Paraneoplastic rheumatoid-like arthritis associated with lung cancer

Background. Paraneoplastic syndrome (PNPS) associated with lung cancer (LC) is characterized by rheumatological, dermatological, endocrinological, neurological, nephrologic and other manifestations. PNPS has become an urgent problem of mo dern 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. Ano ther 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 diffe rentiation, 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 bo dies. 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.


Introduction
Lung cancer (LC) is considered the most frequent form of the malignant neoplasms [1][2][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][9][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
Statistical analysis of the data was carried out using computer variational, nonparametric, correlative, one-(ANO-VA) 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 (τ), even dispersions of Brown -Forsythe (BF), multivariate dispersion of Wilcoxon -Rao (WR), Student (t)and McNemar -Fisher's (χ 2 ) 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.
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 χ 2 =21.50, p<0.001 : 1 -exudative pleurisy, 2 -compression syndrome, 3 -obstructive atelectasis, 4 -tracheal invasion, 5 -esophageal invasion, 6chest wall invasion, 7 -pericardial invasion, 8 -rib invasion, 9 -compression of the upper vena cava , 10 -  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][20][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].

1.
There is a confirmed interaction of LC and comorbid 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.   1  2  3  4  5  6  7  8  9  10  11  12  13  14  15  16  17 p BF