Management of Peripheral Arthritis in Patients With Psoriatic Arthritis: An Updated Literature Review Informing the 2021 GRAPPA Treatment Recommendations.

OBJECTIVE: We aimed to compile evidence for the efficacy and safety of therapeutic options for the peripheral arthritis domain of psoriatic arthritis (PsA) for the revised 2021 Group in Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) treatment recommendations. METHODS: A working group consisting of clinicians and patient research partners was convened. We reviewed the evidence from new randomized controlled trials (RCTs) for PsA treatment from February 19, 2013, to August 28, 2020. We used the Grading of Recommendations Assessment, Development, and Evaluation (GRADE)-informed approach to derive evidence for the classes of therapeutic options for 3 patient groups: (1) naïve to treatment, (2) inadequate response to conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), and (3) inadequate response to biologic DMARDs (bDMARDs). Recommendations were derived through consensus meetings. RESULTS: The evidence review included 69 RCTs. We derived GRADE evidence for each class of therapeutic options and achieved consensus for the recommendations. For patients naïve to treatment, the working group strongly recommends csDMARDs (methotrexate, sulfasalazine, leflunomide) and phosphodiesterase 4 inhibitors, and emphasizes regular assessment and early escalation to achieve treatment target. bDMARDs (tumor necrosis factor inhibitors [TNFi], interleukin 17 inhibitors [IL-17i], IL-12/23i, IL-23i) and Janus kinase inhibitors (JAKi) are also strongly recommended. For patients with inadequate response to csDMARDs, we strongly recommend TNFi, IL-17i, IL-12/23i, IL-23i, and JAKi. For those who had prior experience with bDMARDs, we strongly recommend a second TNFi, IL-17i, IL-23i, and JAKi. The evidence supporting nonpharmacological interventions was very low. An expert panel conditionally recommends adequate physical activity, smoking cessation, and diet to control weight gain. CONCLUSION: Evidence supporting optimal therapy for the peripheral arthritis domain of PsA was compiled for the revised 2021 GRAPPA treatment recommendations.

Regulatory T cells enhance Th17 migration in psoriatic arthritis which is reversed by anti-TNF.

Regulatory T cells (Treg) prevent the migration of effector T cells toward sites of inflammation, thereby limiting disease progression. We investigated this aspect of Treg function using psoriatic arthritis (PsA) as an exemplar of chronic inflammation. Patients with PsA had an increased Th17:Treg ratio which was reversed by anti-tumor necrosis factor (TNF) therapy. Utilizing an in vitro migration assay, Treg from patients with PsA treated with conventional therapy paradoxically boosted CCR6+ effector T-cell (a surrogate for Th17) migration toward CCL20. In contrast, Treg from patients with PsA treated with anti-TNF suppressed CCL20-driven effector T-cell migration. The boosting effect of TNF blockade upon Treg suppression of migration was accompanied by increased effector T-cell CCL20 production and enhanced interaction between Treg and effector T cells. This study provides mechanistic insight into Treg modulation of effector T-cell migration in patients with chronic inflammation and how this can be targeted by therapy.

CD4 T-Cell Dysregulation in Psoriatic Arthritis Reveals a Regulatory Role for IL-22.

Dysregulation of interleukin-22 (IL-22) has been associated with autoimmune diseases but divergent effects upon inflammation have hampered efforts to define its contribution to pathogenesis. Here, we examined the role of IL-22 in patients with psoriatic arthritis (PsA). In the peripheral blood of PsA patients, there was a decrease in IL-22+CD4+ T cells compared with healthy controls resulting in a heightened CD4+ IFNγ+/IL-22+ ratio accompanied by diminished CCR6 expression. IL-22 expressing cells were depleted primarily from the central memory CD4 T-cell subset in PsA patients. Paradoxically IL-22 and particularly interferon-gamma (IFNγ) production were elevated within a CD4+ T-cell subset with phenotypic markers characteristic of naïve T cells (CD3+CD4+CD27+CD45RA+CCR7+CD95-IL-2Rß-) from PsA patients with the highest IFNγ+/IL-22+ ratio of all the CD4 subsets. These unconventional "naïve" CD4+ T cells from PsA patients displayed some phenotypic and functional characteristics of memory cells including a marked proliferative response. Increased IFNγ production from these unconventional "naïve" T cells from PsA patients promoted greater expression of the chemo-attractant CXCL9 by HaCaT keratinocytes compared with their healthy counterparts. Treatment with anti-TNF therapy reversed these abnormalities in this T-cell subset though did not affect the frequency of IL-22+ T cells overall. Furthermore, blockade of IL-22 enhanced the IFNγ mediated release of CXCL-9. These results reveal CD4+ T-cell dysregulation in patients with PsA which can be reversed by anti-TNF and highlight the regulatory properties of IL-22 with important implications for therapeutic approaches that inhibit its production.

The use of rituximab in newly diagnosed patients with systemic lupus erythematosus: long-term steroid saving capacity and clinical effectiveness.

BACKGROUND: Previous reports indicate that treating patients with lupus (SLE) at or close to the time of diagnosis successfully without using any, or minimal, corticosteroids by using B-cell depletion (BCD) is possible in the short-term. It is not however known whether using BCD is as effective or reduces corticosteroid use in the long-term. We report the long-term (up to 7 years) use of BCD with respect to its steroid-saving capacity and clinical effectiveness in newly diagnosed SLE. METHODS: Sixteen female patients with SLE were treated at, or shortly after diagnosis, with BCD therapy (BCDT) minimising the routine use of oral steroids. Post-treatment, most patients were given hydroxychloroquine (n=14) and azathioprine (n=10). The British Isles Lupus Assessment Group (BILAG) disease activity index was used for clinical assessment. Serum antidouble-stranded DNA (dsDNA) antibodies, complement (C3), erythrocyte sedimentation rate (ESR), circulating B lymphocytes (CD19+) and total inmmunoglobulins were tested every 2-6 months (average of 4.5 years) (SD 2) post-treatment. Disease activity and steroid requirement were compared with three patients with SLE treated conventionally, each matched for ethnicity, sex, age, clinical features, disease duration at diagnosis and follow-up period. RESULTS: All patients given rituximab achieved BCD. The mean number of flares during follow-up (new BILAG A or B) was 2.63 (SD 3) in the BCDT group and 4 (SD 3.6) in the controls (NS, p=0.14). Post-BCDT, mean anti-dsDNA antibody level fell from 1114 U/mL (SD 1699.3) to 194 (SD 346.7) at 18 months (p=0.043), mean serum ESR fell by >70% at 6 months maintained during follow-up and serum C3 level normalised in 8 patients. The mean cumulative prednisolone dose at 60 months for the patients who underwent BCDT (n=11) was 4745.67 mg (SD 6090 mg) vs 12 553.92 mg (SD 12 672 mg) for the controls (p=0.01). CONCLUSIONS: Early treatment of patients with SLE with BCDT is safe, effective and enables a reduction in steroid use.

Early treatment with rituximab in newly diagnosed systemic lupus erythematosus patients: a steroid-sparing regimen.

OBJECTIVES: To assess the effectiveness of B-cell depletion therapy (BCDT) as a steroid-sparing treatment in newly diagnosed SLE patients. METHODS: Eight female SLE patients were treated with BCDT using a rituximab/CYC-based regimen aiming to avoid the routine use of oral steroids. Post-treatment, patients were given AZA. The BILAG disease activity index was used for clinical assessment. Serum anti-dsDNA, complement (C3), ESR, circulating B lymphocytes (CD19(+)) and protein : creatinine ratio were tested at 0, 1, 3, 6 and 12 months post-treatment. Disease activity and steroid requirement over the first 6 months of treatment were compared with three SLE patients treated conventionally, each carefully matched for ethnicity, sex, age at disease onset and disease duration at diagnosis. RESULTS: All patients achieved B-cell depletion (CD19 count <0.005 × 10(9)/l). The mean decrease in global BILAG at 6 months for the BCDT patients was -12.0 vs 13.22 for the controls. Post-BCDT, no patient developed any significant deterioration, mean ESR fell from 70.12 to 17.14 mm/h at 6 months, mean serum anti-dsDNA antibody levels fell by >70% at 1 month and serum C3 level normalized in two patients by 6 months. There were no adverse events. The mean cumulative prednisolone dose at 6 months for the BCDT patients was 1287.3 mg (range 250-4501.8 mg) vs 2834.6 mg (range 0-6802.5 mg) for the controls. CONCLUSION: Early treatment of SLE patients with BCDT is safe and effective and enables a reduction in the overall steroid burden.

Delays in recognition and management of giant cell arteritis: results from a retrospective audit.

Prompt institution of corticosteroids (CS) can prevent devastating neuro-ophthalmic complications (NOC) in patients with giant cell arteritis (GCA). Guidelines on managing GCA place emphasis on early recognition of symptoms and prompt treatment of the disease where there is a high index of clinical suspicion. The aims of this study are to review the clinical findings in patients with GCA, evaluate the baseline practice in diagnosis and treatment and to identify delays in treating patients with NOC. The study utilised retrospective case notes review of patients diagnosed with GCA between 2003 and 2008. Sixty-five patients were identified (47 females, 18 males, mean age, 75 years). A significant minority presented with constitutional, polymyalgic and ischaemic symptoms. Mean time from symptom onset to diagnosis of GCA was 35 days. CS were not delayed in those diagnosed with GCA. Recognition of ischaemic symptoms was slow. Visual loss at presentation occurred in 16 patients (24.6%). Ten patients (15.4%) presented with NOC in the absence of headache, seven (70%) of whom developed permanent visual impairment. Five (7.7%) patients had cerebrovascular complications. There are major delays in the recognition and treatment of GCA. There is a high incidence of irreversible ischaemic complications which may partly result from diagnostic and treatment delay.