Treatment strategies for elderly-onset rheumatoid arthritis in the new era

ABSTRACT Elderly-onset rheumatoid arthritis (EORA) is characterized by acute onset and clinical features of high disease activity. Anti-cyclic citrullinated peptide antibody (ACPA) positivity or the presence of bone erosions predicts a radiological joint destruction of EORA, but ACPA-negative EORA with a polymyalgia rheumatica (PMR) phenotype may also present. Biological disease-modifying antirheumatic drugs (bDMARDs) and Janus kinase inhibitors were beneficial both in older and in younger patients in terms of risk–benefit balance. Implementation of a treat-to-target strategy could improve EORA outcomes, but older patients have more age-related comorbidities and interstitial lung disease than younger patients. Baseline comorbidities, more frequent methotrexate dose-dependent adverse events, serious infections, cardiovascular disease events, and malignancy all influence the choice of treatment and the treatment goals for older patients. Based on articles reviewed here, it is suggested that current treatment strategies for younger patients are also useful for ACPA-positive EORA and for ACPA-negative EORA with bone erosion. Differential diagnosis of ACPA-negative EORA without erosive arthritis and PMR with peripheral manifestations is challenging, and the treatment strategy of patients presenting with this overlap phenotype remained unclear. An appropriate treatment strategy for all patients with EORA still needs to be developed.

Giant cell arteritis with cervical radiculopathy mimicking polymyalgia rheumatica and elderly-onset rheumatoid arthritis: a case report

Background Giant cell arteritis has a wide variety of clinical symptoms, one of them being cervical radiculopathy, which mainly involves the C5 nerve root. If the patient does not develop typical clinical symptoms of giant cell arteritis but has C5 radiculopathy, it may be misdiagnosed as polymyalgia rheumatica or elderly-onset rheumatoid arthritis due to old age, high serum inflammatory markers, and difficulty in raising both upper limbs. Case presentation A 72-year-old Japanese man with a month-long history of dyspnea on exertion and with difficulty in raising both upper limbs was referred to our hospital because of elevated serum C-reactive protein (12.62 mg/dL). He had no typical symptoms of giant cell arteritis such as headache, jaw claudication, visual loss, and fever. The patient tested negative for rheumatoid factor and anti-cyclic citrullinated peptide antibody, and matrix metalloproteinase-3 was within the normal range (54.3 ng/mL). Musculoskeletal ultrasound examination showed absence of tenosynovitis, bursitis, and synovitis, and the patient did not meet the classification criteria of polymyalgia rheumatica or rheumatoid arthritis; hence, those two diseases were unlikely. A precise neurological examination suggested bilateral C5 and C6 anterior radiculopathy and left C4 radiculopathy. Since cervical magnetic resonance imaging showed no mechanical causality, cervical radiculopathy of unknown origin was suggested. Fluorodeoxyglucose positron emission tomography/computed tomography revealed increased fluorodeoxyglucose lineal uptake along the vessel walls, including temporal arteries, vertebral arteries, and axillary arteries. Results of the biopsy of the left superficial temporal artery were compatible with giant cell arteritis. He was successfully treated with 30 mg of prednisolone, and both upper limbs could be elevated. Conclusions If the patient was misdiagnosed with polymyalgia rheumatica or elderly-onset rheumatoid arthritis based on only clinical symptoms and laboratory data, his symptoms might not improve due to insufficient steroid dose and vascular complications may occur later. Although rare, peripheral neuropathy in giant cell arteritis may include cervical radiculopathy. The musculoskeletal ultrasound and precise neurological examination were the turning points for the diagnosis of this case, and making a careful diagnosis using these methods was important.

bFGF could be a biomarker of malignancy in RS3PE syndrome: an ambispective single-center cohort analysis of 51 patients

Objectives Remitting seronegative symmetrical synovitis with pitting edema (RS3PE) is a rare inflammatory arthritis, with a higher incidence of malignancy. The aim of this study is to identify biomarkers for predicting malignancy in RS3PE. Methods A total of 51 patients with RS3PE from September 2007 to May 2019 were retrospectively reviewed and followed for up to 5 years, with 15 patients with osteoarthritis (OA) and 14 patients with elderly-onset rheumatoid arthritis (EORA) as disease controls. Serum levels of angiogenesis cytokines were measured by electrochemiluminescent immunoassay and Luminex Human Magnetic Assay. Clinical data and laboratory parameters were analyzed to identify risk factors for malignancy. Results A total of forty-eight RS3PE patients (94.1%) were available with follow-up data; 8 patients (16.7%) were diagnosed with malignancy, of which 6 patients were hematological tumor; and 2 patients were solid tumors. Serum levels of basic fibroblast growth factor (bFGF) were exclusively higher in RS3PE patients with malignancy [14.21 (7.52, 23.18) ng/mL] than RS3PE patients without malignancy [4.32 (2.88, 7.42) ng/mL], OA [3.20 (2.20, 5.30) ng/mL], and EORA [3.20 (2.20, 5.30) ng/mL]. The optimal cut-off value of bFGF for malignancy was 10ng/mL in RS3PE. Logistic regression analysis indicated that elevation of bFGF was a risk factor for malignancy in RS3PE. Conclusions This study indicated that bFGF was elevated in RS3PE patients with malignancy and could serve as a biomarker for predicting paraneoplastic RS3PE.

Should we reconsider the definition of elderly-onset rheumatoid arthritis in an ageing society?

ABSTRACT Objectives The management of elderly-onset rheumatoid arthritis (EORA) is challenging due to progressive functional disability, increased comorbidities, and high drug-related risks. EORA is defined as disease onset after 60 years since 1985. We assessed whether this cut-off age was optimal in a progressively ageing society. Methods This study used two cohorts of consecutive rheumatoid arthritis (RA) patients: the Nippon Medical School (NMS) cohort (n = 204) and the Keio cohort (n = 296). Clinical findings independently correlated with the age of RA onset were selected as ‘EORA features’ from previously reported EORA characteristics using univariable and multivariable regression analyses. Receiver operating characteristic curve analysis was conducted to determine the cut-off age that best selected patients with all EORA features. Results Acute onset, negative anti-cyclic citrullinated peptide antibody, and high erythrocyte sedimentation rate were selected as ‘EORA features’ in both cohorts. Patients with all EORA features were more numerous with age and almost exclusively older than 65 years. The optimal EORA cut-off age was 73 years with an area under the curve (AUC) of 0.82 in the NMS cohort and 68 with an AUC of 0.93 in the Keio cohort. In the NMS cohort, Health Assessment Questionnaire-Disability Index and comorbidities in patients with disease onset between 60 years and the projected cut-off age were similar to those in younger-onset RA, but differed from those in patients with disease onset older than the projected cut-off age. Conclusion The optimal EORA cut-off age was greater than the conventional definition, but this needs to be validated in different patient populations.

bFGF could be a Biomarker of Malignancy in RS3PE Syndrome: an Ambispective Single Center Cohort Analysis of 51 Patients

ObjectivesRemitting seronegative symmetrical synovitis with pitting edema (RS3PE) is a rare inflammatory arthritis, with a higher incidence of malignancy. The aim of this study is to identify biomarkers for predicting malignancy in RS3PE.MethodsA total of 51 patients with RS3PE from September 2007 to May 2019 were retrospectively reviewed and followed for up to 5 years, with 15 patients with osteoarthritis (OA) and 14 patients with elderly-onset rheumatoid arthritis (EORA) as disease controls. Serum levels of angiogenesis cytokines were measured by electrochemiluminescent immunoassay and Luminex Human Magnetic Assay. Clinical data and laboratory parameters were analyzed to identify risk factors for malignancy.ResultsA total of forty-eight RS3PE patients (94.1%) were available with follow-up data, 8 patients (16.7%) were diagnosed with malignancy, of which 6 patients were hematological tumor, and 2 patients were solid tumor. Serum levels of basic fibroblast growth factor (bFGF) were exclusively higher in RS3PE patients with malignancy [14.21 (7.52, 23.18) ng/mL] than RS3PE patients without malignancy [4.32 (2.88, 7.42) ng/mL], OA [3.20 (2.20, 5.30) ng/mL] and EORA [3.20 (2.20, 5.30) ng/mL]. The optimal cut-off value of bFGF for malignancy was 10ng/mL in RS3PE. Logistic regression analysis indicated that elevation of bFGF was a risk factor for malignancy in RS3PE.ConclusionsThis study indicated that bFGF was elevated in RS3PE patients with malignancy and could serve as a biomarker for predicting paraneoplastic RS3PE.

Comparison of the drug retention and reasons for discontinuation of tumor necrosis factor inhibitors and interleukin-6 inhibitors in Japanese patients with elderly-onset rheumatoid arthritis—the ANSWER cohort study

Background This multi-center, retrospective study aimed to clarify retention rates and reasons for discontinuation of either tumor necrosis factor inhibitors (TNFi) or interleukin-6 inhibitors (IL-6i) in patients with elderly-onset rheumatoid arthritis (EORA). Methods Patients with rheumatoid arthritis (RA) enrolled in a Japanese multicenter observational registry between 2011 and 2020 were included. EORA was defined as RA with onset at 60 or over. To adjust confounding by indication for treatment with TNFi or IL-6i, a propensity score based on multiple baseline characteristics variables was used to compare the drug retention and causes for discontinuation between TNFi and IL-6i. Adjusted cumulative incidence of drug discontinuation for each reason was compared between the two groups using the Fine-Gray model. Results Among a total of 9,550 patients in the registry, 674 TNFi and 297 IL-6i initiators with EORA were identified. Age, the proportion of females, disease duration, and baseline disease activity at the time of TNFi or IL-6i initiation were similar between the two groups. After adjusting for differences in baseline characteristics between the two groups, overall drug discontinuation was significantly lower in the IL-6i as compared to the TNFi (HR = 0.71, 95%CI = 0.59–0.86, p < 0.001). The adjusted cumulative incidence of discontinuation due to lack of effectiveness was lower with the IL-6i (HR = 0.46, 95%CI = 0.33–0.63, p < 0.001) while those due to adverse events (HR = 0.82, 95%CI = 0.56–1.18, p = 0.28) or achievement of clinical remission (HR = 1.09, 95%CI = 0.62–1.91, p = 0.76) were similar between the two groups. Conclusions In EORA patients initiating a TNFi or IL-6i, significantly higher drug retention was observed with IL-6i. Discontinuation due to lack of effectiveness was significantly less frequent in IL-6i while discontinuations due to adverse event or achievement of clinical remission were similar between the two groups.

Similarity of response to biologics between elderly-onset rheumatoid arthritis (EORA) and non-EORA elderly patients: from the FIRST registry

Objective Increasing numbers of patients are developing rheumatoid arthritis (RA) at an older age, and optimal treatment of elderly-onset RA (EORA) patients is attracting greater attention. This study aimed to analyze the efficacy and safety of biological/targeted synthetic disease-modifying anti-rheumatic drugs (b/tsDMARDs) in EORA and non-EORA elderly patients. Methods A cohort of RA patients treated with b/tsDMARDs were retrospectively analyzed. Among patients who were ≥60 years old, those who developed RA after age 60 years were categorized as EORA, while others were categorized as non-EORA elderly. Disease activity were compared between the EORA and non-EORA elderly groups. Results In total, 1,040 patients were categorized as EORA and 710 as non-EORA elderly. There were not significant differences in characteristics at baseline between the two groups. The proportion of patients with low and high disease activity was comparable at week 2, 22 and 54 between in the EORA and the non-EORA elderly group. There was not significant difference in reasons of the discontinuation of b/tsDMARDs between the two groups. Elderly onset did not affect changes in CDAI and HAQ-DI as well as reasons of the discontinuation between the two groups. The trajectory analysis on CDAI-responses to b/tsDMARDs for 54 weeks identified three response patterns. The proportions of patients categorized into each group and CDAI-response trajectories to b/tsDMARDs were very similar between EORA and non-EORA elderly patients. Conclusion CDAI response patterns to b/tsDMARDs and hazard ratio of adverse events were similar between EORA and non-EORA elderly patients.

Comparison of the drug retention and reasons for discontinuation of Tumor Necrosis Factor Inhibitors and Interleukin-6 Inhibitors in patients with Elderly-onset Rheumatoid Arthritis-the ANSWER cohort study

Background: This multi-center, retrospective study aimed to clarify retention rates and reasons for discontinuation of either Tumor Necrosis Factor inhibitors (TNFi) or Interleukin-6 Inhibitors (IL-6i) in patients with elderly-onset rheumatoid arthritis (EORA).Methods: Patients with rheumatoid arthritis (RA) enrolled in a Japanese multicenter observational registry between 2011 and 2020 were included. EORA was defined as RA with onset at 60 or over. To adjust confounding by indication for treatment with TNFi or IL-6i, a propensity score based on multiple baseline characteristics variables was used to compare the drug retention and causes for discontinuation between TNFi and IL-6i. Adjusted cumulative incidence of drug discontinuation for each reason was compared between the two groups using the Fine-Gray model. Results: Among a total of 9550 patients in the registry, 674 TNFi and 297 IL-6i initiators with EORA were identified. Age, the proportion of females, disease duration, and baseline disease activity at the time of TNFi or IL-6i initiation were similar between the two groups. After adjusting for differences in baseline characteristics between the two groups, overall drug discontinuation was significantly lower in the IL-6i as compared to the TNFi (HR=0.71, 95%CI=0.59-0.86, p<0.001). The adjusted cumulative incidence of discontinuation due to lack of effectiveness was lower with the IL-6i (HR=0.46, 95%CI=0.33-0.63, p<0.001) while those due to adverse events (HR=0.82, 95%CI=0.56-1.18, p=0.28) or achievement of clinical remission (HR=1.09, 95%CI=0.62-1.91, p=0.76) were similar between the two groups.Conclusions: In EORA patients initiating a TNFi or IL-6i, significantly higher drug retention was observed with IL-6i. Discontinuation due to lack of effectiveness was significantly less frequent in IL-6i while discontinuations due to adverse event or achievement of clinical remission were similar between the two groups.