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19
Практична медицина / Practical Medicine
БШЬ.
СуГЛОБИ. JOINTS. I ХРЕБЕТ SPINE I
УДК616.72-002.77:616.24-006]-07-092 DOI: 10.22141/2224-1507.10.1.2020.199724
O.V. Syniachenko <E, M.V. lermolaieva, P.A. Stepko, S.M. Verzilov, Yu.O. Potapov
Donetsk National Medical University, Lyman, Ukraine
Paraneoplastic rheumatoid-like arthritis associated with lung cancer
For citation: Bol', sustavy, pozvonocnik. 2020;10(1):51-56. doi: 10.22141/2224-1507.10.1.2020.199724_
Abstract. Background. Paraneoplastic syndrome (PNPS) associated with lung cancer (LC) is characterized by rheu-matological, dermatological, endocrinological, neurological, nephrologic and other manifestations. PNPS has become an urgent problem of modern oncology, but specifics of its course and immediate tumor process have not been investigated enough. The purpose was to estimate the clinical laboratory manifestations of paraneoplastic (neoplasmic) rheumatoid-like arthritis (RLA) within the context of its associations with LC individual signs. Materials and methods. PNPS was detected in 258 (16%) patients with LC and RLA in 41 (16%) cases of PNPS. These patients (29 men and 15 women with an average age of 57 years) made up the main group of this study, and other 217 patients with PNPS (177 men and 40 women with an average age of 59 years) were included into the comparison group. Another control group was formed by 105 patients (22 men and 83 women aged 46 years) with primary rheumatoid arthritis (RA) without LC. Results. LC with RLA is characterized by the accelerated midlobar localization of tumor process (7.4 times more often), its small-cell variant (5.3 times more often) with a low degree of differentiation, the presence of exudative pleurisy, neoplasms germinating into esophagus and metastases growing into the skeleton (pubic, iliac, femoral and sacral bone, jaw and spine). By contrast to the RA, RLA is characterized by oligoarthritis, enthesopathies, seronegativity by the rheumatoid factor and antibodies to cyclic citrulline peptide, less manifested activity and stages of the articular syndrome (by 1/4), higher damage rate of radiocarpal joints (1.8 times), shoulder joints (4.8 times), metacarpal (2.4 times) and metatarsophalangeal (2.5 times) joints, absence of osteousuras, intra-articular chondromic bodies, Steidi and Goff bodies. Conclusions. Formation of paraneoplastic RLA is observed in every sixth patient with PNPS caused by LC, which is accompanied by specific features not only of tumor process, but also by joint syndrome in comparison with the primary RA. The obtained data necessitate the further investigation in order to develop criteria for early diagnosis of RLA and informative prognostic factors for the further course of LC.
Keywords: cancer; lung; paraneoplastic syndrome; arthritis
Introduction
Lung cancer (LC) is considered the most frequent form of the malignant neoplasms [1-3]. Furthermore, the autoimmune articular paracancrotic alterations occur in up to 4% of LC cases [4]. Paraneoplastic syndrome (PNPS) is not immediately associated with a primary neoplasm and its metastases; however, it is generated by the complex inflammatory systemic and local distant alterations, often in the form of the rheumatic and tumor overlap [5, 6].The PNPS attending LC manifests itself by rheumatoid-like arthritis (RLA) [7], reducing the survival rate of patients with this malignant tumor [8-10], while a successful LC treatment (surgery, radiation chemotherapy) may be followed by the RLA signs' disappearance [11, 12]. By contrast to the "primary" rheumatoid arthritis (RA), the RLA mostly affects
middle and large joints (for instance, glenohumeral one), has an acute or sub-acute onset and involves a periarticular swelling [13]. Overall, the remitting seronegative synovitis should be a warning against a tumor process in case of absent glucocorticoid treatment [14]. The issue of PNPS attending LC is relevant, though unresolved, in the modern rheumatology and oncology [15, 16].
Our aim of study is to determine frequency and clinical features of paraneoplastic (neoplasmic) rheumatoid-like arthritis (RLA) attending LC, analyze the interaction of its course with tumor process, evaluate the PNPS risk factors
Materials and methods
A cross-sectional observation involved 1669 LC patients aged 24-87 years (mean age 59±0.2 years), among whom
© 2020. The Authors. This is an open access article under the terms of the Creative Commons Attribution 4.0 International License, CC BY, which allows others to freely distribute the published article, with the obligatory reference to the authors of original works and original publication in this journal.
Для кореспонденци: Синяченко Олег Володимирович, доктор медичних наук, професор, член-кореспондент НАМН Укра'1'ни, Донецький нацюнальний медичний ушверситет, вул. Привок-зальна, 27, м. Лиман, Донецька обл., 84404, Укра'на, е-mail: synyachenko@ukr.net; контактний тел.: (050) 471 47 58.
For correspondence: Oleh Syniachenko, Corresponding member of the NAMS of Ukraine, MD, PhD, Professor, Donetsk National Medical University, Privokzalna st., 27, Lyman, Donetsk region, 84404,Ukraine; e-mail: synyachenko@ukr.net; phone: +38(050) 471 47 58. Full list of author information is available at the end of the article.
89% males and 11% females. The right-hand localization of cancer was characteristic of 57% patients, left-hand — of 42%, bilateral — of 1%. The upper lobe LC was diagnosed in 29% cases, middle-upper lobe LC — in 21%, upper-lower left-hand LC — in 20%, lower LC — in 13%, mediastinal LC - in 11%, midlobar - in 3%, middle-lower LC - 2%. The small-cell histological variant was diagnosed in 19 % cases, while the non-small-cell histological variant — in 82%, among them adenocarcinoma accounted for 37% of all examined cases and 46 % of the non-small-cell cases, planocellular carcinoma — for 35 and 43% respectively, and large-cell carcinoma — for 9 and 11%.
The IB and IIA stages were diagnosed in 1% LC cases, IIB — in 4%, IIIA — in 35%, IIIB — in 26%, IV — in 34%. The mean integral stage index (StT) was 5.9±0.03 r.u., integral severity index of tumor process (IWT) - 2.9±0.02 a.u., evaluated according to the formula:
IWT = ln[T + N2 + (ZM)2],
where ln — natural logarithm, T - international index of the primary tumor, N - international index of metastasis in the regional lymph nodes, EM - sum of metastases in the distant organs. Among the LC signs, 10% reported exudative pleurisy, 8% —compression syndrome, 7% - tracheal invasion, 3% - rib and chest wall invasion, respectively, 2% - esopha-geal invasion, 1% — pericardial invasion. 4% cases had obstructive atelectasis, 3% — compression of the recurrent nerve, 2% - compression of the upper vena cava. Metastatic spreading of LC to lymph nodes was found in 81% of observations, to distant organs — in 31%, to the skeleton — in 20%.
Among all the LC patients, a principal group of paraneoplastic (neoplasmic) rheumatoid-like arthritis (RLA) patients was recruited (79 patients, i.e. 5%), while the con-
trol group was made out of the remaining patients with no PNPS signs. The RLA course was compared with the classic "primary" RA course of 105 patients, matched for age, sex and duration (second control group). In order to diagnose LC and its metastases, we used radiography, computed tomography, magnetic resonance imaging (Multix-Com-pact-Siemens, Germany; Somazom-Emotion-6-Siemens, Germany; Gygoscan-Intera-Philips, Netherlands; cyclotron Siemens-RDS-Eclipse-RD, Germany), fibroscope (Olympus-GIF-Q20, Japan), sonograph (Envisor-Philips, Netherlands).
Statistical analysis of the data was carried out using computer variational, nonparametric, correlative, one- (ANOVA) and multifactorial (ANOVA/MANOVA) dispersion analysis (Microsoft Excel and Statistica-Stat-Soft, USA). Mean values (M), their standard deviations (SD) and errors (SE), Pearson's parametric correlation coefficients (r) and Kendall's non-parametric correlation coefficients (t), even dispersions of Brown — Forsythe (BF), multivariate dispersion of Wilcoxon — Rao (WR), Student (t)and McNemar — Fisher's (x2) tests, and the reliability of statistical indices (p) were estimated. In this study, the critical level of significance in terms of statistical hypotheses' verification was considered to be 0.05. The positive predictive value (PPV) was also calculated.
Results
The principal (I) group of RLA patients and control (II) group with no PNPS did not differ in terms of age, side of tumor affection and form of disease (central, peripheral). However, in the principal (I) group lower-lobe LC localization was 6.9 times rarer (x2=5.62, p=0.02), while mediastinal LC — 6.0 times rarer (x2=4.45, p=0.04); midlobar LC — 7.4 times more frequent (x2=16.96, p<0.001), while the small-cell histological variant — 5.3 more frequent
Fig. 1. Differences of certain joint disorder frequencies in the principal and control group Joints: 1- metacarpophalangeal, 2 - interphalangeal (manus), 3 - metatarsophalangeal, 4 - radiocarpal, 5 - glenohumeral, 6 -maxillary, 7 - talocrural, 8 - interphalangeal (pedis), 9 - knee, 10 - sternoclavicular, 10 - femoral, 11 - cubital.
(%2=51.13, p<0.001). The ratio of small-cell LC to non-small-cell LC in the I group was 5:1, while in the II group - 1:2. The distribution of adenocarcinoma, planocellular carcinoma and large-cell carcinoma in the principal and control group was 18:1:0 and 4:3:1 respectively (%2=16.41, p<0.001). But for the large-cell carcinoma, there were no cases of apical Pancoast — Tobias LC, diagnosed in 4.2% of other patients. According to the multivariate dispersion of Wilcoxon — Rao, RLA affects the integral clinical LC features significantly (WR=7.89, p<0.001).
In the principal group of RLA patients, the ratio of polyarthritis and oligoarthitis was 2:1, while in the control group - 34:1 (%2=25.15, p<0.001). The RLA patients had no maxillary joint disorders (%2=5.57, p=0.018), suffered from interphalangeal joint arthritis 2.3 times less frequently (x2=26.66, p<0.001), from metacarpophalangeal joint arthritis - 2.4 times less frequently (%2=37.18, p<0.001), radiocarpal joint arthritis — 1.8 times less frequently (X2=15.95, p<0.001), glenohumeral joint arthritis — 4.8 times less frequently (%2=11.56, p=0.001), all of these data reflected in Fig. 1. The symmetrical joint disorders were observed 13.0 times less frequently in the principal group, and 25.0 times more often in the control group (%2=113.65, p<0.001).
In the non-RLA patient group, there were no enthesopathies, which afflicted 22% of patients in the principal group (x2=49.36, p<0.001). Furthermore, the RLA patients had 7.9 times as many tendovaginitides (X2=23.18, p<0.001), though 3.7 times as few Marie -Bamberger osteoarthropathies (%2=7.46, p=0.006). By contrast to the RA patients (second control group), RLA was characterized by 15.7 times more frequent seronegativity by the rheumatoid factor (%2=62.77, p<0.001), 1.5 times by the anti—citrullinated protein antibodies (%2=11.22, p=0.001), and twice as many cases of tendovaginitides (%2=6.00,
p=0.014). If the osteousuras, intra-articular chondromic bodies, Steidi and Goff bodies were found in 51%, 24%, 6% and 4% of control patients, respectively, such X-ray-sonographic signs of LC-associated articular syndrome were absent. In the RLA group, the DAS level was 24% lower (t=5.65, p=0.001), while the Lansbury index was 28% lower (t=3.57, p=0.001).
It should be stressed that in the RLA group not only the character of articular syndrome were different, but the tumor process differed as well. In the principal (RLA) group (Fig. 2) exudative pleurisy was diagnosed twice as often (x2=5.14, p=0.02), esophageal invasion — 14.6 times as often (x2=10.62, p=0.001), metastatic spreading to the skeleton — 3.1 times as often (%2=42.86, p<0.001), though these patients had no cases of neoplasms germinating into trachea (x2=4.32, p=0.04).
The principal group did not differ from the control group of LC patients did not differ in terms of tumor stages; however, the neoplasms in the RLA group was less differentiated (t=4.03, p<0.001) and had a significantly more aggravated (by 14%) course (t=3.21, p=0.002). The number of skeletal metastases in case of RLA was 2.8 times larger (t=5.17, p<0.001).
Discussion
The RLA present in LC patients had a significant influence on the integral character of skeletal metastasizing, demonstrated by the multivariate dispersion of Wilcoxon — Rao (WR=9.04, p<0.001). This fact is confirmed by the performed Wilcoxon — Rao analysis (WR=9.04, p<0.001), by the univariate distribution and nonparametric comparative McNemar — Fisher's test (Fig. 3). The RLA is closely associated with metastases growing into jaws (D=23.28, p<0.001) and pubic bone (D=11.04, p=0.001), absent in the control group (respectively %2=21.50, p<0.001
1 23456789 10 11
• principal group O control group
Fig.2. Frequency of some LC signs among the principal group and control group patients (%) Joints: 1 - exudative pleurisy, 2 - compression syndrome, 3 - obstructive atelectasis, 4 - tracheal invasion, 5 - esophageal invasion, 6 -chest wall invasion, 7 - pericardial invasion, 8 - rib invasion, 9 - compression of the upper vena cava, 10 - compression of the recurrent nerve 11 - metastatic spreading to the skeleton.
Fig. 3. Reliability of RLA effect (p BF) on the LC skeletal metastasizing Joints: 1 - ileum, 2 - sacrum, 3 - jaw, 4 - sacroiliac joint, 5 - pubic bone, 6 - spine, 7 - femur, 8 - coxofemoral joint, 9 - clavicle, 10 -sternum, 11 - scapula, 12 - cubital joint, 13 - knee joint, 14 - tibia, 15 - rib, 16 - glenohumeral joint, 17 - glenohumeral bone.
and x2=10.67, p=0.001). The RLA patients had skeletal metastases significantly (p<0.001) more often (2.1 times) (X2=8.18), had femoral metastases 3.5 times more often (X2=6.93), had sacroiliac metastases 5.3 times more often (%2=148.18), had iliac metastases 7.7 times more often (X2=42.43), had sacral metastases 9.2 times more often (X2=41.02).
According to the reference data, the RLA is more often observed with lung adenocarcinoma [17] and with bone metastases [18]; its course is naturally associated with C-reactive protein (CRP) and seronegativity by the rheumatoid factor (RF) [13], corresponding with the data obtained. The fact of interaction of RA and oncological pathology's effects is mostly attributed to the manifest similarity of immune system deregulation in both diseases [19-21]. The frequency of RLA and RA's effect interaction is aggravated by the genetic affinity to both pathological processes, namely GSAs and DEGs genes' mutation [22, 23]. We did not observe any RLA cases resembling the adult Still's disease or, to the same extent, isolated gonitis, pointed out by the reference data [24, 25].
Conclusions
1. There is a confirmed interaction of LC and co-morbid RA development; the frequency of such PNPS, clinical features of its course and association with a background tumor process (severity of neoplasm, character of growth into the adjunct organs and metastasizing, apical localization, small-cell and non-small-cell histological variant) are described.
2. RLA is characterized by the accelerated midlobar localization of tumor process, its small-cell variant, the presence of exudative pleurisy, neoplasms germinatin into esophagus and metastases growing into the skeleton.
3. There are differences of clinic-laboratory RLA and the so-called "primary" (idiopathic) RA signs.
4. RLA is characterized by oligoarthritis, enthesopathies, seronegativity by the rheumatoid factor
and antibodies to cyclic citrulline peptide, low frequency of radiocarpal joint, shoulder joint, metacarpal and metatarsophalangeal joint damage, absence of osteousuras, intra-articular chondromic bodies, Steidi and Goff bodies.
5. Further LC-associated RLA studies are likely to help improve the early diagnostics quality for both groups of diseases, develop prognostic criteria and raise the effectiveness of the individual combined medical technology of treatment.
Conflict of interests and financial support. Authors report no conflict of interests or financial support from any individuals or business entities in obtaining the findings, fees or other remunerations.
Information on the individual author's contributions
Syniachenko O.V. — study's concept and writing the peper; Iermolaieva M.V. — analysis of the literature, design of the study; Stepko P.A. — examining the cancer patients, statistical processing; Verzilov S.M. — examining the arthritis patients, designing figures; Potapov Yu.O. - examining the patients, analysis of findings.
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OTpuMaHo/Reeeived 17.02.2020 Рецензовaно/Revised 27.02.2020 npui/iH^TO go Apyi<y/Accepted 06.03.2020 ■
Information about authors
O.V. Syniachenko, MD, PhD, Professor, Corresponding member of NAMS of Ukraine, Honorary Scientist and Technician of Ukraine, Lyman, head of Department of Internal medicine 1, Donetsk National Medical University of Health Ministry of Ukraine, Lyman http://orcid.org/0000-0003-4201-5166
M.V. lermolaieva, MD, PhD, Professor, Department of Internal medicine 1, Donetsk National Medical University of Health Ministry of Ukraine, Lyman P.A. Stepko, Assistant at the Department of oncology, Donetsk National Medical University of Health Ministry of Ukraine, Lyman S.M. Verzilov, PhD, Associate Professor at the Department of Internal medicine 1, Donetsk National Medical University of Health Ministry of Ukraine, Lyman Yu.O. Potapov, PhD, Associate Professor at the Department of Internal medicine 1, Donetsk National Medical University of Health Ministry of Ukraine, Lyman
Синяченко О.В., Ермолаева М.В., Степко Ф.А., Верзилов С.Н., Потапов Ю.А. Донецкий национальный медицинский университет, г. Лиман, Украина
Паранеопластический ревматоидоподобный артрит при раке легкого
Резюме. Актуальность. Паранеопластический синдром (ПНПС) при раке легкого (РЛ) характеризуется ревматологическими, дерматологическими, эндокринными, неврологическими, нефрологическими и другими проявлениями. ПНПС стал актуальной проблемой современной онкологии, но особенности его течения и непосредственное течение самого опухолевого процесса остаются недостаточно изученными. Цель исследования: оценить клинико-лабора-торные проявления паранеопластического (неоплазменного) ревматоидоподобного артрита (РПА) в контексте связей с отдельными признаками РЛ. Материалы и методы. ПНПС выявлен у 258 (16 %) больных РЛ, а РПА — в 41 (16 %) случае ПНПС. Эти пациенты (27 мужчин и 14 женщин, средний возраст 57 лет) составили основную группу наблюдения, а остальные 217 пациентов с ПНПС (177 мужчин и 40 женщин, средний возраст 59 лет) вошли в группу сравнения. Еще одну контрольную группу сформировали 105 больных (22 мужчины и 83 женщины, средний возраст 46 лет) с первичным ревматоидным артритом (РА) без РЛ. Результаты. РЛ с РПА характеризуется учащением среднедолевой локализации опухолевого процесса (в 7,4 раза), его мелкоклеточного варианта (в 5,3 раза) с низкой степенью дифференциации,
наличием экссудативного плеврита, прорастанием неоплазмы в пищевод и развитием метастазов в скелет (в лобковую, подвздошную, крестцовую и бедренную кости, в челюсти и позвоночник). При сравнительной оценке с РА для РПА более типичны олигоартрит, возникновение энтезопатий, се-ронегативность по ревматоидному фактору и антителам к циклическому цитруллиновому пептиду, достоверно меньшие (на 1/4) активность и стадийность суставного синдрома, более частое поражение лучезапястных (в 1,8 раза), плечевых (в 4,8 раза), пястно- (в 2,4 раза) и плюснефаланговых суставов (в 2,5 раза), отсутствие остеоузур, интраартикуляр-ных хондромных тел, тел Штайди и Гоффа. Выводы. Формирование паранеопластического РПА наблюдается у каждого шестого больного с ПНПС, обусловленным РЛ, что сопровождается особенностями не только опухолевого процесса, но и суставного синдрома в сравнении с первичным РА. Полученные данные диктуют необходимость дальнейших исследований для выработки критериев ранней диагностики РПА и информативных прогностических факторов в отношении дальнейшего течения РЛ.
Ключевые слова: рак; легкое; паранеопластический синдром; артрит
Синяченко О.В., Ермолаева М.В., Степко П.А., Верз'шов С.М., Потапов Ю.О. Донецький нац'юнальний медичний унiверситет, м. Лиман, Украина
Паранеопластичний ревматоiдоподiбний артрит при раку легеш
Резюме. Актуальтсть. Паранеопластичний синдром (ПНПС) при раку легеш (РЛ) характеризуемся ревматолопчни-ми, дерматолопчними, ендокринними, невролопчними, не-фролопчними та шшими проявами. ПНПС став актуальною проблемою сучасно! онкологи, але особливосй його перебцу та безпосереднш перебп самого пухлинного процесу залиша-ються недостатньо вивченими. Мета: оцшити клшко-лабо-раторш прояви паранеопластичного (неоплазмового) ревма-тоiдоподiбного артриту (РПА) у контексп зв'язив з окреми-ми ознаками РЛ. Матерiали та методи. ПНПС виявлено у 258 (16 %) хворих на РЛ, а РПА — у 41 (16 %) випадку ПНПС. Щ пащенти (27 чоловшв та 14 жшок, середнш вш 57 роив) становили основну групу спостереження, а решта 217 пацен-тш з ПНПС (177 чоловшв и 40 ж1нок, середнш вж 59 роив) увшшли до групи порiвняння. Ще одну групу сформували 105 хворих (22 чоловши й 83 жшки, середнш вж 46 роив) з пер-винним ревматощним артритом (РА) без РЛ. Результати. РЛ з РПА характеризуеться почастшанням средньочастково! ло-калiзацii пухлинного процесу (в 7,4 раза), його дабноклггин-ного варiанта (в 5,3 раза) з низькими ступенями диференща-
цй, наявшстю ексудативного плевриту, проростанням нео-плазми в стравохщ та розвитком метастазiв у скелет (у лобкову, клубову, крижову й стегнову истки, в щелепи та хребет). При порiвняльнiй оцшщ з РА для РПА бшьш типовi олпоартрит, виникнення ентезопатш, серонегатившсть за ревматощним фактором i антитшами до циктчного цитрулшового пептиду, вiрогiдно меншi (на 1/4) актившсть й стадшшсть суглобово-го синдрому, бшьш часте ураження променево-зап'ясткових (у 1,8 раза), плечових (у 4,8 раза), п'ястково- (у 2,4 раза) i плес-нофалангових суглобiв (у 2,5 раза), вiIдсутнiсть остеоузур, ш-траартикулярних хондромних тш, тш Штайдi й Гоффа. Вис-новки. Формування паранеопластичного РПА спостерггаеть-ся в кожного шостого хворого з ПНПС, обумовленим РЛ, що супроводжуеться особливостями не лише пухлинного проце-су, а й суглобового синдрому порiвняно з первинним РА. От-римаш даш диктують необхiIднiсть подальших дослщжень для створення критерив ранньо! дiагностики РПА та шформатив-них прогностичних чинник1в щодо подальшого перебiгу РЛ. Ключовi слова: рак; легеня; паранеопластичний синдром; артрит
