Riitta Koivuniemi

Amyloidosis is frequently undetected in patients with rheumatoid arthritis

Prevalence of AA amyloid in rheumatoid arthritis (RA) is still unclear. The objective of this retrospective study was whether dedicated re-examination of autopsy tissues from RA patients increases the detection rate of amyloid compared to routine examination. Amyloid was re-examined in tissue samples and detection rate compared with original reports of 369 consecutively autopsied RA patients and 370 non-RA patients matched for sex, age, and year of autopsy between 1952 and 1991. Re-examination of 90% of the 739 cases showed doubling of the prevalence of amyloid compared with the original reports: from 18 to 30% in RA and from 2 to 4% in non-RA patients. In RA patients, cardiac amyloid was as frequent as renal amyloid. In RA patients with amyloid at re-examination, amyloidosis had been diagnosed before autopsy in 37%, and these patients had more inflammation and longer disease duration than RA patients without amyloid. Only 56% of RA patients with renal amyloid were known to have proteinuria. In conclusion, this autopsy study shows that amyloid in RA is a common finding which remains frequently undetected. In patients with active and long-lasting RA, a systematic search for amyloid may enable early diagnosis of amyloidosis, which will require effective suppression of inflammation.

Cardiovascular diseases in patients with rheumatoid arthritis.

Objectives: To study cardiovascular autopsy findings and the lifetime prevalence of cardiovascular diseases (CVDs) in patients with rheumatoid arthritis (RA). Method: In 369 RA patients and their reference cases without any rheumatic disease (non-RA), we studied CVDs recorded on autopsy reports at consecutive autopsies from 1952 to 1991. From autopsy referrals by clinicians, we recorded lifetime CVDs. In RA patients autopsied from 1973, we evaluated clinical data. Results: From 1952 to 1991, RA patients had, compared with non-RA, myocardial infarction (MI; 26% vs. 41%) and cerebral infarction (14% vs. 28%) less frequently but cardiac amyloidosis (28% vs. 3%), pericarditis (27% vs. 8%), and diffuse myocardial abnormality (21% vs. 11%) more frequently reported at autopsy. Of RA patients autopsied from 1973, 40% had had a diagnosis of congestive heart failure (CHF) and coronary heart disease (CHD) during their lifetime. The RA patients with CHF had a higher mean erythrocyte sedimentation rate (ESR) than those without CHF. In RA patients, MI or myocardial abnormality at autopsy had no such correlation. In RA, male sex, ischaemic electrocardiogram changes, diabetes, hypertensive disease, and severe radiographic changes typical for RA were associated with MI detected at autopsy. No such associations emerged with respect to diffuse myocardial abnormality. When disorders potentially causing diffuse myocardial damage were excluded, RA patients had, on autopsy reports, compared to non-RA, diffuse myocardial abnormality more frequently (21% vs. 12%, p = 0.002). Cardiac amyloidosis showed no correlation to this. Conclusion: RA patients seem to have an increased risk for myocardial damage. The influence of inflammation on the myocardium in RA needs further studies.

Juvenile Chronic Arthritis in Adult Life: A Study of Long-term Outcome in Patients with Juvenile Chronic Arthritis or Adult Rheumatoid Arthritis

Abstract: We compared the prognostic factors and outcome of 30 patients with juvenile chronic arthritis (JCA) extending into adult life with those of 30 patients with adult rheumatoid arthritis (RA) at a university adult rheumatology clinic; pairs were matched for sex and duration of disease (mean 8 years). One-third of JCA patients had seronegative polyarticular disease and another third had oligoarticular disease. In a third of the JCA patients, the clinical presentation changed during the follow-up. Over half of the RA patients had seropositive polyarticular and a one-third had seronegative polyarticular disease. Fewer seropositive patients were recorded in the JCA group than in the RA group both at the beginning (16.7% versus 56.7%; p = 0.003) and at the end of the follow-up (14.3% versus 59.3%; p = 0.001). JCA patients developed less radiographic changes than RA patients (46.7% versus 76.7%; p = 0.034); oligoarthritis in the JCA group had the best prognosis whereas seropositive polyarthritis in the RA group had the worst prognosis. Significantly more patients with JCA than RA (60% versus 23%; p = 0.009) were in remission at the end of the follow-up. In conclusion, when studied in adult life, the long-term prognosis is better in patients with JCA than in those with RA.

Causes of death in patients with rheumatoid arthritis from 1971 to 1991 with special reference to autopsy

Rheumatoid arthritis (RA) patients have premature mortality, mostly attributed to cardiovascular diseases (CVDs). We studied causes of death (CoDs) and contribution of autopsy to them in RA patients treated at a single hospital responsible for primary to tertiary RA treatment in Helsinki. In 1971–1991, 960 RA patients died. The leading CoDs were CVDs, RA, and infections. Over 1971–1991, RA and renal deaths declined, but other CoDs showed no change. Autopsied patients died more frequently than nonautopsied of coronary heart disease (CHD) and gastrointestinal disorders, but less frequently of RA, renal, and endocrinologic diseases. Our finding of autopsied patients having CHD more frequently as a CoD may indicate that CHD, which may be asymptomatic in RA, may be overlooked during lifetime.

Causes of death in patients with rheumatoid arthritis autopsied during a 40-year period

We studied causes of death (CoDs) between 1952 and 1991 assessed by a clinician before autopsy and then determined at autopsy by a pathologist in 369 subjects with rheumatoid arthritis (RA) and 370 subjects without RA (non-RA). We analysed clinical data for RA subjects between 1973 and 1991. In RA subjects, leading autopsy-based CoDs were RA, cardiovascular diseases and infections. Between diagnoses of CoDs by the clinician and those determined by the pathologist, RA subjects had lower agreement than did the non-RA regarding coronary deaths (Kappa reliability measure: 0.33 vs. 0.46). In non-RA subjects, autopsy-based coronary deaths showed a decline since the 1970s with no such decline in RA. Between subjects treated at any time during RA with disease-modifying anti-rheumatic drugs and those without, autopsy-based CoDs were similar. Coronary death being less accurately diagnosed in RA subjects may indicate that coronary heart disease in RA patients often remains unrecognized.

Constitutive STAT3 Phosphorylation in Circulating CD4(+) T Lymphocytes Associates with Disease Activity and Treatment Response in Recent-Onset Rheumatoid Arthritis

The aim of the present study was to examine constitutive signal transducer and activator of transcription 3 (STAT3) phosphorylation in circulating leukocytes as a candidate biomarker in rheumatoid arthritis (RA). 25 patients with recent-onset, untreated RA provided samples for whole blood flow cytometric determination of intracellular STAT3 phosphorylation, expressed as relative fluorescence units. The occurrence of constitutive STAT3 phosphorylation was evaluated by determining proportion of STAT3-phosphorylated cells among different leukocyte subtypes. Plasma levels of interleukin (IL)-6, IL-17 and IL-21 were measured by immunoassay, radiographs of hands and feet were examined and disease activity score (DAS28) was determined. Biomarkers were restudied and treatment response (according to European League Against Rheumatism) was determined after 12 months of treatment with disease-modifying antirheumatic drugs. At baseline, constitutive phosphorylation of STAT3 occurred in CD4+ T cells of 14 (56%) patients, CD8+ T cells of 13 (52%) patients, in CD19+ B cells of 7 (28%) patients, and in CD14+ monocytes of 12 (48%) patients. STAT3 phosphorylation levels of CD4+ T cells associated with DAS28, and those of all leukocyte subtypes studied associated with erosive disease. The presence of constitutive STAT3 phosphorylation in CD4+ T lymphocytes, pSTAT3 fluorescence intensity of CD4+ and CD8+ T cells and C-reactive protein (CRP) levels at baseline associated with good treatment response. In conclusion, constitutive STAT3 phosphorylation in circulating CD4+ T cells is common in recent-onset untreated RA and associates with good treatment response in patients characterized by high disease activity and the presence of systemic inflammation.

Periodontitis in early and chronic rheumatoid arthritis: a prospective follow-up study in Finnish population

Objectives To investigate the association between rheumatoid arthritis (RA) and periodontitis with special emphasis on the role of antirheumatic drugs in periodontal health. Design Prospective follow-up study. Patients with early untreated RA and chronic active RA were examined at baseline and 16 months later. Controls were examined once. Settings and participants The study was conducted in Finland from September 2005 to May 2014 at the Helsinki University Hospital. Overall, 124 participants were recruited for dental and medical examinations: 53 were patients with early disease-modifying antirheumatic drug (DMARD) naїve RA (ERA), 28 were patients with chronic RA (CRA) with insufficient response to conventional DMARDs. After baseline examination, patients with ERA started treatment with synthetic DMARDs and patients with CRA with biological DMARDs. Controls were 43 age-matched, gender-matched and community-matched participants. Outcome measures Degree of periodontitis (defined according to the Center for Disease Control and Prevention and the American Academy of Periodontology). Prevalence of periodontal bacteria (analysed from plaque samples), clinical rheumatological status by Disease Activity Score, 28-joint count (DAS28), function by Health Assessment Questionnaire (HAQ) and treatment response by European League Against Rheumatism (EULAR) criteria. Results Moderate periodontitis was present in 67.3% of patients with ERA, 64.3% of patients with CRA and 39.5% of control participants (p=0.001). Further, patients with RA had significantly more periodontal findings compared with controls, recorded with common periodontal indexes. In the re-examination, patients with RA still showed poor periodontal health in spite of treatment with DMARDs after baseline examination. The prevalence of Porphyromonas gingivalis was higher in patients with ERA with periodontal probing depth ≥4 mm compared with patients with CRA and controls. Antirheumatic medication did not seem to affect the results. Conclusions Moderate periodontitis was more frequent in patients with RA than in controls. Patients with ERA and CRA exhibited poorer periodontal health parameters when compared with controls. There was no association between antirheumatic treatment and periodontal parameters.

Somatic mutations in clonally expanded cytotoxic T lymphocytes in patients with newly diagnosed rheumatoid arthritis

Somatic mutations contribute to tumorigenesis. Although these mutations occur in all proliferating cells, their accumulation under non-malignant conditions, such as in autoimmune disorders, has not been investigated. Here, we show that patients with newly diagnosed rheumatoid arthritis have expanded CD8+ T-cell clones; in 20% (5/25) of patients CD8+ T cells, but not CD4+ T cells, harbour somatic mutations. In healthy controls (n=20), only one mutation is identified in the CD8+ T-cell pool. Mutations exist exclusively in the expanded CD8+ effector-memory subset, persist during follow-up, and are predicted to change protein functions. Some of the mutated genes (SLAMF6, IRF1) have previously been associated with autoimmunity. RNA sequencing of mutation-harbouring cells shows signatures corresponding to cell proliferation. Our data provide evidence of accumulation of somatic mutations in expanded CD8+ T cells, which may have pathogenic significance for RA and other autoimmune diseases.

Malignancies in patients with rheumatoid arthritis.

Mortality due to malignancies, albeit with some controversy, is not increased in patients with rheumatoid arthritis (RA) (1, 2), except for lymphoproliferative malignancies (2) and lung cancer (3). In 369 RA patients (280 females) and their controls without any rheumatic disease (non-RA), we studied the autopsy findings, autopsy-based immediate, underlying, and contributory causes of death (CoDs) from death certificates, and the accuracy of CoDs with respect to malignancies. Patients were autopsied (autopsy rate; mean 76%) from 1952 to 1991 at Kivelä Municipal Hospital, which is responsible for special health care of internal diseases and primary to tertiary care of RA, as described earlier (4). From 1973, we studied the clinical data for RA patients. If a CoD was not mentioned on autopsy referral, but verified as such at autopsy, the CoD was considered as unrecognized to the clinician pre-mortem. Comparisons between groups were performed with χ2 or Fisher’s exact test and by Student’s t-test. Statistical significance of linearity was evaluated by the linear-by-linear association test. The local ethics committee approved the study. As monotherapy or in combination, disease modifying anti-rheumatic drugs (DMARDs), including aurothiomalate, anti-malarials, sulfasalazine, penicillamine, auranofin, azathioprine (used by three patients), and cyclophosphamide (by seven), were used by 138 (82%) patients. From 1973 to 1991, the proportion of patients with DMARDs remained unchanged. Acetylsalicylic acid (ASA) was used by 142 (95%) RA patients. Compared to non-RA cases, RA patients died less frequently of malignancies (Table 1). In neither group did deaths caused by malignancies show a major change over time. Malignant CoD was undetected pre-mortem in one-third of RA patients (Figure 1) and in one-third of non-RA cases. Duration of RA (±SD) was longer in patients dying of lymphoma than in those dying of other causes (27 ± 9 years vs. 17 ± 11 years, p = 0.050). Of RA patients on azathioprine, one died of lymphoma. None of the patients on cyclophosphamide died of malignancy. Mortality in RA patients caused by lymphoproliferative malignancies is increased (2), in parallel with our study in which RA patients died of lymphoma slightly more frequently than non-RA cases. Our RA patients died, compared to non-RA, less frequently of breast cancer and reproductive system malignancies, in line with others’ findings (1, 2, 5). In hospital-based studies comprising 1000 RA patients or more, deaths caused by breast cancer were decreased. In these studies, breast cancer caused death in three RA patients (expected number 5.2, a non-significant finding) (1) and in one RA patient and six controls (2). In the latter study, uterine and ovarian cancer appeared to be also less frequent in RA. These caused death in three RA patients and six controls. Furthermore, ovarian cancer caused death in 2% of RA patients and 11% of controls in an autopsy study (5). In postmenopausal women, ASA usage has been associated with decreased overall mortality and decreased mortality due to malignancy (6). Because the numbers of our patients with breast cancer and reproductive system malignancies were small, the results should be interpreted with caution and further studies are needed. We have found no studies about accuracy of CoDs in RA patients. One meta-analysis on various populations demonstrated that one-third of CoDs may be incorrect (7), close to our findings. Furthermore, the level of clinician’s certainty as to diagnosis pre-mortem has been shown to have no correlation with final diagnosis determined at autopsy (8). In patients autopsied at a university hospital between 1986 and 1995, frequently undiagnosed malignant CoDs were gastrointestinal (GI) malignancies (9), close to our findings, in which GI malignancies, along with lymphoma, in RA patients were most frequently undetected pre-mortem. Our study has some limitations. No clinical data before 1973 were available for RA patients. Despite the high autopsy rate, not all RA patients who died were included. It is generally thought that an autopsy population may invite biases. However, we have previously shown that the rate of malignant deaths in autopsied RA patients treated at Kivelä Hospital was close to that in those without autopsy from 1971 to 1991 (10). Furthermore, CoDs here are likely to be accurate because they are based on autopsy, the gold standard (7). In conclusion, lymphoma mortality in RA patients treated with conventional DMARDs, but not with methotrexate or biological therapy, seems to be increased, but mortality due to breast cancer and reproductive system malignancies may be reduced. Sc an d J R he um at ol D ow nl oa de d fr om in fo rm ah ea lth ca re .c om b y U ni ve rs ity o f N or th T ex as o n 11 /0 9/ 14

Inflammatory biomarkers in saliva and serum of patients with rheumatoid arthritis with respect to periodontal status

Abstract Objective: To study prospectively the association of salivary and serum matrix metalloproteinase (MMP)-8, tissue inhibitor of MMPs (TIMP)-1 and interleukin (IL)-6 with periodontal and systemic inflammation in rheumatoid arthritis (RA). We hypothesized that biomarker concentrations reflect inflammation. Methods: Fifty three early untreated RA (ERA) and 28 chronic RA (CRA) patients, underwent rheumatological and dental examinations at baseline and one year later after starting first conventional or biological disease modifying antirheumatic drug. We included 43 control subjects. Saliva and serum samples were analyzed for MMP-8, TIMP-1 and IL-6. Periodontal health was assessed by bleeding on probing (BOP), pocket depth (PD) and periodontal inflammatory burden index (PIBI); RA disease activity was assessed by disease activity score DAS28. Joint destruction was analyzed by the modified Sharp-van der Heijde (SHS) method. Results: Serum MMP-8 (p < .001; p < .001) and IL-6 (p < .001; p = .002) were significantly higher in CRA vs. other study groups during the study. Salivary MMP-8 (p = .010) and IL-6 (p = .010) were significantly higher in ERA vs. other study groups at baseline. Salivary MMP-8 was associated with periodontal parameters. Conclusion: Elevated serum concentrations of MMP-8 and IL-6 in CRA patients reflected chronic RA, while elevated salivary concentrations of MMP-8 levels in ERA patients reflected increased periodontal inflammation. Key messages Concentrations of inflammatory biomarkers in serum and saliva were different between patients with RA and healthy controls. Concentrations of MMP-8 and of IL-6 in serum were elevated in patients with chronic RA reflecting joint inflammation and the burden of established RA. Concentrations of MMP-8 in saliva was elevated already at the early stage of RA and the level of salivary MMP-8 was associated with poor periodontal health both in patients with early and in those with chronic RA.