Extracutaneous manifestations

Progression to systemic PAN

None Fever Arthralgia Weight loss Acrocyanosis

3.6. Clinical manifestations Clinical features of patients with CPAN are summarized in Table 3 and also shown in pictures 1, 2 and 3. The main cutaneous manifestations were ulcers (63.7%), livedo racemosa (54.5%), subcutaneous nodules (50.0%), atrophie blanche lesions (45.4%) and purpuras (27.3%). In all cases the lower limbs were affected by one or more lesions; upper limbs were affected in 6 cases (27.3%) and the trunk was affected in 6 cases (27.3%). The ulcers could be located in the lower limbs in all cases and only one patient had ulcerations also found in the trunk. Livedo racemosa was described as generalized in 4 patients (18.9%), 4 had involvement of lower limbs (18.9%), 2 had simultaneous involvement of upper and lower limbs (9.1%), and 2 had the trunk associated the lower limbs (9.1%). The subcutaneous nodules were located in the lower limbs in all patients and one of them also had nodules in upper limbs concomitantly. Atrophic blanche lesions and purpura were restricted to the lower limbs in all patients. In 68.2% of the cases local symptoms were associated with the cutaneous lesions; 14 patients reported pain (63.7%), which was associated with the ulcers in 11 cases and with the subcutaneous nodules in the 3 other cases. Paresthesia like symptoms such as numbness and tingling were reported in 8 patients (29.6%) and, after electromyography, 5 of them (22.7%) were diagnosed with mononeuritis multiplex. Extracutaneous manifestations were described in 4 patients (18.2%), 2 of them had fever and arthralgia, 1 presented weight loss and 1 had acrocyanosis. Fever and weight loss in these cases didn't fulfill the patterns described in diagnostic criteria for systemic PAN. No case of CPAN progressed to the systemic form of the disease over follow-up period. 3.7. Laboratory examination Abnormalities in complete blood count were detected in 3 cases (13.6%), all of them with anemia. None of them presented changes in white blood cell count or platelets. Renal function and urine analysis Table 2 Comorbidities in patients with CPAN. Diseases



Systemic arterial hypertension Diabetes mellitus Interstitial granulomatous dermatitis Subacute cutaneous lupus erythematosus Sjögren syndrome Multiple sclerosis Neoplasm (ductal breast carcinoma)

6 3 1 1 1 1 1

were normal in all cases and liver transaminases were slightly elevated in 2 cases (9.1%). Complement levels were within the range of normal in all samples. Antinuclear antibodies (ANA) tested positive in 5 patients, all of them showing a nuclear speckled pattern. Antineutrophil cytoplasmic antibodies (ANCA) came out reagent in 2 patients with a titer of 1:40 in both cases. Protein electrophoresis was normal in all cases. All cases were tested for thrombophilias. Four patients presented high serum levels of D-dimer, 8 presented high serum levels of lipoprotein (a), one patient had a positive anti-cardiolipin antibody and 2 patients had high serum levels of fibrinogen. The PPD test was performed in 13 cases and it was positive (≥5 mm) in 6 of them (46.1%). Four were treated for tuberculosis with isoniazid, rifampicin, ethambutol and pyrazinamide; one went under prophylactic treatment with isoniazid for 6 months and the remainder was instructed to keep only clinical follow-up without drug intervention according to the consultation provided by the Infectious Diseases Department. The renal artery duplex scanning was performed in 13 patients and in none of them signs of significant stenosis were observed. Serological markers of HBV, HCV, and HIV infection were negative in all cases. The antistreptolysin O test was positive in 2 out of 8 patients. The main epidemiological and clinical features and laboratory tests of the 22 patients studied are summarized in Table 4. 4. Discussion Systemic PAN is rare; CPAN is even more so, the true incidence of which is unknown. This cutaneous vasculitis affects all ages, ranging from children to the elderly. While most small studies did not demonstrate any gender predominance among patients with CPAN, a large one with 79 cases found a male:female ratio of 1:1.7 [4]. Nakamura et al. [31] made a study with 22 patients with age ranging from 17 to 77 years with female patients comprising 86%. The prevalence in woman was also found in the present study. According to Furukawa CPAN frequently affects female aged over 40 years, with numbers of patients peaking at 50–59 years of age [32]. In the current study, female's mean age was lower, but when male and female were analyzed together the mean age at the time of diagnosis (39.4 years) was similar to that observed in other studies, like the research made by Ishibashi and Chen with 14 patients with a mean age of 41.5 years [33]. Comorbidities may be present in 60% of cases of CPAN as demonstrated in the study conducted by Daoud et al. [4] The results of this study, however, revealed no comorbidities in the majority of our patients (63.7%).

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Table 4 Epidemiological and clinical features and laboratories test of the 22 patients. Case n°

Sex/age at onset (yr)

Cutaneous manifestations

Localization

Local symptoms

Mononeuritis multiplex

Laboratory examination

PPD

Research for thrombophilias

Follow-up (months)

1

F/36

LR, U, N, AB

LL, UL, T

2

F/52

LR, AB

LL

3

M/37

U, N

LL

Pain Paresthesia Pain Paresthesia −

Yes

C-ANCA 1:40





14

Yes

↑ Transaminases

+

↑ D-dimer

12





− ↑ Lp(a) IgM Anti-cardiolipin +

4

M/24

LR, U, AB, P

LL

Pain



7



↑ Lp(a)

62



↑ Lp(a)

17

+

↑ Fibrinogen ↑ D-dimer ↑ Lp(a) ↑ Fibrinogen

55

↑ Lp(a)

82

− − − − −

132 78 77 120 19



51

5

F/58

U, N, AB, P

LL

Pain Paresthesia

6

F/31

U, AB, P

LL



7

F/31

N

LL

Pain

Anemia ANA 1:160 ↑ Transaminases

8

F/61

LR, U, N, AB

LL

Pain

Anemia

+





9

F/61

LR, U,

LL, T

10 11 12 13 14

M/34 F/21 F/29 F/47 M/9

LR U, AB, P LR, N U, N, AB, P LR

LL, UL, T LL LL LL LL, UL

15

M54

U, AB, P

LL

16

F/34

LR, U

LL

17

F/54

LR, N

LL, UL, T

18

F/43

LR, U, AB

LL, UL, T

19

F/15

U, N

LL, UL

Pain Paresthesia Paresthesia Pain − − − Pain Paresthesia Pain Paresthesia Pain Pain Paresthesia Pain

20

F/58

U, N

LL

21 22

F/48 F/30

N LR

LL LL, T

Yes

Yes

− ANA 1:640 ANA 1:320 ASO + −

− +

ANA 1:80

107

6

ANA 1:640

+

↑ D-dimer ↑ Lp(a) −

C-ANCA 1:40





132

ASO +

+

24

Pain

Anemia



− −

− −

− ↑ D-dimer ↑ Lp(a) − ↑ Lp(a)



Yes

60 14

43 52 60

F = Female; M = Male. LR = Livedo racemosa; U = Ulcers; N = Nodules; AB = Atrophie blanche; P = Purpura. LL = Lower limbs; UL = Upper limbs; T = Trunk. Lp(a) = Lipoprotein (a).

The most common clinical findings, seen in 80% of the cases of CPAN, are the painful subcutaneous nodules on the lower extremities with edema and swelling. The nodules frequently have a diameter ranging from 0.5 to 3 cm and are multiple, red-dark reddish-purple and can often complicated by ulceration, which may be present up to 50% of cases. They are easily palpated than visualized and are usually the first manifestation of the disease [1–5]. In this study, subcutaneous nodules were present in half of the cases. According to the international literature, the reticular livedo is present in 50% to 80% of cases. It may also be the first manifestation of the disease. In our patients, we observed livedo racemosa in all cases. Other lesions that could be present are petechiaes, purpuras, skin necrosis, urticarial lesions, swelling and blisters. The legs are the main site of involvement of all types of skin manifestations, a fact that was confirmed in the findings of this study [1–5]. The term atrophie blanche is used as a descriptive term denoting atrophic ivory-white stellate scars with thin telangiectasias on the lower limbs with hyperpigmentation of the surrounding skin, that are histologically characterized by endothelial proliferation, segmental hyaline degeneration of the vessel wall, and deposition of fibrin within the vessel wall and lumina. For many years it was used as a diagnostic label synonymous with livedoid vasculitis [34]. However, disorders such as venous stasis and antiphospholipid antibody syndrome, have been linked to atrophie blanche lesions, as well as cutaneous vasculitis, especially CPAN. In a retrospective study of 29 patients with atrophie blanche that submitted deep and multiple skin biopsies at the Department of Dermatology of Johns Hopkins Medical Institutions, 6 had underlying medium sized vasculitis consistent with CPAN, three of whom had previously been diagnosed to have livedoid vasculitis on

superficial biopsies. The authors emphasized that repeated and deep biopsies are often necessary to reveal the accurate underlying pathology of necrotizing medium sized vasculitis in the reticular dermis and the subcutis, especially in the setting of atrophie blanche lesions [35]. According to PAN diagnostic criteria, which were established by the Ministry of Health, Labour and Welfare of Japan, a disease with both cutaneous and at least one extracutaneous symptom with appropriate histopathological findings can be diagnosed as PAN. The same is true according to diagnostic criteria established by the American College of Rheumatology. In addition, recently Nakamura et al. established diagnostic criteria for CPAN (Table 5). Both clinical and histological criteria must be present to confirm the diagnosis of CPAN after systemic manifestations are ruled out [31]. The prevalence of MM observed in our study was 22.7%, showing congruence with the literature. Electroneuromyography was performed to confirm the diagnosis only in patients complaining of paresthesia in the same region of cutaneous lesions. A positive result compatible with MM was found in 62.5% of cases. A study conducted by Furukawa with 22 patients, found 32% prevalence of neurological manifestations [32], while the largest analysis led by Daoud involving 79 CPAN patients revealed clinical evidence of neuropathy in 22% of cases [4]. For many years the questions surrounding CPAN as to which extent such disease could be seen as a distinct clinical entity or as a mere early stage of systemic PAN, remained unanswered. Nowadays, sufficient evidence originated from recent studies showed that most cases did not progress from CPAN to systemic disease [2,4,36–38]. On the other hand one study with 20 patients documented two cases of CPAN that progressed to systemic PAN after 18 and 19 years of evaluation; but it is interrogated if this patients wouldn't be in fact cases of systemic

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Table 5 Diagnostic criteria for CPAN. Compatible clinical findings Histopathological findings

Exclusion manifestations

Subcutaneous nodules, livedo, purpura, ulcers Fibrinoid necrotizing vasculitis of small and medium-sized arteries - Fever (≧38 °C, ≧2 weeks), weight loss (6 kg or more in 6 months) - Hypertension - Rapidly progressive renal failure, renal infarction - Cerebral hemorrhage, cerebral infarction - Myocardial infarction, ischemic heart disease, pericarditis, heart failure - Pleuritis - Intestinal hemorrhage, intestinal infarction - Peripheral neuropathy out of the affected skin lesion - Arthralgia (arthritis) or myalgia (myositis) out of the skin lesion - Abnormal arteriography (multiple microaneurysm, stenosis and obliteration).

PAN which had cutaneous findings as the first clinical manifestations [39]. Contrariwise to systemic disease, in CPAN there is no evidence of autoimmune abnormalities detected by ANA, ANCA, rheumatoid factor, cryoglobulin tests and decreased complement levels. Nevertheless, the application of these tests is important to exclude other forms of vasculitis or rheumatologic diseases [4]. Most patients studied had normal laboratory tests, while few cases were positive for ANA and ANCA; it was also observed that some patients had abnormalities in coagulation tests. The most common infectious agent associated with CPAN in this study was M. tuberculosis. The Mantoux test, also known as test for purified protein derivative or PPD test, was positive and indicated previous contact with the tuberculosis bacillus in 6 of 13 patients who were submitted to the test (46.1%). In Brazil, tuberculosis is an endemic public health problem with an estimate incidence of 58 cases/100,000 inhabitants [40]. However, there is a lack of prevalence and epidemiological studies indicating an ideal cut-off point for the size of the PPD in our population. Callado et al. [40] studying the prevalence of reactive PPD prior to infliximab use in Fortaleza (Northeast in Brazil) found 27% of their controls (198 individuals without rheumatologic disease) with positive reaction to PPD (≥ 5 mm), and 13% of positivity in the group previously to the use of the biological therapy (157 patients with rheumatic diseases). A total prevalence of positive PPD tests in Callado et al. [40] series was 24.5%. In our study, we found 46.1% of positive PPD tests, a number more expressive. Our findings strengthen the necessary prophylaxis to tuberculosis before use of immunosuppressive therapy in CPAN patients, in this setting and put M. tuberculosis as a potential trigger immune stimulus for this vasculitis. Other cases of CPAN induced by M. tuberculosis were reported previously, however the pathophysiological mechanism involved in this process is still to be explained in detail. Different mechanisms have been described as direct microbial invasion of endothelial cells, participation in immune complex mediated damage of vessel walls and stimulation of autoreactive B and/or T lymphocytes [15]. The remaining tests used for the identification of etiologic agents were negative and, despite 2 positive results for ASLO, none of them had clinical evidence of former streptococcal infection. As a retrospective review, our study has several limitations. Clinical features were determined by review of medical histories submitted and described by numerous dermatologists at a tertiary care and referral center. Findings such as atrophie blanche may be underrepresented in our study group if they were not specifically described in the dermatological exam. To our knowledge, our study is the largest epidemiological and clinical follow-up of CPAN cases in Brazil. There is, however, a limitation of

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