COVID-19 and Mixed Cryoglobulinemia Syndrome: Long-Term Survey Study on the Prevalence and Outcome, Vaccine Safety, and Immunogenicity.

PURPOSE: Mixed cryoglobulinemia syndrome (MCs) is a rare immunoproliferative systemic disorder with cutaneous and multiple organ involvement. Our multicenter survey study aimed to investigate the prevalence and outcome of COVID-19 and the safety and immunogenicity of COVID-19 vaccines in a large MCs series. METHODS: The survey included 430 unselected MCs patients (130 M, 300 F; mean age 70 ± 10.96 years) consecutively collected at 11 Italian referral centers. Disease classification, clinico-serological assessment, COVID-19 tests, and vaccination immunogenicity were carried out according to current methodologies. RESULTS: A significantly higher prevalence of COVID-19 was found in MCs patients compared to Italian general population (11.9% vs 8.0%, p < 0.005), and the use of immunomodulators was associated to a higher risk to get infected (p = 0.0166). Moreover, higher mortality rate was recorded in MCs with COVID-19 compared to those without (p < 0.01). Patients' older age (≥ 60 years) correlated with worse COVID-19 outcomes. The 87% of patients underwent vaccination and 50% a booster dose. Of note, vaccine-related disease flares/worsening were significantly less frequent than those associated to COVID-19 (p = 0.0012). Impaired vaccination immunogenicity was observed in MCs patients compared to controls either after the first vaccination (p = 0.0039) and also after the booster dose (p = 0.05). Finally, some immunomodulators, namely, rituximab and glucocorticoids, hampered the vaccine-induced immunogenicity (p = 0.029). CONCLUSIONS: The present survey revealed an increased prevalence and morbidity of COVID-19 in MCs patients, as well an impaired immunogenicity even after booster vaccination with high rate of no response. Therefore, MCs can be included among frail populations at high risk of infection and severe COVID-19 manifestations, suggesting the need of a close monitoring and specific preventive/therapeutical measures during the ongoing pandemic.

Absent or suboptimal response to booster dose of COVID-19 vaccine in patients with autoimmune systemic diseases.

Autoimmune systemic diseases (ASD) show impaired immunogenicity to COVID-19 vaccines. Our prospective observational multicenter study aimed at evaluating the seroconversion elicited by COVID-19 vaccine over the entire vaccination cycle including the booster dose. Among 478 unselected ASD patients originally evaluated at the end of the first vaccination cycle (time 1), 344 individuals were re-evaluated after a 6-month period (time 2), and 244 after the booster vaccine dose (time 3). The immunogenicity of mRNA COVID-19 vaccines (BNT162b2 and mRNA-1273) was assessed by measuring serum IgG-neutralizing antibody (NAb) on samples obtained at the three time points in both patients and 502 age-matched controls. In the 244 ASD group that received booster vaccine and monitored over the entire follow-up, the mean serum NAb levels (time 1, 2, and 3: 696.8 ± 52.68, 370.8 ± 41.92, and 1527 ± 74.16SD BAU/mL, respectively; p < 0.0001) were constantly lower compared to controls (p < 0.0001), but they significantly increased after the booster dose compared to the first two measurements (p < 0.0001). The percentage of patients with absent/suboptimal response to vaccine significantly decreased after the booster dose compared to the first and second evaluations (time 1, 2, and 3: from 28.2% to 46.3%, and to 7.8%, respectively; p < 0.0001). Of note, the percentage of patients with absent/suboptimal response after the booster dose was significantly higher compared to controls (19/244, 7.8% vs 1/502, 0.2%; p < 0.0001). Similarly, treatment with immune-modifiers increased the percentage of patients exhibiting absent/suboptimal response (16/122, 13.1% vs 3/122, 2.46%; p = 0.0031). Overall, the above findings indicate the usefulness of booster vaccine administration in ASD patients. Moreover, the persistence of a significantly higher percentage of individuals without effective seroconversion (7.8%), even after the booster dose, warrants for careful monitoring of NAb levels in all ASD patients to identify those with increased risk of infection. In this particularly frail patients' setting, tailored vaccination and/or therapeutic strategy are highly advisable.

Impaired immunogenicity to COVID-19 vaccines in autoimmune systemic diseases. High prevalence of non-response in different patients' subgroups.

Autoimmune systemic diseases (ASD) may show impaired immunogenicity to COVID-19 vaccines. Our prospective observational multicenter study aimed to evaluate the seroconversion after the vaccination cycle and at 6-12-month follow-up, as well the safety and efficacy of vaccines in preventing COVID-19. The study included 478 unselected ASD patients (mean age 59 ± 15 years), namely 101 rheumatoid arthritis (RA), 38 systemic lupus erythematosus (SLE), 265 systemic sclerosis (SSc), 61 cryoglobulinemic vasculitis (CV), and a miscellanea of 13 systemic vasculitis. The control group included 502 individuals from the general population (mean age 59 ± 14SD years). The immunogenicity of mRNA COVID-19 vaccines (BNT162b2 and mRNA-1273) was evaluated by measuring serum IgG-neutralizing antibody (NAb) (SARS-CoV-2 IgG II Quant antibody test kit; Abbott Laboratories, Chicago, IL) on samples obtained within 3 weeks after vaccination cycle. The short-term results of our prospective study revealed significantly lower NAb levels in ASD series compared to controls [286 (53-1203) vs 825 (451-1542) BAU/mL, p < 0.0001], as well as between single ASD subgroups and controls. More interestingly, higher percentage of non-responders to vaccine was recorded in ASD patients compared to controls [13.2% (63/478), vs 2.8% (14/502); p < 0.0001]. Increased prevalence of non-response to vaccine was also observed in different ASD subgroups, in patients with ASD-related interstitial lung disease (p = 0.009), and in those treated with glucocorticoids (p = 0.002), mycophenolate-mofetil (p < 0.0001), or rituximab (p < 0.0001). Comparable percentages of vaccine-related adverse effects were recorded among responder and non-responder ASD patients. Patients with weak/absent seroconversion, believed to be immune to SARS-CoV-2 infection, are at high risk to develop COVID-19. Early determination of serum NAb after vaccination cycle may allow to identify three main groups of ASD patients: responders, subjects with suboptimal response, non-responders. Patients with suboptimal response should be prioritized for a booster-dose of vaccine, while a different type of vaccine could be administered to non-responder individuals.

Inflammatory rheumatic diseases with onset after SARS-CoV-2 infection or COVID-19 vaccination: a report of 267 cases from the COVID-19 and ASD group.

OBJECTIVES: To better define the spectrum of new-onset post-COVID-19 and post-COVID-19 vaccine inflammatory rheumatic diseases (IRD) from a large multicentric observational study. METHODS: Consecutive cases of IRD encountered during a 12-month period and satisfying one of the following inclusion criteria: (a) onset of the rheumatic manifestations within 4 weeks from SARS-CoV-2 infection or (b) onset of the rheumatic manifestations within 4 weeks from the administration of one of the COVID-19 vaccines ws recruited. RESULTS: The final analysis cohort comprised 267 patients, of which 122 (45.2%) in the post-COVID-19 and 145 (54.8%) in the postvaccine cohort. Distribution of IRD categories differed between the two cohorts: the post-COVID-19 cohort had a higher percentage of patients classified as having inflammatory joint diseases (IJD, 52.5% vs 37.2%, p=0.013) while the post-vaccine cohort had a higher prevalence of patients classified as polymyalgia rheumatica (PMR, 33.1% vs 21.3%, p=0.032). No differences were detected in the percentage of patients diagnosed with connective tissue diseases (CTD 19.7% vs 20.7%, p=0.837) or vasculitis (6.6% vs 9.0%, p=0.467). Despite the short follow-up period, IJD and PMR patients' response to first-line therapy was favourable, with both groups achieving a drop in baseline disease activity scores of ~30% and ~70% respectively. CONCLUSION: Our article reports the largest cohort published to date of new-onset IRD following SARS-CoV-2 infection or COVID-19 vaccines. Although causality cannot be ascertained, the spectrum of possible clinical manifestations is broad and includes IJD, PMR, CTD and vasculitis.

Central Retinal Vein Prethrombosis Secondary to Retinal Vasculitis: Early Detection and Treatment.

The aim was to report a case of central retinal vein prethrombosis (CRVP), responsive to systemic steroids. An 18-year-old male presented with right sudden blurred vision and central scotoma for 2 days. Right best-corrected visual acuity (BCVA) measured 6/36, and fundoscopy revealed vascular congestion and blurred disc margins. Fluorescein angiography (FA) showed CRVP secondary to retinal vasculitis. Systemic oral prednisone was started. Six months later, right BCVA was 6/6, FA showed reduced vascular congestion, and retinal vasculitis and residual optic disc hyperfluorescence resolved. CRVP should be considered in young patients with sudden central scotoma. Early systemic steroids might be effective in the treatment of "active" retinal vasculitis.

Tumour necrosis factor alpha inhibitor therapy and rehabilitation for the treatment of ankylosing spondylitis: a systematic review.

OBJECTIVES: To systematically review the evidence for a synergistic effect of combining rehabilitation with biological anti-tumour necrosis factor (TNF) therapy in patients with ankylosing spondylitis (AS). METHODS: Data were analysed to identify the most effective rehabilitation programmes, the best endpoints for effectiveness, and patient subgroups most likely to benefit from combination therapy. Systematic MEDLINE and Embase searches were performed to identify studies evaluating rehabilitation programmes and biological therapy in patients with AS. Evidence was categorised by study type, and efficacy, adverse effects and other outcomes were summarised. RESULTS: Of the 75 studies identified, 13 investigated the combination of a rehabilitation programme with TNF inhibitor therapy, while the remainder studied rehabilitation with standard therapy (often not specified). Data from these few studies suggest that combined rehabilitation plus anti-TNF therapy is more effective in terms of symptom severity, disease activity, disability and quality-of-life indices versus biologic alone or rehabilitation with standard medical therapy, or, in non-comparative studies, compared with baseline. The most effective rehabilitation appears to be supervised or in-patient programmes with an educational component. Available data do not provide guidance on most appropriate endpoints or identify patients most likely to benefit from combination therapy. Combined, TNF inhibitor and rehabilitation therapy appear to have a synergistic effect, possibly due to increased adherence to exercise. Exercise regimes are more effective if supervised and include an education component. CONCLUSIONS: Further randomized, controlled trials comparing endpoints and investigating longer-term benefits of combining TNF inhibitors with rehabilitation in different AS subgroups are needed.

Type-1 response in peripheral CD4+ and CD8+ T cells from patients with Hashimoto's thyroiditis.

OBJECTIVE: In this study we performed single-cell analysis of the intracellular cytokine expression in peripheral CD4+ and CD8+ lymphocytes from patients with Hashimoto's thyroiditis (HT) to investigate the type-1 response separately for the two lymphocyte sub-populations. DESIGN AND METHODS: Twenty-nine patients affected by HT and 20 healthy subjects, matched for sex and age, were enrolled. After the analysis of the lymphocyte sub-populations, the intracellular content of interferon-gamma (IFN-gamma) in phorbolmyristate acetate (PMA)-stimulated CD4+ and CD8+ lymphocytes was assayed. Moreover, the CD4+ lymphocytes were also evaluated for the intracellular expression of IL-4. RESULTS: No significant differences in CD3+, CD4+ and CD8+ lymphocytes were found between HT patients and control subjects. However, the HT patients showed higher numbers of CD4+ IFN-gamma+, CD4+ IL-4+ and CD8+ IFN-gamma+ (t-test, P< or =0.001) cells than the control subjects. Analysing the intracellular expression of IFN-gamma and IL-4 in relation to thyroid function, we found that the euthyroid patients (18 cases) showed more expression of IL-4 in CD4+ lymphocytes than the control subjects, without any significant modification of IFN-gamma expression in CD4+ and CD8+ lymphocytes. However, the hypothyroid patients (11 cases) showed an increase of IFN-gamma expression in both CD4+ and CD8+ lymphocytes with respect to the control subjects and the euthyroid patients. Moreover, the expression of IL-4 in CD4+ cells from hypothyroid patients was significantly lower than that seen in the euthyroid cases and comparable to that found in the control subjects. CONCLUSIONS: Our study has demonstrated that the peripheral CD4+ and CD8+ T lymphocytes from the HT patients show a type-1 activation strictly correlated to the occurrence of hypothyroidism. Further studies will be needed to clarify the exact role of peripheral lymphocytes in HT and whether they could provide a reliable marker of thyroid immune involvement.

Efficacy of bosentan in the treatment of a patient with mixed connective tissue disease complicated by pulmonary arterial hypertension.

This study aimed to investigate the efficacy of bosentan in the treatment of severe pulmonary hypertension in a young female patient with mixed connective tissue disease (MCTD) associated with antiphospholipid syndrome. A 27-year-old woman presented with sudden onset of dyspnea. She had not experienced any dyspnea before this period, and she was known to have MCTD. Laboratory tests showed positive results for antinuclear antibodies, anti-RNP antibodies, anticardiolipin antibodies, beta(2)-glycoprotein I, and lupus anticoagulant. A complete echocardiographic study was performed demonstrating a pulmonary artery systolic pressure (PAPs) of 85 mmHg. Treatment with bosentan was initiated. After 12 days, the patient improved clinically. After 6 months of therapy, the follow-up echocardiography showed a near-normalization of PAPs. Patients who develop PAH secondary to an underlying systemic disease often have a poor survival rate. In this report, we describe a correlation between anticardiolipin antibodies and rapidly progressive pulmonary hypertension. Indeed, the patient in this study very likely improved secondary to the effect of bosentan which produces systemic and pulmonary vasodilatation associated with pulmonary vascular remodeling as well as possible antifibrotic, anti-inflammatory and antiatherothrombotic effects on cells of lungs damaged by an aPL-antibody mediated mechanism.

Assessment of intestinal permeability and orocecal transit time in patients with systemic sclerosis: analysis of relationships with epidemiologic and clinical parameters.

OBJECTIVE: The aim of this study was to assess intestinal permeability (IP) in patients with systemic sclerosis (SSc) and to relate the results with general disease activity and gastrointestinal involvement. METHODS: Twenty-eight females and four males were studied. Patients with severe gastrointestinal involvement were excluded. Thirty-three healthy volunteers served as controls. Intestinal permeability was assessed by means of the orally administered cellobiose/mannitol sugar (Ce/Ma) test. Intestinal transit time (ITT) was investigated with the H2-lactulose breath test. RESULTS: The mean value of IP in 32 SSc patients was significantly higher than in 33 controls ( P<0.05), although it fell within the normal range. Eleven patients showed abnormally high individual IP values (>0.028) that significantly correlated to disease duration ( r=0.73). Altered IP was associated with the higher but not statistically relevant presence of anti-Scl70 antibodies (9/11) and to more severe gastrointestinal involvement. More than half of the SSc patients showed slower orocecal transit times on the H2 breath test. In particular, delayed ITT was observed in 60% of patients with increased IP and in all patients with moderate gastrointestinal involvement according to the scleroderma severity scale. CONCLUSION: Intestinal permeability was altered in 11/32 SSc patients. Correlations between increased IP and duration of disease and degree of gastrointestinal involvement appear to support the hypothesis of secondary involvement of the intestinal barrier, and the presence of anti-Scl70 antibodies in 82% of the patients with higher IP clearly reinforces the hypothesis of an altered immune response in these subjects.