Pragmatic targets for moderate/severe SLE and their implications for clinical care and trial design: sustained DORIS or LLDAS for at least 6 months is sufficient while their attainment for at least 24 months ensures high specificity for damage-free progression.

OBJECTIVES: Treatment targets in systemic lupus erythematosus (SLE) have been validated in unselected-in terms of severity-cohorts, which limits their generalisability. We assessed remission (Definition of Remission in SLE (DORIS)) and Lupus Low Disease Activity State (LLDAS) in a historical cohort of 348 patients with active moderate-to-severe disease and median follow-up of 5 years. METHODS: Active SLE was defined as Physician Global Assessment ≥1.5 and/or SLE Disease Activity Index 2000 ≥6, requiring therapy intensification. DORIS/LLDAS, organ damage, flares and adverse events were monitored. Shared frailty survival, generalised linear models and K-means clustering were applied. RESULTS: Sustained DORIS and LLDAS for ≥6 months occurred in 41.1% and 80.4%, respectively, and resulted in reduced damage accrual (HR: 0.58; 95% CI 0.36 to 0.93 and 0.61; 0.43 to 0.86) and severe flares (HR: 0.14; 0.08 to 0.27 and 0.19; 0.13 to 0.27). LLDAS without DORIS was also protective (HR: 0.65; 0.43 to 0.98 for damage, 0.49; 0.36 to 0.67 for flares). Models fitting increasing duration of targets showed that DORIS ≥50% and LLDAS ≥60% of time, or alternatively, ≥24 and ≥36 months, achieved optimal balance between feasibility (20.2-41.7%) and specificity (73.3-86.1%) for damage-free outcome. These targets were linked to reduced serious adverse events (risk ratio (RR): 0.56-0.71), hospitalisation (RR: 0.70) and mortality (RR: 0.06-0.13). Patients with predominant arthritis and mucocutaneous disease experienced reduced DORIS/LLDAS, compared with counterparts with major organ involvement. Conventional drugs were more frequently used in the former group, whereas potent immunosuppressive/biological agents in the latter. CONCLUSIONS: In moderate-to-severe SLE, sustained DORIS/LLDAS for at least 6 months is sufficient, while attainment for at least 24 months ensures higher specificity for damage-free progression, thus facilitating treat-to-target strategies and clinical trials. Arthritis and skin disease represent unmet therapeutic needs that could benefit from novel biologics.

Patterns of comorbidities differentially affect long-term functional evolution and disease activity in patients with 'difficult to treat' rheumatoid arthritis.

BACKGROUND: Characterisation of the long-term outcome of patients with 'difficult to treat' (D2T) rheumatoid arthritis and factors contributing to its evolution are unknown. Herein, we explored the heterogeneity and contributing factors of D2T long-term outcome. METHODS: Patients included from a prospective single centre cohort study. The EULAR definition of D2T was applied. Longitudinal clustering of functional status (modified Health Assessment Questionnaire (mHAQ)) and disease activity (Disease Activity Score-28 (DAS28)) were assessed using latent-class trajectory analysis. Multiple linear mixed models were used to examine the impact of comorbidities and their clusters on the long-term outcome. RESULTS: 251 out of 1264 patients (19.9%) were identified as D2T. Younger age, fibromyalgia, osteoarthritis, DAS28-erythrocyte sedimentation rate (ESR) at first biological or targeted synthetic disease-modifying antirheumatic drug (b/ts-DMARD) initiation and failure to reduce DAS28-ESR scores within the first 6 months of b/ts-DMARD therapy were significant predictors of patients becoming D2T. Long-term follow-up (total of 5872 person-years) revealed four groups of functional status evolution: 18.2% had stable, mildly compromised mHAQ (mean 0.41), 39.9% had gradual improvement (1.21-0.87) and two groups had either slow deterioration or stable significant functional impairment (HAQ>1). Similarly, four distinct groups of disease activity evolution were identified. Among the different clusters of comorbidities assessed, presence of 'mental-health and pain-related illnesses' or 'metabolic diseases' had significant contribution to mHAQ worsening (p<0.0001 for both) and DAS28 evolution (p<0.0001 and p=0.018, respectively). CONCLUSION: D2T patients represent a heterogeneous group in terms of long-term disease course. Mental-health/pain-related illnesses as well as metabolic diseases contribute to long-term adverse outcomes and should be targeted in order to optimise the prognosis of this subset of rheumatoid arthritis.

Distinct long-term disease activity trajectories differentiate early on treatment with etanercept in both rheumatoid arthritis and spondylarthritis patients: a prospective cohort study.

To characterize disease activity trajectories and compare long-term drug retention between rheumatoid (RA) and spondylarthritis (SpA) patients initiating tumor necrosis factor inhibitor (TNFi) treatment (etanercept). Prospective observational study of RA, axial (AxSpA) and peripheral SpA (PerSpA) patients initiating etanercept during 2004-2020. Kaplan-Meier plots were used for drug retention comparisons and multivariable Cox regression models for predictors of discontinuation. Long-term disease activity trajectories were identified by latent class growth models using DAS28-ESR or ASDAS-CRP as outcome for RA and AxSpA respectively. We assessed 711 patients (450 RA, 178 AxSpA and 83 PerSpA) with a median (IQR) follow-up of 12 (5-32) months. At 5 years, 22%, 30% and 21% of RA, AxSpA and PerSpA patients, respectively, remained on therapy. Etanercept discontinuation was independent of the diagnosis and was predicted by gender and obesity in both RA and SpA groups. Four disease activity (DA) trajectories were identified from 6th month of treatment in both RA and AxSpA. RA patients in remission-low DA groups (33.7%) were younger, had shorter disease duration, fewer comorbidities and lower baseline disease activity compared to moderate (40.6%) & high DA (25.7%) groups. In AxSpA 74% were in inactive-low DA and they were more often males, non-obese and had lower number of comorbidities compared to higher ASDAS-CRP trajectories. In RA and AxSpA patients, disease activity trajectories revealed heterogeneity of TNFi treatment responses and prognosis. Male gender, lower baseline disease activity and fewer comorbidities, characterize a favourable outcome in terms of disease burden accrual and TNFi survival.

Comorbidities Burden and Implementation of the Treat-to-Target Strategy in Predicting Real-World Patient Outcomes in Spondyloarthritides.

New biologic and small molecule targeted agents have expanded the armamentarium of Spondyloarthritides (SpA), allowing more therapeutic options for patients who do not respond to therapy. The implementation of the treat-to-target (T2T) strategy with close monitoring and frequent treatment adaptations targeting disease remission has been proposed as the means to prevent radiographic progression and long-term adverse outcomes. In this project we will employ the "University of Crete Rheumatology Clinic Registry" to prospectively study in real-world practice musculoskeletal and extraarticular disease activity, patient function, comorbidities, sociodemographics, imaging, compliance to therapy and other lifestyle factors in axial and peripheral SpA patients. The predictive value of these variables in long-term (2years) outcomes will be evaluated. We will also assess the implementation of the T2T approach as well as its impact on long-term patients' outcomes (quality of life, productivity, adverse events). The successful completion of this study could pave the way for improved and personalized therapy in patients with SpA.

Persistence of Depression and Anxiety despite Short-Term Disease Activity Improvement in Patients with Systemic Lupus Erythematosus: A Single-Centre, Prospective Study.

Mental disorders such as anxiety and depression are prevalent in systemic lupus erythematosus (SLE) patients, yet their association with the underlying disease activity remains uncertain and has been mostly evaluated at a cross-sectional level. To examine longitudinal trends in anxiety, depression, and lupus activity, a prospective observational study was performed on 40 adult SLE outpatients with active disease (SLE Disease Activity Index [SLEDAI]-2K ≥ 3 [excluding serology]) who received standard-of-care. Anxiety and depression were determined at baseline and 6 months by the Hospital Anxiety and Depression Scale. Treatment adherence was assessed with the Morisky Medication Adherence Scale-4. Increased anxiety (median [interquartile range] HADS-A: 11.0 [7.8]) and depression (HADS-D: 8.0 [4.8]) were found at inclusion, which remained stable and non-improving during follow-up (difference: 0.0 [4.8] and −0.5 [4.0], respectively) despite reduced SLEDAI-2K by 2.0 (4.0) (p < 0.001). Among possible baseline predictors, paid employment­but not disease activity­correlated with reduced HADS-A and HADS-D with corresponding standardized beta-coefficients of −0.35 (p = 0.017) and −0.27 (p = 0.093). Higher anxiety and depression correlated with lower treatment adherence (p = 0.041 and p = 0.088, respectively). These results indicate a high-mental disease burden in active SLE that persists despite disease control and emphasize the need to consider socioeconomic factors as part of comprehensive patient assessment.

Lupus Nephritis: Improving Treatment Options.

Despite improvements in patient and renal death rates following the introduction of potent immunosuppressive drugs in earlier decades, a sizeable fraction of patients with lupus nephritis is burdened with suboptimal or delayed responses, relapses, chronic use of glucocorticoids and accrual of renal (chronic renal insufficiency) and extra-renal organ damage. The recently approved combinatory treatments comprising belimumab or voclosporin added to conventional agents, especially mycophenolate, hold promise for further improving disease outcomes and enabling a faster steroid tapering, thus being relevant to the treat-to-target context. However, it remains uncertain whether these dual regimens should become the first-line choice for all patients or instead be prioritized to certain subgroups. In the present article, we summarize the existing lupus nephritis management recommendations, followed by a critical appraisal of the randomized trials of belimumab and voclosporin, as well as the available data on obinutuzumab and other novel compounds under development. We conclude that pending the identification of accurate clinical, histological, or translational predictors for guiding personalized decisions, it is of utmost importance that lupus nephritis patients are monitored closely with appropriate treatment adjustments aiming at a prompt, deep response to ensure long-term preservation of kidney function.

Correction: Nikoloudaki et al. Persistence of Depression and Anxiety despite Short-Term Disease Activity Improvement in Patients with Systemic Lupus Erythematosus: A Single-Centre, Prospective Study. J. Clin. Med. 2022, 11, 4316.

There was an error in the original publication [...].

Clinical response trajectories and drug persistence in systemic lupus erythematosus patients on belimumab treatment: A real-life, multicentre observational study.

Objective: To obtain real-world data on outcomes of belimumab treatment and respective prognostic factors in patients with systemic lupus erythematosus (SLE). Methods: Observational study of 188 active SLE patients (median disease duration 6.2 years, two previous immunosuppressive/biological agents) treated with belimumab, who were monitored for SLEDAI-2K, Physician Global Assessment (PGA), LLDAS (lupus low disease activity state), remission (DORIS/Padua definitions), SELENA-SLEDAI Flare Index, SLICC/ACR damage index and treatment discontinuations. Group-based disease activity trajectories were modelled followed by multinomial regression for predictive variables. Drug survival was analysed by Cox-regression. Results: At 6, 12 and 24 months, LLDAS was attained by 36.2%, 36.7% and 33.5%, DORIS-remission by 12.3%, 11.6% and 17.8%, and Padua-remission by 21.3%, 17.9% and 29.0%, respectively (attrition-corrected). Trajectory analysis of activity indices classified patients into complete (25.5%), partial (42.0%) and non-responder (32.4%) groups, which were predicted by baseline PGA, inflammatory rash, leukopenia and prior use of mycophenolate. During median follow-up of 15 months, efficacy-related discontinuations occurred in 31.4% of the cohort, especially in patients with higher baseline PGA (hazard ratio [HR] 2.78 per 1-unit; 95% CI 1.32-5.85). Conversely, PGA improvement at 3 months predicted longer drug retention (HR 0.57; 95% CI 0.33-0.97). Use of hydroxychloroquine was associated with lower risk for safety-related drug discontinuation (HR 0.33; 95% CI 0.13-0.85). Although severe flares were reduced, flares were not uncommon (58.0%) and contributed to treatment stops (odds ratio [OR] 1.73 per major flare; 95% CI 1.09-2.75) and damage accrual (OR 1.83 per mild/moderate flare; 95% CI 1.15-2.93). Conclusions: In a real-life setting with predominant long-standing SLE, belimumab was effective in the majority of patients, facilitating the achievement of therapeutic targets. Monitoring PGA helps to identify patients who will likely benefit and stay on the treatment. Vigilance is required for the prevention and management of flares while on belimumab.

Visceral Varicella-Zoster Virus Infection Presenting with Severe Abdominal Pain without a Rash in a Patient with Psoriatic Arthritis Treated with Infliximab Biosimilar and Steroids: A Case Report.

Visceral herpes zoster following reactivation of dormant varicella-zoster virus can rarely occur, usually in highly immunosuppressed patients, and may present with abdominal pain without the relevant rash. In the absence of skin manifestations, diagnosis of visceral herpes zoster is extremely difficult, while computed tomography may reveal isolated periarterial fat stranding. We describe a rare case of visceral herpes zoster in a medically immunocompromised adult with psoriatic arthritis, who presented with acute abdomen, was diagnosed based on computed tomography findings and subsequent serum polymerase chain reaction results, and was appropriately treated with an uneventful recovery. This case underlines the significance of considering varicella-zoster virus infection as a cause of severe abdominal pain even in the absence of rash in this setting, and highlights the potential role of appropriately performed computed tomography in such unusual and complex cases, where early diagnosis and initiation of treatment is extremely important for a favorable outcome.

Lower lobe pneumonia presenting as singultus (hiccups).

BACKGROUND: Persistent hiccups can be a debilitating symptom and many such patients present to the emergency department seeking relief. A variety of serious conditions have been associated with persistent hiccups. Cases of pneumonia as a cause of hiccups have been rarely described. CASE PRESENTATION: A 79-year-old male patient presented to the hospital due to persistent hiccups for 4 days. Despite lack of new respiratory symptoms or fever, a chest x-ray demonstrated a left lower lobe consolidation, which was also confirmed with a chest CT. The patient was treated with levofloxacin and at 1-month follow-up hiccups had completely resolved, while a repeat chest CT demonstrated resolution of the consolidation. CONCLUSIONS: The presentation of pneumonia in elderly patients may be atypical and may lack the symptoms and signs observed in younger patients. Hiccups may be the main presenting symptom of pneumonia.

Atypical Presentation of IgA Nephropathy Mimicking Acute Pyelonephritis.

BACKGROUND: IgA glomerulonephritis may present with hematuria, flank pain, and fever. This clinical presentation may be easily confused with acute pyelonephritis. CASE REPORT: We present the case of a 25-year-old female with a typical clinical presentation for acute pyelonephritis (high fever, left flank pain, left costovertebral angle tenderness, hematuria, elevated inflammatory markers, and a hypoenhancing region in the left kidney on contrast-enhanced computed tomography). However, urine and blood cultures were both negative, the serum creatinine was elevated, and the urinalysis revealed significant proteinuria and dysmorphic red blood cells. A kidney biopsy confirmed a diagnosis of IgA nephropathy. She was treated with a combination of lisinopril and methylprednisolone, with good response. CONCLUSION: Gross hematuria, especially in the absence of pyuria or bacteriuria, should raise the suspicion for underlying IgA nephropathy, even if the rest of the clinical presentation is typical for a urinary tract infection. The presence of significant proteinuria, red blood cell casts, and dysmorphic red blood cells are useful clues suggesting glomerular disease.