Effectiveness and safety of rituximab in special types of rheumatoid arthritis.

OBJECTIVES: To elucidate the efficacy and safety of rituximab in special types of rheumatoid arthritis. METHODS: We retrospectively reviewed all patients with rheumatoid arthritis with lymphoproliferative disorder or vasculitis treated with rituximab between April 2010 and June 2022 at Keio University Hospital. We assessed the effectiveness of rituximab using the Disease Activity Score for 28 joints-erythrocyte sedimentation rate (DAS28-ESR), Clinical Disease Activity Index (CDAI), and safety of rituximab during the disease course. We also assessed the glucocorticoid-sparing effects of rituximab. RESULTS: We included eight patients with a history of lymphoproliferative disorder and five patients with rheumatoid vasculitis. They were treated with rituximab without high-dose glucocorticoid. The mean DAS28-ESR and CDAI scores significantly improved 12 months after rituximab administration (DAS28-ESR, 4.7 vs. 2.7, p < .001; CDAI, 16.0 vs. 5.1, p = .006, respectively), and the dose of prednisolone was reduced from a mean of 7.4 mg/day to 4.0 mg/day at 12 months (p = .05) and 3.2 mg/day at the last visit (p = .04). During the mean follow-up period of 52 months, we recorded one recurrence of lymphoproliferative disorder (not B-cell type) in patients with a history of lymphoproliferative disorder and remarkable improvement of skin ulcers in patients with vasculitis. CONCLUSION: B-cell depletion by rituximab may be a useful treatment option for patients with lymphoproliferative disorder and rheumatoid vasculitis.

Rheumatoid vasculitis in 2023: Changes and challenges since the biologics era.

BACKGROUND: Significant changes in the epidemiology and natural history of rheumatoid vasculitis (RV) have occurred with the introduction of biological therapies such as TNF inhibitors (TNFi) and rituximab. PURPOSE: This scoping review aims to address the key current challenges and propose updated criteria for RV. This will aid future descriptive observational studies and prospective therapeutic trials. METHODOLOGY: The MEDLINE database was searched for eligible articles from inception through December 2022. Articles were selected based on language and publication date after 1998, corresponding to the approval of the first TNFi in rheumatic diseases. RESULTS: Sixty articles were included in the review. The mean incidence of RV has decreased since the approval of biologic therapies in RA, from 9.1 (95% CI: 6.8-12.0) per million between 1988 and 2000 to 3.9 (95% CI: 2.3-6.2) between 2001 and 2010, probably due to significant improvement in RA severity and a decrease in smoking habits. Factors associated with an increased risk of RV include smoking at RA diagnosis, longer disease duration, severe RA, immunopositivity, and male gender (regardless of age). Homozygosity for the HLA-DRB104 shared epitope is linked to RV, while the presence of HLA-C3 is a significant predictor of vasculitis in patients without HLA-DRB104. Cutaneous (65-88%), neurologic (35-63%), and cardiac (33%) manifestations are common in RV, often associated with constitutional symptoms (70%). Histologic findings range from small vessel vasculitis to medium-sized necrotizing arteritis, but definite evidence of vasculitis is not required in the 1984 Scott and Bacon diagnostic criteria. Existing data on RV treatment are retrospective, and no formal published guidelines are currently available. CONCLUSION: The understanding of RV pathogenesis has improved since its initial diagnostic criteria, with a wider range of clinical manifestations identified. However, a validated and updated criteria that incorporates these advances is currently lacking, impeding the development of descriptive observational studies and prospective therapeutic trials. PRIMARY FUNDING SOURCE: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Successful peficitinib monotherapy for the new-onset skin manifestations of rheumatoid vasculitis after long-term treatment with tocilizumab for rheumatoid arthritis.

Rheumatoid vasculitis (RV) is a severe extra-articular systemic manifestation of rheumatoid arthritis (RA). Its prevalence has been decreasing for decades because of improved early diagnosis of RA and advances in RA treatment, but it remains a life-threatening disease. The standard treatment for RV has been a glucocorticoid and disease-modifying antirheumatic drugs. Biological agents, including antitumour necrosis factor inhibitors, are also recommended for refractory cases. However, there are no reports of Janus kinase (JAK) inhibitor use in RV. We experienced a case of an 85-year-old woman with a 57-year history of RA who had been treated with tocilizumab for 9 years after receiving three different biological agents over 2 years. Her RA seemed to be in remission in her joints, and her serum C-reactive protein had decreased to 0.0 mg/dL, but she developed multiple cutaneous leg ulcers associated with RV. Because of her advanced age, we changed her RA treatment from tocilizumab to the JAK inhibitor peficitinib in monotherapy, after which the ulcers improved within 6 months. This is the first report to indicate that peficitinib is a potential treatment option for RV that can be used in monotherapy without glucocorticoids or other immunosuppressants.

Biological therapy in rheumatoid vasculitis: a systematic review.

Rheumatoid vasculitis (RV) is one of the most severe extra-articular manifestations of rheumatoid arthritis, with significant morbidity and mortality, requiring aggressive treatment with corticosteroids and/or immunosuppressants. Recently, biological drugs were included in its therapeutic armamentarium. The objective of this study was to perform a systematic review on the use of biological drugs in the treatment of RV. A systematic literature review was performed based on PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) recommendations and searching articles in MEDLINE/PubMed, Cochrane, SciELO, Scopus, and Virtual Health Library electronic databases. Secondary references were also evaluated. The methodological quality of the selected studies was evaluated by the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) criteria. Altogether, five articles, assessing the use of biological drugs, were included. Globally, 35 patients participated in the studies, of which 21 were treated with rituximab (RTX) in cycles of 1000 mg every 2 weeks; 9 used infliximab 5 mg/kg; 3 used infliximab 3 mg/kg; and 2 used etanercept 25 mg twice/week. In general, an improvement in clinical picture, reduction of the mean daily dose of corticosteroids, and improvement in the Birmingham Vasculitis Activity Score was achieved by the end of the treatment. Complete remission occurred in almost 70% of the cases. The adverse effect rate was 34%, mainly due to infections. There were two deaths, one due to sepsis and the other due to uncontrolled vasculitis, after the biological drug withdrawal, following the development of sepsis. Based on the results of the present review, we believe that the use of biological therapy such as RTX and anti-tumor necrosis factor α can be beneficial in treating this complication.

Programmed cell death protein 1 inhibitor-induced recalcitrant mixed small and medium vessel vasculitis.

Pembrolizumab, a programmed cell death protein 1 (PD1) inhibitor, has been known to be associated with several adverse reactions, including immune related adverse events. In less than one percent of patients, PD1 inhibitors have been linked to the development of connective tissue disease. Patients with previously known connective tissue disease are hypothesized to be at increased risk of flares in as many as 40% of cases. A 70-year-old man with a past medical history significant for rheumatoid arthritis in remission and stage IV lung adenocarcinoma presented to the dermatology clinic after one cycle of nivolumab and eight cycles of pembrolizumab exhibiting worsening, painful bilateral lower extremity ulcers for approximately one month. On the lower legs, three large black retiform eschars and bullous purpuric plaques were observed. Vasculitis is a rare complication of PD1 inhibitor therapy, with the majority of cases reported in literature either medium vessel or large vessel vasculitis. Only glucocorticoids have proven effective for PD1-induced vasculitis and these patients generally require multi-specialty management.

18 F-fluorodeoxyglucose positron emission tomography/computed tomography in patients with polymyalgia rheumatica: Screening for vasculitis. / 18 F-FDG PET/TC en pacientes con polimialgia reumática: despistando vasculitis.

OBJECTIVE: Polymyalgia rheumatica (PR) can be associated with large vessel vasculitis (LVV). We evaluate the diagnostic role of 18F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) and its impact on the treatment of LVV associated with PR. MATERIALS AND METHODS: Retrospective study of patients diagnosed with PR. Data was collected from health records. Blood analysis included acute-phase reactants (APR), C-reactive protein (CRP) and erythrocyte sedimentation rate. An 18F-FDG PET/CT scan was performed in those patients whose symptoms persisted, in those with elevated APR, those who required higher doses of steroids or those who had atypical features of PR (low-grade fever, weight loss, among others). RESULTS: Twenty-three were eligible; 48% (n = 11) of the patients were diagnosed with LVV associated with PR. The site was heterogeneous, but mostly involved the aorta. In 80% of the patients with LVV, a disease-modifying antirheumatic drug was added to their treatment. Elevated CRP values were associated with the likelihood of presenting LVV. CONCLUSIONS: LVV is not uncommon, clinical features and elevated CRP levels should raise suspicion of LVV associated with PR. 18F-FDG PET/CT is useful in identifying LVV associated with PR.

Rituximab Therapy for Systemic Rheumatoid Vasculitis: Indications, Outcomes, and Adverse Events.

OBJECTIVE: To characterize the indication, outcomes, and adverse effects of rituximab (RTX) treatment in a large single-center cohort of patients with systemic rheumatoid vasculitis (RV). METHODS: We retrospectively reviewed the medical charts of 17 patients treated with RTX for systemic RV from 2000 to 2017. Clinical characteristics, outcomes, and adverse effects were analyzed. RESULTS: At RV diagnosis, mean age was 59 years, 59% were female, 94% were white, and 82% had positive rheumatoid factor. At the time of initiating RTX, median Birmingham Vasculitis Activity Score for rheumatoid arthritis was 4.0 (interquartile range 2.0-7.5). RV presented in the skin in 8 patients (47%), as mononeuritis multiplex in 2 (12%), inflammatory ocular disease in 2 (12%), and affected multiple organ systems in 5 (29%). RTX was used for induction therapy in 8 patients (47%), relapsing RV in 4 (24%), second-line therapy in 2 (12%), and salvage therapy or in combination with another agent in 3 (18%). At 3 months, 2 (13%) of 15 patients with available followup information achieved complete remission (CR), and 10 (67%) achieved partial response (PR). At 6 months, 6 patients (40%) achieved CR, 8 (53%) achieved PR, and one had no response. At 12 months, 8 of 13 patients with available records (62%) had CR and 5 patients (38%) had PR. CONCLUSION: Systemic RV is difficult to treat effectively. CR of RV was achieved in 62% and PR in 38% of patients within 12 months of RTX use. Further evidence is needed to inform treatment for patients with RV.

Severe Mononeuritis Multiplex due to Rheumatoid Vasculitis in Rheumatoid Arthritis in Sustained Clinical Remission for Decades.

Rheumatoid vasculitis (RV) usually occurs in patients with refractory rheumatoid arthritis (RA). An 80-year-old woman was transferred to our hospital because of muscle weakness and paresthesia in all 4 limbs. She had been diagnosed with RA 30 years ago and achieved sustained clinical remission. At presentation, polyarthritis and drop foot were observed, and rheumatoid factor was prominently elevated. A peripheral nerve conduction test revealed mononeuritis multiplex in her limbs. We suspected that RV had developed rapidly despite RA having been stable for many years and started immunosuppression therapy with steroids combined with azathioprine. The treatment prevented worsening of muscle weakness and paresthesia.

Glucocorticoid-sensitive Paroxysmal Atrial Fibrillation, Sick Sinus Syndrome, and Mitral Regurgitation in a Patient with Malignant Rheumatoid Vasculitis.

An 80-year-old woman with rheumatoid arthritis presented with chest pain. Clinical examination revealed new-onset paroxysmal atrial fibrillation with symptomatic sinus pauses and worsening mitral regurgitation, which were both resistant to conventional therapies. Based on her skin lesions, an increase in pleural and pericardial effusion, possible myocardial involvement, and a positive finding for immune complex testing, rheumatoid vasculitis was diagnosed. Subsequent glucocorticoid therapy suppressed systemic inflammation, resulting in structural, functional, and electrical reverse remodeling of the left atrium with complete remission of atrial arrhythmias and also an improvement of mitral regurgitation. This case highlights the importance of evaluating the underlying disease activity in a case of de novo paroxysmal atrial fibrillation associated with systemic autoimmune disease.

A case of rheumatoid vasculitis with acquired reactive perforating collagenosis.

A 55-year-old man with rheumatoid arthritis (RA) presented hyperkeratotic erythematous papules with crusts or blisters on his limbs and buttocks. A histological study showed acquired reactive perforating collagenosis. Soon, skin lesions changed to umbilicated lesions with black necrosis, and the scar from his skin biopsy ulcerated with induration due to rheumatoid vasculitis. Systemic corticosteroids and tacrolimus administration resolved the RA and skin lesions. Rheumatoid vasculitis with acquired reactive perforating collagenosis has not been reported previously.

Inflammatory arthritis and crystal arthropathy: Current concepts of skin and systemic manifestations.

Systemic inflammatory disorders frequently involve the skin, and when cutaneous disease develops, such dermatologic manifestations may represent the initial sign of disease and may also provide valuable prognostic information about the underlying disorder. Familiarity with the various skin manifestations of systemic disease is therefore paramount and increases the likelihood of accurate diagnosis, which may facilitate the implementation of an appropriate treatment strategy. An improvement in quality of life and a reduction in the degree of morbidity may also be a realized benefit of accurate recognition of these skin signs. With this context in mind, this review highlights the salient clinical features and unique dermatologic manifestations of rheumatoid arthritis, adult-onset Still's disease, and the crystal arthropathy, gout.

Rheumatoid Vasculitis: A Diminishing Yet Devastating Menace.

PURPOSE OF REVIEW: Rheumatoid vasculitis (RV) is an unusual complication of long-standing rheumatoid arthritis, which is characterized by the development of necrotizing or leukocytoclastic vasculitis involving small or medium-sized vessels. In this review, we aim to provide an update on the epidemiology, pathogenesis, clinical presentation, and management of this challenging extra-articular manifestation. RECENT FINDINGS: RV is heterogenous in its clinical presentation depending on the organ and size of blood vessels involved. The most common organs involved are the skin and peripheral nerve. Based on recent population studies, the incidence has significantly decreased with early recognition and the advent of immunosuppressive drugs and biologics; however, the mortality rates remain high. RV remains a serious extra-articular manifestation of RA that needs to be promptly recognized and treated. No consensus is available on treatment, given the ongoing debate of whether the biologics can trigger or treat RV.

A Case of Rheumatoid Vasculitis Involving Hepatic Artery in Early Rheumatoid Arthritis.

Rheumatoid vasculitis is a rare, but most serious extra-articular complications of long-standing, seropositive rheumatoid arthritis (RA). Vasculitis of hepatic artery is an extremely rare but severe manifestation of rheumatoid vasculitis. A 72-year-old woman who presented with polyarthralgia for 2 months was diagnosed with early RA. Since she had manifestations of livedo reticularis, and liver dysfunction which was atypical for RA patients, a percutaneous needle liver biopsy was performed revealing arteritis of a medium-sized hepatic artery. Extensive investigations did not reveal evidences of other systemic causes such as malignancy or systemic vasculitis. The patient was diagnosed with rheumatoid vasculitis involving hepatic arteries based on Bacon and Scott criteria for rheumatoid vasculitis. With high dose corticosteroid and cyclophosphamide induction and methotrexate and tacrolimus maintenance treatment, she was successfully recovered. Association of rheumatoid vasculitis at very early stages of the disease may represent an early aggressive form of RA.

Connective Tissue Disorder-Associated Vasculitis.

Vasculitides secondary to connective tissue diseases are classified under the category of 'vasculitis associated with systemic disease' in the revised International Chapel Hill Consensus Conference (CHCC) nomenclature. These secondary vasculitides may affect any of the small, medium or large vessels and usually portend a poor prognosis. Any organ system can be involved and the presentation would vary depending upon that involvement. Treatment depends upon the type and severity of presentation. In this review, we describe secondary vasculitis associated with rheumatoid arthritis, systemic lupus erythematosus, sarcoidosis, relapsing polychondritis, systemic sclerosis, Sjogren's syndrome and idiopathic inflammatory myositis, focusing mainly on recent advances in the past 3 years.

Recurrent Stenosis of the Ileum Caused by Rheumatoid Vasculitis.

A 65-year-old man with a 20-year history of rheumatoid arthritis was transferred to our hospital due to a second episode of intestinal obstruction, a fever, and joint pain within the previous 6 months. He had an extremely high rheumatoid factor level and decreased complement levels. Abdominal computed tomography, a small bowel series, and small intestinal endoscopy revealed severe ileal stenosis. Resection of the stenotic lesion was performed, and a histopathological examination revealed vasculitis. Rheumatoid vasculitis was diagnosed, and the patient began treatment with prednisolone and methotrexate, which improved his condition. Rheumatoid vasculitis is a rare, but possible cause of recurrent bowel obstruction.

Methotrexate-mediated activation of an AMPK-CREB-dependent pathway: a novel mechanism for vascular protection in chronic systemic inflammation.

AIMS: Premature cardiovascular events complicate chronic inflammatory conditions. Low-dose weekly methotrexate (MTX), the most widely used disease-modifying drug for rheumatoid arthritis (RA), reduces disease-associated cardiovascular mortality. MTX increases intracellular accumulation of adenosine monophosphate (AMP) and 5-aminoimidazole-4-carboxamide ribonucleotide which activates AMP-activated protein kinase (AMPK). We hypothesised that MTX specifically protects the vascular endothelium against inflammatory injury via induction of AMPK-regulated protective genes. METHODS/RESULTS: In the (NZW×BXSB)F1 murine model of inflammatory vasculopathy, MTX 1 mg/kg/week significantly reduced intramyocardial vasculopathy and attenuated end-organ damage. Studies of human umbilical vein endothelial cells (HUVEC) and arterial endothelial cells (HAEC) showed that therapeutically relevant concentrations of MTX phosphorylate AMPKα(Thr172), and induce cytoprotective genes including manganese superoxide dismutase (MnSOD) and haem oxygenase-1 (HO-1). These responses were preserved when HUVECs were pretreated with tumour necrosis factor-α to mimic dysfunctional endothelium. Furthermore, MTX protected against glucose deprivation-induced endothelial apoptosis. Mechanistically, MTX treatment led to cyclic AMP response element-binding protein (CREB)(Ser133) phosphorylation, while AMPK depletion attenuated this response and the induction of MnSOD and HO-1. CREB siRNA inhibited upregulation of both cytoprotective genes by MTX, while chromatin immunoprecipitation demonstrated CREB binding to the MnSOD promoter in MTX-treated EC. Likewise, treatment of (NZW×BXSB)F1 mice with MTX enhanced AMPKα(Thr172) phosphorylation and MnSOD, and reduced aortic intercellular adhesion molecule-1 expression. CONCLUSIONS: These data suggest that MTX therapeutically conditions vascular endothelium via activation of AMPK-CREB. We propose that this mechanism contributes to the protection against cardiovascular events seen in patients with RA treated with MTX.