Asymptomatic hyperuricemia and radiographic progression of rheumatoid arthritis
DOI: 10.32364/2587-6821-2022-6-8-470-479
A.Yu. Tsinserling1, V.I. Mazurov1,2, I.Z. Gaydukova1,2, M.S. Petrova1,2, O.V. Inamova1,2, R.A. Bashkinov1,2, N.T. Gonchar2
1Clinical Rheumatological Hospital No. 25, St. Petersburg, Russian Federation
2I.I. Mechnikov North-Western State Medical University, St. Petersburg, Russian Federation
Background: clinical and radiological studies on this issue remain unknown, despite the existing pathomorphological prerequisites, indicating the mutually potentiative effect of hyperuricemia (HU) on the radiographic progression (RP) in rheumatoid arthritis (RA).
Aim: to study the association between the HU, the activity of RA, RP and the possibilities of their correction.
Patients and Methods: among 967 patients included in the St. Petersburg City Register of HU from January 2011 to October 2021, 232 patients with RA and HU (uric acid (UA) level > 360 µmol/L) were selected, for which 232 patients of the comparison group with RA without HU were selected by random selection from the same register. A comparison of the demographic characteristics of patients (gender, age), their clinical, laboratory and radiological patterns and the ongoing treatment was conducted.
Results: patients with RA and HU and without HU were comparable in age, gender, activity, disease course and the received baseline therapy. In patients with RA and HU, there was a higher (p=0.03) increase in the joint space narrowing (JSN) value of the feet. In patients with RA and HU, RP in all evaluated parameters (p<0,001) exceeded RP in patients with RA without HU. The article reveales direct correlations in the JSN of the feet and hands with the UA level, UA clearance, UA daily excretion, daily protein loss, as well as blood glucose and cholesterol levels, despite the well-known risk factors for the RA progression (age, disease duration, positivity according to RF and CCPA, elevated ESR and CRP level). Patients with HU and RP only reached the target UA levels in 27% of cases when treated with allopurinol, while patients without RP reached the target level in 80% of cases.
Conclusion: HU in patients with RA is associated with RP, which indicates the need for its timely detection and correction.
Keywords: rheumatoid arthritis, asymptomatic hyperuricemia, radiographic progression, urate-lowering therapy, allopurinol.
For citation: Tsinserling A.Yu., Mazurov V.I., Gaydukova I.Z. et al. Asymptomatic hyperuricemia and radiographic progression of rheumatoid arthritis. Russian Medical Inquiry. 2022;6(8):470–479 (in Russ.). DOI: 10.32364/2587-6821-2022-6-8-470-479.
Background
Asymptomatic hyperuricemia (HU) is now regarded as a generally recognized risk factor for the development and progression of musculoskeletal, cardiovascular, and metabolic disorders, and chronic kidney disease both in the general population and patients with rheumatoid arthritis (RA) [1–5]. Meanwhile, data on the effects of uric acid (UA), its metabolism, and HU on the radiological progression (RP) of RA are scarce. There are pathogenic prerequisites for considering RA and HU as factors mutually stimulating joint damage. In RA, mobile inflamed joint is considered to be affected by ischemia-reperfusion injury (IRI). Xanthine oxidoreductase (XOR) is an enzyme that contributes to IRI. The activity of XOR in the human synovial membrane is reported. R.E. Allen et al. [6] investigated tissue samples collected from 3 healthy individuals and 5 patients with RA. Radioanalysis to evaluate the conversion of [14C]xanthine to [14C]UC was applied. Synovial membrane in RA contains 0.67–305 μg/g of 14C, while healthy synovial membrane contains only 1.2–5.0 μg/g of 14C, thereby indirectly establishing an increase in XOR activity in inflamed joints.
A study [7] measured concentrations of hypoxanthine, xanthine, and urates in the synovial membrane and blood in 13 patients with RA. Blood level of hypoxanthine was higher than in healthy individuals. Meanwhile, concentrations of hypoxanthine, xanthine, and urates in the synovial fluid were higher than their blood levels. Positive correlations were established between the levels of xanthine and urates in blood and synovial fluid. These findings indirectly demonstrate a local enhancement of purine metabolism in inflamed joints in RA and increased diffusion of oxypurines from the joint cavity into the plasma. No associations between metabolite levels and disease duration, radiological features, or synovial fluid cells were found. Purine metabolites are not associated with lab signs of systemic inflammation, excepting a weak correlation between plasma urate and serum haptoglobin [7].
D. Pekhlivanov et al. [8] have found that UA and calcium levels reduce as RA activity increases. These parameters directly correlate with the severity of joint destruction. Methods for grading the severity of joint destruction are not addressed in this study.
Other authors suggest a direct role of UA in chronic inflammation in RA by increasing the production of C-reactive protein (CRP), cytokines, and superoxide by neutrophils [9]. Monosodium urate (MU) crystals can negatively affect local bone remodeling through excessive osteoclast generation and poor osteoblast differentiation [9].
All the known studies are morphological and provide a pathogenic basis for the association between UA metabolism and inflammation in RA. Meanwhile, we failed to find any foreign or domestic clinical and radiological studies on the correlation between UA exchange and RP in RA. Therefore, given the potential association between RA progression and HU, a study on structural lesions of joints in RA in the presence or absence of HU is relevant. The effects of the treatment for asymptomatic HU (diet, allopurinol) on RP in RA and HU have been poorly studied and are scientifically and practically important.
Aim
To assess the association between HU, RA activity, RP, and their potential management.
Patients and Methods
232 patients with RA and HU who were selected from 967 patients included in the St. Petersburg HU Register from January 2011 to October 2021 were enrolled to perform retrospective analysis. 232 patients with RA but no HU were randomly selected to compose the comparison group. HU was defined as a ≥1-fold increase in serum UA >360 µmol/L.
Inclusion criteria were the presence of informed consent for inclusion in the register, RA established by the 2010 EULAR/ACR criteria, and age over 18 at the time of inclusion in the study. Exclusion criteria were gout, secondary HU, other rheumatic diseases (excepting secondary osteoarthritis), acute or chronic infections (HIV, hepatitis B & C), and exacerbations of chronic diseases.
Assessment of demographic characteristics, RA activity, and RP. The study provides demographic characteristics of patients (gender, age), presence of HU, and clinical, lab, and radiological hallmarks of RA.
X-ray exam was performed using the Q-RAD-Digital DRX-Series system. Radiographic stages of RA were graded with the modified Steinbrocker Staging System as follows:
Stage 1: periarticular osteoporosis
Stage 2: + narrowing of joint space, single (1–4) erosion
Stage 3: + multiple erosions, subluxation
Stage 4: + ankylosis
RP was assessed using the Simple Erosion Narrowing Score (SENS) based on Sharp/van der Heijde score. A total of 32 joints of hands (2–5th proximal interphalangeal, 1–5th metacarpophalangeal, 1st carpometacarpal, 1st interphalangeal, multangular [trapezoid + trapezium bone], talocalcaneonavicular, lunate-capitate, radiocarpal, and ulnocarpal joints) and 12 joints of feet (1-5th metatarsophalangeal, interphalangeal joint of the big toe) were scored for erosions. 30 joints of hands (2–5th proximal interphalangeal, 1–5th metacarpophalangeal, 3rd–5th carpometacarpal, trapezio-navicular, scaphoid-lunate-capitate, and radiocarpal joints) and 12 joints of the feet (1–5th metatarsophalangeal, interphalangeal joint of the first toe) were scored for joint space narrowing. A joint was considered damaged if any erosion and/or joint space narrowing (even minimal) was found. A joint is scored 1 point if there is erosion at least at one location and another 1 point if joint space narrowing is present. The maximum total SENS ranges from 0 to 86 [10]. A change in the erosion score and/or joint space narrowing score of hands and/or feet by at least 1 point was regarded as RP. Hand and foot joint X-ray was performed yearly (±3 months).
Statistical was performed using the SOFA (Statistica Open For All) software (v. 1.5.4). Normality was tested graphically. Quantitative traits were represented as mean (M) and standard deviation (SD) in normal distribution and median (Me), minimum and maximum values, and interquartile interval [Q25; Q75] in non-normal distribution. Qualitative traits were represented in absolute values. Event frequency was calculated as a percentage. The χ2 test was applied to compare qualitative variables. To compare two groups by quantitative variables, t-test (paired for dependent groups and unpaired for independent groups with normal distribution), Mann–Whitney test (for independent groups), and Wilcoxon test (for dependent groups) in non-normal distribution were used. Three or more groups were compared using ANOVA (in normal distribution) or Kruskal-Wallis ANOVA (in non-normal distribution). Pearson correlation coefficient (in normal distribution) or Spearman’s rank correlation coefficient (in non-normal distribution) were calculated to determine correlations between events.
Ethical aspects. Patient data were included in the register anonymously. As a result, an individual patient could not be assigned as a person, each patient was assigned an individual number. The study was approved by the local ethics committees of the I.I. Mechnikov North-Western State Medical University and St. Petersburg Clinical Rheumatological Hospital No. 25.
Results
Baseline demographic and RA characteristics are listed in Table 1.
Patients of both groups were matched by age, gender, disease duration, activity, and treatment (see Table 2).
Table 3 provides data on prescribing urate-lowering therapy (UST) in patients with HU. Indications for prescribing allopurinol were inefficacy of prior efforts to normalize UA level, very high cardiovascular risk, and patient consent (some patients refused allopurinol and proceeded to diet or adjusted treatment for comorbidities).
Only data on 73 patients were addressed since we failed to collect full evidence due to refusal to seek further work-up, loss of communication, etc. Table 4 illustrates the RP parameters initially documented in each patient during follow-up visits. The mean duration of follow-up was 8.46±4.74 years.
Statistical analysis established some characteristics of RA (irrespective of HU) associated with changes in RP rate. Thus, in RA with systemic manifestations, RP progressed more slowly (3.5 [1; 9] years, p=0.02).
Changes in erosion score were most significant in patients with advanced clinical stage of RA (3.5 [1; 12]; p=0.04 vs. other clinical stages). Moreover, most rapid RP was reported in patients with radiographic stage 2 (1 [1; 6] years; p=0.04). Patients with RP had higher ESR (28.4 (12.9) mm/h, p=0.01) and daily UA excretion (3.7 [1.3; 6.1] mmol/day, p=0.02). Seropositivity for RF and CCP antibodies was associated with a higher score of bone erosions of the foot (two joints [0; 12], p=0.01). Correlation analysis revealed associations (p<0.05) shown in Table 5.
As Table 5 illustrates, more correlations with erosion score are reported in patients with HU than in patients without HU. Moreover, in HU, both blood UA and overall UA turnover positively correlated with RP parameters. Despite the same direction of correlations between UA turnover and RP in RA and the presence/absence of HU, strengths of these relationships are different: the correlation between RP and UA turnover in HU was moderate and strong, while the correlation between RP and UA turnover without HU was weak or lacking.
Discussion
Risk factors for RP in RA have been long known, i.e., being female, high titers of RF, CCP antibodies, an early appearance of joint erosions, high disease activity at onset, polyarticular lesions, HLA-Dw4 and HLA-Dw14 (DRB1*04 gene), and inefficacy of basic NSAIDs for 6 months. The sensitivity and specificity of detecting CCP antibodies in terms of predicting Sharp index progression is 67% and 56%, respectively. The rate of increase in erosion count in different phases of RA is variable, being the highest in the first 5 to 6 years. The relative erosion count increases from 18.3% at onset to 28.9% after 12 months, and up to 44.6% after 24 months despite a significant reduction in disease activity. New erosions appear in 33% of patients after 2 years. The RADIKAL study produced similar results [11, 12]. Our findings again support the role of standard risk factors (positive RF, CCP antibodies, disease activity, high RP rate at early stages, high RP frequency at late stages) in the development of RA.
Changes in UA levels have never been considered a potential risk factor for RP in RA. Published data suggesting mechanisms for realizing the negative effects of UA on RP in RA are available.
1. Direct involvement of UA in inflammation and joint destruction
UA/MU crystals in blood and tissues (including joints) stimulate the production of pro-inflammatory cytokines. UA/MU crystals act as DAMPs being recognized by pattern recognition receptors (e.g., Toll-like receptors) on innate immune cells. These cells act as antigen-presenting cells to further activate adaptive immune cells [13]. Alternatively, UA/MU crystals activate the production of pro-inflammatory cytokines through the intracellular signaling system [14]. These effects maintain disease activity and promote joint destruction.
Thus, a dose-dependent effect of increasing production of tumor necrosis factor (TNF) after blood monocytes exposure to MU crystals was empirically demonstrated. TNF, in turn, is known to be one of the key pro-inflammatory cytokines playing an important role in the pathogenesis of immunoinflammatory diseases, in particular, RA [15]. In contrast, calcium pyrophosphate or hydroxyapatite crystals do not stimulate a significant TNF production.
The effects of MU crystals (alone or in combination with TNF or IL-1β) on the activation of synovial fibroblasts (SFs) in patients with RA and healthy individuals were investigated in vitro [14]. MU crystals significantly increase the release of proinflammatory IL-6, CXCL8, and matrix metalloproteinase-1 from SFs in both groups [14]. Treating with MU crystals and TNF/IL-1β provided a synergic effect. The release of these molecules stimulated by MU crystals is regulated by intracellular activation of extracellular signal-regulated kinases but not p38 mitogen-activated protein kinases [14].
2. Induction of oxidative stress and endothelial dysfunction
XOR is involved in human UA synthesis at the final stages. XOR can act as a xanthine dehydrogenase/XDH (catalyzes oxidation of hypoxanthine to xanthine) and xanthine oxidase/XO (catalyzes oxidation of xanthine to UA). XDH can be converted to XO with the generation of reactive oxygen species. Free radicals are also released during UA synthesis (hydrogen peroxide in two-electron oxygen reduction or superoxide anion radical in one-electron oxygen reduction) [16]. Extracellular UA generally acts as an antioxidant (but interaction with certain molecules, e.g., myeloperoxidase, results in the generation of urate hydroperoxide, a strong oxidant), while intracellular UA has only oxidant properties [17]. Thus, superoxide anion radical interacts with nitric oxide (NO) to generate peroxynitrite with oxidant properties, thereby reducing NO availability. Alternatively, NO synthesis is inhibited by the effect of O2– on the intracellular signaling system, with further impairment of vasodilation and development of endothelial dysfunction and inflammation [18].
R. Wang et al. [19] have demonstrated that exposure of SF collected from patients with RA to MU crystals induces the expression of vascular cell adhesion molecule 1, responsible for leukocyte adhesion to the vascular wall and further activation and dysfunction of the endothelium.
In view of existing prerequisites, our findings appeared reasonable and establish a more severe damage to joints in patients with RA and HU than in patients with RA but no HU. Moreover, strong correlations between UA levels and progression of structural damage of hand and foot joints were revealed in HU. Meanwhile, in patients without HU, these correlations were weak or lack. The strength of relationship between HU and progression of joint lesions is similar to the strength of relationship between the progression of joint lesions and inflammatory marker (CRP/ESR) levels. Hence, an increase in UA levels (even if its excretion is also high) is hypothesized to be an independent proinflammatory marker.
Given these data, low-purine diet and urate-lowering therapy (ULT) should be included in the management plan for RA if he/she has HU. However, in our study, only 72-80% of patients with HU were recommended with diet, and less than 33% received allopurinol. Moreover, patients without RP received ULT twice as often as patients with similar progression. In patients who received allopurinol, target UA levels were achieved in 27% of individuals with RP and 80% of individuals without RP. These findings are evident of close relationships between RP and UA metabolism and a need to titrate allopurinol dosage to the target level to seek a positive effect of UA level improvement on RP in RA. Finally, the adherence of patients with HU to diet and ULT is important. The fact that patients without RP achieve UA target levels more often indirectly indicate less severe disorders of purine metabolism.
The limitations of our study are its retrospectivity and the small number of patients with certain data presented.
Conclusions
In RA, hyperuricemia is associated with RP. This phenomenon requires extensive studies to further investigate the mechanisms of the harmful effect of purine metabolism disorders on joints and to develop adequate approaches to timely diagnosis and management.
Preliminary data demonstrate that in RA, achieving target UA levels in the setting of diet and treatment with allopurinol is associated with the lack of RP in most cases. In contrast, failure to achieve target UA levels is associated with RP.
About the authors:
Alexandra Yu. Tsinserling — rheumatologist, Clinical Rheumatological Hospital No. 25; 30, Bolshaya Podyacheskaya str., St. Petersburg, 190068, Russian Federation; ORCID iD 0000-0003-4860-0518.
Vadim I. Mazurov — Dr. Sc. (Med.), Academician of the Russian Academy of Sciences, Honored Scientist of the Russian Federation, Head of the Center of Autoimmune Diseases, Clinical Rheumatological Hospital No. 25; 30, Bolshaya Podyacheskaya str., St. Petersburg, 190068, Russian Federation; Chief Scientific Consultant, Director of the Research Institute of Rheumatology, Head of the Department of Therapy, Rheumatology, Temporary Disability Examination and Quality of Medical Care named after E.E. Eichwald, I.I. Mechnikov North-Western State Medical University; 41, Kirochnaya str., St. Petersburg, 191015, Russian Federation; ORCID iD 0000-0002-0797-2051.
Inna Z. Gaydukova — Dr. Sc. (Med.), Professor of the Department of Therapy, Rheumatology, Temporary Disability Examination and Quality of Medical Care named after E.E. Eichwald, I.I. Mechnikov North-Western State Medical University; 41, Kirochnaya str., St. Petersburg, 191015, Russian Federation; Clinical Rheumatological Hospital No. 25; 30, Bolshaya Podyacheskayа str., St. Petersburg, 190068, Russian Federation; ORCID iD 0000-0003-3500-7256.
Roman A. Bashkinov — rheumatologist, Clinical Rheumatological Hospital No. 25; 30, Bolshaya Podyacheskaya str., St. Petersburg, 190068, Russian Federation; postgraduate student of the Department of Therapy, Rheumatology, Examination of Temporary Disability and Quality of Medical Care named after E.E. Eichwald, I.I. Mechnikov North-Western State Medical University; 41, Kirochnaya str., St. Petersburg, 191015, Russian Federation; ORCID iD 0000-0001-9344-1304.
Marianna S. Petrova — C. Sc. (Med.), Chief Medical Officer, Head of the City Clinical Center for Gout, Clinical Rheumatological Hospital No. 25; 30, Bolshaya Podyacheskaya str., St. Petersburg, 190068, Russian Federation; Associate Professor of the Department of Therapy, Rheumatology, Examination of Temporary Disability and Quality of Medical Care named after E.E. Eichwald, I.I. Mechnikov North-Western State Medical University; 41, Kirochnaya str., St. Petersburg, 191015, Russian Federation; ORCID iD 0000-0001-5261-6614.
Oksana V. Inamova — C. Sc. (Med.), Chief Officer of Clinical Rheumatological Hospital No. 25; 30, Bolshaya Podyacheskayа str., St. Petersburg, 190068, Russian Federation; Head of the Research Institute of Rheumatology, Assistant Professor of the Department of Therapy, Rheumatology, Temporary Disability Examination and Quality of Medical Care named after E.E. Eichwald, I.I. Mechnikov North-Western State Medical University; 41, Kirochnaya str., St. Petersburg, 191015, Russian Federation; ORCID iD 0000-0001-9126-3639.
Nikolay T. Gonchar — C. Sc. (Med.), Associate Professor of the Department of Public Health, Economics and Healthcare Management, I.I. Mechnikov North-Western State Medical University; 41, Kirochnaya str., St. Petersburg, 191015, Russian Federation.
Contact information: Inna Z. Gaydukova, e-mail: ubp1976@list.ru.
Financial Disclosure: no authors have a financial or property interest in any material or method mentioned.
There is no conflict of interests.
Received 29.07.2022.
Revised 23.08.2022.
Accepted 15.09.2022.
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