Conventional Immunosuppression Research Articles

Effectiveness of janus kinase inhibitors in relapsing giant cell arteritis in real-world clinical practice and review of the literature

BackgroundA substantial proportion of patients with giant cell arteritis (GCA) relapse despite standard therapy with glucocorticoids, methotrexate and tocilizumab. The Janus kinase/signal transducer and activator of transcription (JAK/STAT) signalling pathway is involved in the pathogenesis of GCA and JAK inhibitors (JAKi) could be a therapeutic alternative. We evaluated the effectiveness of JAKi in relapsing GCA patients in a real-world setting and reviewed available literature.MethodsRetrospective analysis of GCA patients treated with JAKi for relapsing disease at thirteen centers in Spain and one center in United States (01/2017-12/2022). Outcomes assessed included clinical remission, complete remission and safety. Clinical remission was defined as the absence of GCA signs and symptoms regardless of the erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) values. Complete remission was defined as the absence of GCA signs and symptoms along with normal ESR and CRP values. A systematic literature search for other JAKi-treated GCA cases was conducted.ResultsThirty-five patients (86% females, mean age 72.3) with relapsing GCA received JAKi therapy (baricitinib, n = 15; tofacitinib, n = 10; upadacitinib, n = 10). Before JAKi therapy, 22 (63%) patients had received conventional synthetic immunosuppressants (e.g., methotrexate), and 30 (86%) biologics (e.g., tocilizumab). After a median (IQR) follow-up of 11 (6-15.5) months, 20 (57%) patients achieved and maintained clinical remission, 16 (46%) patients achieved and maintained complete remission, and 15 (43%) patients discontinued the initial JAKi due to relapse (n = 11 [31%]) or serious adverse events (n = 4 [11%]). A literature search identified another 36 JAKi-treated GCA cases with clinical improvement reported for the majority of them.ConclusionsThis real-world analysis and literature review suggest that JAKi could be effective in GCA, including in patients failing established glucocorticoid-sparing therapies such as tocilizumab and methotrexate. A phase III randomized controlled trial of upadacitinib is currently ongoing (ClinicalTrials.gov ID NCT03725202).

#2811 Factor B inhibition with iptacopan in C3 glomerulopathy recurrence after transplantation: a case presentation

Abstract Background and Aims C3 glomerulopathy (C3G) is a clinical-pathological entity resulting from dysregulation of the alternative pathway of the complement system (APC) in the fluid phase. The recurrence risk of C3G after kidney transplantation is about 70% with high risk of graft loss. Standard treatment relies on nephroprotection and unspecific immunosuppression but there are currently new molecules that target specifically APC under development. A novel factor B inhibitor, iptacopan, has shown promising results both in native kidney and transplant recurrence cases in a phase II trial. Method We present a real-world clinical case of early C3G recurrence after kidney transplantation treated with iptacopan (Novartis MAPs program). Patient was vaccinated for encapsulated bacteria. Iptacopan was initiated 200 mg BID. We also present histological response. Results 38-year-old male with chronic kidney disease secondary to C3G initially presented with nephrotic syndrome and hematuria at the age of 31y following a respiratory infection. Blood test showed low serum C3 levels and the presence of C3 nephritic factor without pathological genetic alterations. Kidney biopsy confirmed membranoproliferative glomerulonephritis (MPGN) with predominant C3 deposition. He progressed to CKD stage G5 requiring hemodialysis instead of nephroprotection and immunosuppression with corticosteroids and mycophenolate; and addition with cyclophosphamide and rituximab after 19 months from onset. Five years later, the patient was admitted as first kidney transplant recipient from deceases donor Maastricht-III. Induction therapy included thymoglobulin, and tacrolimus, mycophenolate, and corticosteroids. He experienced delayed graft function requiring hemodialysis. An early biopsy proved C3G recurrence with endocapillary proliferation without C4d deposit and absence of donor specific antibodies. Despite conventional immunosuppression and addition of rituximab and plasma exchange; hemodialysis requirement still be present. So, because C3G pathophysiological base, iptacopan was begun with successful clinical response as he reached hemodialysis discontinuation; and kidney function stabilized after one year of treatment with an estimated glomerular filtration rate about 30 mL/min/1.73 m2. In the follow-up biopsy 5 months later, deposit of C3 in the glomerulus disappeared compared to the post-transplant recurrence but with persistence of endocapillary and mesangial proliferation (see Fig. 1). However, interestingly, he experienced a clinical recurrence with acute kidney injury and hematuria after unintentional iptacopan discontinuation, which was resolver after reinitiating and recovering its previous graft function. No infectious complications were observed after one year of treatment with factor B inhibitor. Conclusion New molecules under development that specifically target APC (fluid phase) may change the treatment scenario of C3G and its recurrence in kidney transplantation. We expose a real-practice early C3G recurrence after kidney transplantation successfully treated with iptacopan. The patient reached kidney function stabilization and disappearance of C3 deposits on immunofluorescence of the follow-up biopsy, identical results as the phase II clinical trial of iptacopan in C3G. So, we might conclude that iptacopan is an effective and safe option for C3G recurrence after kidney transplantation. But, data from randomized studies are needed in order to confirm the efficacy and safety of new inhibitors of the APC as iptacopan.

#3140 Investigating the impact of Anti-IL5 therapy in eosinophilic granulomatosis with polyangiitis (EGPA): a three year longitudinal perspective

Abstract Background and Aims In the randomized, placebo-controlled MIRRA trial [1] for relapsing and refractory eosinophilic granulomatosis with polyangiitis (EGPA), adjuvant therapy with 300 mg anti-IL5 mAB Mepolizumab [MEPO] for 12 months (M), accrued longer times in remission, reduced steroid exposure and reduced relapse rates [1]. The aim of this study is to analyze the outcome of 100 mg MEPO monthly s/c for a minimum of 36 months. Changes to adjuvant immunosuppression and indications for anti-IL5 class switch from MEPO 100 mg s/c to Benralizumab (BRZ) or Reslizumab (Res) were assessed. Method In this observational study, 20 EGPA patients received anti-IL5 therapy for a minimum of 36M (range 49-68M). All commenced on 100 mg s/c MEPO every four weeks. Anti-IL5 therapy switched to BRZ or Res due to partial response or intolerance. Assessment time points included MEPO commencement, 6, 12, 18, 24 and 36 months. Results Overall, there was a 50% reduction in steroid dose by 12 months. This continued to reduce to 24M, by which time 2 were off steroids and a further 10/20 (50%) on weaning dose ≤ prednisolone 5 mg/day. Mean steroid dose continued to decrease to 36 months. The number on adjuvant conventional immunosuppressants (ACIS), reduced over time from 10/20 (50%) at M0 to 4/20 (20%) by M24. Clinical benefits included ANCA serology normalized in all four positive patients by 12 months. Mean eosinophil count reduced from 0.42 mg ± 0.33 × 109/L at M0 to 0.04 ± 0.03 × 109/L at 12 and 24M. BVAS reduced from median 5 [3-7], to 0 [0-1] by 24M. The change in mean FEV1 over 12 months was from (M0) 2.11 ± 0.66 to (M12) 2.39 ± 0.62 and FVC (M0) 3.42 ± 0.87 to (M12) 3.67 ± 0.93/105.60 ± 20.47 respectively. All 20 EGPA patients receiving anti -IL5 therapy, ranging from 49-68M remain on therapy. At 36M, 9 have remained on 100 mg s/c MEPO. 10 (50%) have switched to an alternative anti-IL5 agent—10 switched to benralizumab, 1 initially on benralizumab to reslizumab. 9/10 had achieved partial response prior to switch (reduction in steroids / relapse rate), 1/10 had no response.. During the duration of the study, 3 patients had a break of therapy, but all resumed anti-IL5 treatment with good response. Hence, all 20 remain on anti-IL5 beyond 24M. After 36M, one patient required cyclophosphamide along with anti-IL5 therapy for myocarditis. A further patient had Rituximab for EGPA/ Rheumatoid arthritis overlap between anti-IL5 agents. Conclusion In this study, there was a 50% reduction in steroid dosage by 12 months and steroid requirements continue to decrease to 36M. By 24 months 2 are steroid free and a further 10 on weaning dose ≤5 mg. Furthermore, the number on adjuvant conventional immunosuppression reduced over the 24M (n = 4 at 24M). This study demonstrates that anti-IL5 therapy serves as a favorable model for steroid and conventional immunosuppressant minimization in EGPA. Clinical benefits of reduction in BVAS, improved pulmonary function tests and reduced serum eosinophilia were recorded. The relapsing nature of EGPA places a dependency of therapy on steroids and this study demonstrated sustained and ongoing improvement annually with continued anti-IL5 therapy. Some participants required a switch in anti-IL5 agent.

Correlation between severe attacks and serum aquaporin-4 antibody titer in neuromyelitis optica spectrum disorder.

Aquaporin 4-immunoglobulin G (AQP4-IgG) specifically targets aquaporin 4 in approximately 80% of Neuromyelitis Optica Spectrum Disorder (NMOSD) cases. NMOSD is presently categorized as anti-AQP4-antibody (Ab) positive or negative based on AQP4-Ab presence. The association between antibody titers and patient prognosis remains unclear. Therefore, the present study explores the correlation between severe attacks and serum AQP4 Ab titers in patients with neuromyelitis optica spectrum disorder. Data were gathered retrospectively from 546 patients with NMOSD between September 1, 2009, and December 1, 2021. Patients were categorized based on their AQP4-Ab titers: AQP4 titer ≥ 1:320 were classified as the high-titer group, AQP4 (+ +), and AQP4 titer of ≤ 1:100 were classified as the low-titer group, AQP4 ( +). Clinical characteristics and prognoses between the two groups were compared. Patients with AQP4 ( +) exhibited few severe optic neuritis (SON) attacks (false discovery rate [FDR] corrected p < 0.001), a reduced percentage experiencing SON attacks, and a lower incidence of visual disability than patients with AQP4 (+ +). Patients with AQP4 (+ +) and AQP4 ( +) NMOSD exhibited significant difference in annual recurrence rate (ARR) (FDR-corrected p < 0.001). The lower AQP4 Ab titer group demonstrated reduced susceptibility to severe relapse with conventional immunosuppressive agents and rituximab (RTX) than the higher titer group. No significant differences in sex, age at onset, coexisting connective tissue diseases, motor disability, or mortality rates were observed between the two groups. Higher AQP4 Ab titers correlated with increased disease severity and visual disability in patients with NMOSD.

Italian S3-Guideline on the treatment of Atopic Eczema - Part 2: non-systemic treatments and treatment recommendations for special AE patient populations, adapted from EuroGuiDerm by the Italian Society of Dermatology and STD (SIDEMAST), the Italian Association of Hospital Dermatologists (ADOI) and the Italian Society of Allergological and Occupational Dermatology (SIDAPA).

SIDeMaST (Società Italiana di Dermatologia Medica, Chirurgica, Estetica e delle Malattie Sessualmente Trasmesse) contributed to the development of the present guideline on the systemic treatment of chronic plaque psoriasis. With the permission of EuroGuiDerm, SIDeMaST adapted the guideline to the Italian healthcare context to supply a reliable and affordable tool to Italian physicians who take care of patients affected by atopic dermatitis. The evidence- and consensus-based guideline on atopic eczema was developed in accordance with the EuroGuiDerm Guideline and Consensus Statement Development Manual. Four consensus conferences were held between December 2020 and July 2021. Twenty-nine experts (including clinicians and patient representatives) from 12 European countries participated. This second part of the guideline includes recommendations and detailed information on basic therapy with emollients and moisturizers, topical anti-inflammatory treatment, antimicrobial and antipruritic treatment and UV phototherapy. Furthermore, this part of the guideline covers techniques for avoiding provocation factors, as well as dietary interventions, immunotherapy, complementary medicine and educational interventions for patients with atopic eczema and deals with occupational and psychodermatological aspects of the disease. It also contains guidance on treatment for pediatric and adolescent patients and pregnant or breastfeeding women, as well as considerations for patients who want to have a child. A chapter on the patient perspective is also provided. The first part of the guideline, published separately, contains recommendations and guidance on systemic treatment with conventional immunosuppressive drugs, biologics and janus kinase (JAK) inhibitors, as well as information on the scope and purpose of the guideline, and a section on guideline methodology.

Italian S3-Guideline on the treatment of Atopic Eczema - Part 1: Systemic therapy, adapted from EuroGuiDerm by the Italian Society of Dermatology and STD (SIDEMAST), the Italian Association of Hospital Dermatologists (ADOI) and the Italian Society of Allergological and Environmental Dermatology (SIDAPA).

SIDeMaST (Società Italiana di Dermatologia Medica, Chirurgica, Estetica e delle Malattie Sessualmente Trasmesse) contributed to the development of the present guideline on the systemic treatment of chronic plaque psoriasis. With the permission of EuroGuiDerm, SIDeMaST adapted the guideline to the Italian healthcare context to supply a reliable and affordable tool to Italian physicians who take care of patients affected by atopic dermatitis. The evidence- and consensus-based guideline on atopic eczema was developed in accordance with the EuroGuiDerm Guideline and Consensus Statement Development Manual. Four consensus conferences were held between December 2020 and July 2021. Twenty-nine experts (including clinicians and patient representatives) from 12 European countries participated. This first part of the guideline includes general information on its scope and purpose, the health questions covered, target users and a methods section. It also provides guidance on which patients should be treated with systemic therapies, as well as recommendations and detailed information on each systemic drug. The systemic treatment options discussed in the guideline comprise conventional immunosuppressive drugs (azathioprine, ciclosporin, glucocorticosteroids, methotrexate and mycophenolate mofetil), biologics (dupilumab, lebrikizumab, nemolizumab, omalizumab and tralokinumab) and janus kinase inhibitors (abrocitinib, baricitinib and upadacitinib). Part two of the guideline will address avoidance of provocation factors, dietary interventions, immunotherapy, complementary medicine, educational interventions, occupational and psychodermatological aspects, patient perspective and considerations for pediatric, adolescent, pregnant and breastfeeding patients.

Spatiotemporal immune atlas of a clinical-grade gene-edited pig-to-human kidney xenotransplant

Pig-to-human xenotransplantation is rapidly approaching the clinical arena; however, it is unclear which immunomodulatory regimens will effectively control human immune responses to pig xenografts. Here, we transplant a gene-edited pig kidney into a brain-dead human recipient on pharmacologic immunosuppression and study the human immune response to the xenograft using spatial transcriptomics and single-cell RNA sequencing. Human immune cells are uncommon in the porcine kidney cortex early after xenotransplantation and consist of primarily myeloid cells. Both the porcine resident macrophages and human infiltrating macrophages express genes consistent with an alternatively activated, anti-inflammatory phenotype. No significant infiltration of human B or T cells into the porcine kidney xenograft is detectable. Altogether, these findings provide proof of concept that conventional pharmacologic immunosuppression may be able to restrict infiltration of human immune cells into the xenograft early after compatible pig-to-human kidney xenotransplantation.

Analysis of belimumab prescription and outcomes in a 10-year monocentric cohort: is there an advantage with early use?

ObjectiveThe objective is to evaluate perscriptions of belimumab (BEL), how these have changed over the years and their impact on clinical outcomes in patients with systemic lupus erythematosus (SLE).MethodsThis is...

Myositis-associated interstitial lung disease

Introduction/ObjectiveTo review the epidemiology, general clinical aspects and diagnosis, impact on morbidity and mortality, and general treatment approaches for myositis-associated ILD. Materials and methodsThe relevant literature was reviewed. ResultsThe clinical, radiographic, and histopathological features of interstitial lung disease (ILD) in idiopathic inflammatory myopathies (IIM) are similar to idiopathic ILD. Patients with a known diagnosis of myositis require prompt clinical evaluation including the determination of myositis-associated autoantibodies. Patients possessing autoantibodies associated with ILD or those with any pulmonary symptoms should undergo a pulmonary function test and high-resolution CT (HRCT) scanning of their lungs. ConclusionDespite the lack of placebo-controlled trials, systemic glucocorticoids are considered the mainstay of initial treatment of myositis-associated ILD. Glucocorticoid-sparing agents are often concomitantly administered, particularly in patients with severe disease. The first-line conventional immunosuppressive drugs include either mycophenolate mofetil or azathioprine. If these agents fail or if the pulmonary features are severe or rapidly progressive, then more aggressive immunosuppressive or immunomodulatory therapy including cyclophosphamide, tacrolimus or cyclosporine, rituximab, IVIg, or tofacitinib can be considered. Further investigations are required to assess the role of novel therapies in the treatment of myositis-associated ILD.

Characteristics and Management of Patients with Alopecia Areata and Selected Comorbid Conditions: Results from a Survey in Five European Countries.

Alopecia areata (AA) is an autoimmune condition that causes non-scarring hair loss and can impose a high psychosocial burden on patients. The presence of comorbid conditions may impact the management of AA in clinical practice. This analysis aims to describe disease characteristics and management of AA in patients with concomitant atopic, autoimmune, and psychiatric comorbid conditions. Data were collected from the Adelphi Disease Specific Programme™, a cross-sectional survey of physicians and their adult patients with AA conducted in France, Germany, Italy, Spain, and the UK between October 2021 and June 2022. Patients' disease severity was based on physician's definition. Physician-reported data on demographics, AA clinical characteristics, comorbid conditions, and information related to AA therapies were analyzed. Analyses were descriptive. Overall, 239 dermatologists provided data for 2083 patients, of which 558 patients (27%) had at least one atopic, autoimmune, or psychiatric comorbid conditions. The most common comorbid conditions were atopic dermatitis, autoimmune thyroid disease, and anxiety. The mean (standard deviation) patient age for the three comorbidity groups was 37.6years (12.1) and 56% of the patients were women (n = 313). In the three comorbidity groups, 51%, 50%, and 55% of patients with atopic, autoimmune, and psychiatric comorbidities had severe AA with disease progression reported as worsening in 30%, 28%, and 30%, respectively, whereas in the group with no comorbidities, 37% were described as having severe AA and 21% getting worse. Scalp hair loss was the primary sign reported across the three groups of comorbid conditions (atopic, 91%; autoimmune, 91%; psychiatric, 88%). Patients with preselected comorbidities presented more frequently AA-related signs and symptoms beyond scalp hair loss than patients without comorbid conditions. These patients were also more likely to receive topical calcineurin inhibitors, topical immunotherapy, conventional systemic immunosuppressants, and oral Janus kinase inhibitors for the treatment of their AA. This analysis provided insights into the burden and management of AA in patients presenting with atopic, autoimmune, and psychiatric comorbid conditions in five European countries.

Tofacitinib therapy for severe pyoderma gangrenosum in a patient with enteropathic arthritis: a case-based review.

Pyoderma gangrenosum (PG) is a rare neutrophilic dermatosis that is associated with systemic inflammatory conditions. Currently, there is no universally accepted standard therapy for PG, but immunosuppressive (IS) treatment seems essential. We report a patient here who was successfully treated with tofacitinib despite being PG-refractory to multiple anti-tumor necrosis factor alpha (anti-TNF) therapies and conventional IS. In addition, we performed a comprehensive review of all cases of PG treated with JAK inhibitors. We identified 27 cases treated with JAK inhibitors. Approximately 80% of the patients achieved complete recovery within a median of 12weeks, even though 17 patients (63%) had received biologics before JAKinib treatment. Notably, this recovery could appear as early as 2weeks. JAK inhibitors may prove useful in the future, particularly for treating immunosuppressive and steroid-resistant pyoderma gangrenosum, according to recent case reports.

Clinical and immunological predictors of post-rituximab paradoxical pemphigus flare: A prospective cohort study.

Background Paradoxical flare of pemphigus following rituximab infusion has been reported previously, however, its incidence or risk factors have not been studied in detail. Objectives To evaluate the clinical and immunological predictors associated with post-rituximab paradoxical pemphigus flare. Materials and Methods This was a prospective cohort study including adult patients with pemphigus vulgaris or foliaceus who were treated with rituximab. Patients were administered 1000 mg of intravenous rituximab on days 0 and 14 (Rheumatoid arthritis (RA) protocol), with or without oral prednisolone and/or conventional immunosuppressive agents. Baseline clinical and immunological predictors of post-rituximab pemphigus flares were assessed. Results Fifty patients (mean age 40.44 ± 12.36 years) with a mean pemphigus disease area index (PDAI) score of 27.8 ± 15.48 were administered rituximab. Post-rituximab flare occurred in 10 (20%) patients after a mean of 14.1 ± 4.33 days after the first rituximab infusion. The mean baseline PDAI score (36.4 ± 11.7 vs. 25.6 ± 15.7, P = 0.02) and serum anti-Dsg1 levels (1216.8 ± 850.1 vs. 592 ± 562.12 RU/mL, P = 0.03) were statistically significantly higher in patients experiencing a flare. Using ROC-curve analysis, a PDAI score of 328 (OR 8.3, 95% CI 1.5-44.7) was 80% sensitive and 67.5% specific in predicting post-rituximab flare, while serum anti-Dsg1 level of 31137.78 RU/ml had a sensitivity of 60% and specificity of 85%. There was no significant difference in terms of affected body surface area, type of pemphigus, starting prednisolone dose, oral immunosuppressive adjuvant, serum anti-Dsg3, serum anti-AchRM3, and peripheral CD19+ B cell population. Limitations Our study is limited by a relatively small sample size. Immunological factors were not evaluated at the time of pemphigus flare. Though these unexpected pemphigus flares are likely to be associated with rituximab infusion, the possibility of spontaneous disease exacerbation cannot be entirely excluded. Conclusions Patients with more severe pemphigus or high serum anti-Dsg1 are at risk of post-rituximab paradoxical flare, and may benefit from rituximab administration under close monitoring.

Are monoclonals the only panacea for treatment of aquaporin-4 positive NMOSD? Experience from a low-&middle-income (LMIC) region

ObjectiveA plethora of monoclonals have ushered up for NMOSD treatment. However, their limited availability and cost concerns poses a challenge for usage in developing nations. We compared relapse rates and disabilities among aquaporin-4 positive(AQP4+ve) patients on conventional immunosuppressants and rituximab in a tertiary referral center in southern India. MethodsThis was a chart review of AQP4+ve patients registered under national demyelination registry maintained at institute. AQP4+ve patients were included if they were on azathioprine, MMF, methotrexate for six months; cyclophosphamide for three months and rituximab for one month. Results207 records were screened, 154 fulfilled inclusion criteria. Drugs used were azathioprine (70), MMF (34) and rituximab (33). All three drugs were non-inferior to each other in terms of ARR reduction. Median EDSS at last follow-up was significantly lower for azathioprine(2;IQR:0–5) and rituximab(2;IQR:0.5–5) than MMF(3.5;IQR:2–5.6), however azathioprine was associated with highest switch rate(34.3%) and was the only drug which required change because of intolerance. Failure rate was least for rituximab(27.3%).Patients on azathioprine and MMF required higher mean duration of concurrent steroids(7.8±7.7 and 4.56±2.17 months respectively) when compared to rituximab(2.77±1.38) and had more relapses due to steroid withdrawal. ConclusionInitial treatment with azathioprine, MMF and rituximab is comparable in terms of ARR reduction. Findings suggest that choice may be guided by adverse event profile of drug, rather than efficacy per se. Concurrent treatment duration with steroids should also guide clinical decision. Switch to second immunomodulation in event of initial failure adds to efficacy benefit, irrespective of the drug chosen.

Anti-intercellular adhesion molecule 1 monomaintenance therapy induced long-term liver allograft survival without chronic rejection

Calcineurin inhibitors (CNIs) are essential in liver transplantation (LT); however, their long-term use leads to various adverse effects. The anti–intercellular adhesion molecule (ICAM)-1 monoclonal antibody MD3 is a potential alternative to CNI. Despite its promising results with short-term therapy, overcoming the challenge of chronic rejection remains important. Thus, we aimed to investigate the outcomes of long-term MD3 therapy with monthly MD3 monomaintenance in nonhuman primate LT models. Rhesus macaques underwent major histocompatibility complex–mismatched allogeneic LT. The conventional immunosuppression group (Con-IS, n = 4) received steroid, tacrolimus, and sirolimus by 4 months posttransplantation. The induction MD3 group (IN-MD3, n = 5) received short-term MD3 therapy for 3 months with Con-IS. The maintenance MD3 group (MA-MD3, n = 4) received MD3 for 3 months, monthly doses by 2 years, and then quarterly. The MA-MD3 group exhibited stable liver function without overt infection and had significantly better liver allograft survival than the IN-MD3 group. Development of donor-specific antibody and chronic rejection were suppressed in the MA-MD3 group but not in the IN-MD3 group. Donor-specific T cell responses were attenuated in the MA-MD3 group. In conclusion, MD3 monomaintenance therapy without maintenance CNI provides long-term liver allograft survival by suppressing chronic rejection, offering a potential breakthrough for future human trials.

Emerging therapies in the medical management of thyroid eye disease

IntroductionThyroid eye disease (TED) is an immune-mediated disorder associated with a heterogenous array of manifestations that may unfavorably impact vision and quality of life. As understanding of this entity’s complex pathogenesis has evolved, so have therapies with novel molecular targets offering promise for improved patient outcomes.ResultsEmerging immunologic therapies for the management of thyroid eye disease have diverse mechanisms of actions and routes of administration. Different conventional and biological immunosuppressive agents have been studied as mediators of the autoimmune and autoinflammatory pathways in thyroid eye disease. Teprotumumab – an anti-IGF-1R monoclonal antibody that has recently emerged as a first-line therapy for active, moderate-to-severe TED – has demonstrated statistically significant improvements in proptosis, diplopia, clinical activity score, and quality of life compared to placebo. Currently under investigation are several other agents, with varying administration modalities, that aim to inhibit IGF-1R: VRDN-001 (intravenous), VRDN-002 or VRDN-003 (subcutaneous), lonigutamab (subcutaneous), and linsitinib (oral). Tocilizumab, a monoclonal antibody of interleukin 6, has played a role in the management of multiple autoimmune and inflammatory conditions and may offer promise in TED. Another incipient biologic target for TED management is the neonatal Fc receptor, inhibition of which has potential to decrease recycling of immunoglobulin and antibody levels; agents addressing this target including monoclonal antibodies as well as antibody fragments. Finally, hypolipidemic agents may play a role as mediators of TED-associated inflammation.ConclusionAmong the agents under investigation that aim to decrease ocular morbidity associated with TED are agents that IGF-1R, interleukin 6, and the neonatal Fc receptor. The management of TED continues to expand with novel immunologic approaches for disease therapy.

Anti-MDA5 antibody-positive dermatomyositis: pathogenesis and clinical progress.

Anti-melanoma differentiation-associated protein 5 (MDA5) antibody-positive dermatomyositis (MDA5-DM) is a subtype of dermatomyositis. Although the aetiology and pathology remain unclear, increasing evidence suggests that viral infection is a potential trigger of MDA5-DM. Multiple factors, including T cells, B cells, neutrophils and macrophages, are implicated in the pathophysiology of MDA5-DM. Distinctive skin rashes, rapidly progressive interstitial lung disease, peripheral lymphopenia and elevated serum ferritin levels are the most prominent clinical and laboratory features of MDA5-DM. Concomitant infection is a common complication of MDA5-DM. The proper evaluation of patients with MDA5-DM requires knowledge of the disease heterogeneity and clinical course variability. Several biomarkers, including serum levels of anti-MDA5 antibodies and biomarkers related to macrophage activation, have been identified as useful tools for monitoring disease activity and prognosis. MDA5-DM shows a poor response to conventional glucocorticoid and immunosuppressant therapy and has a poor overall prognosis. Therefore, there is an urgent need to explore the key pathogenic mechanisms of MDA5-DM and develop novel therapeutic options for patients. This Review discusses recent clinical progress and pathogenic findings of MDA5-DM.

A description of alopecia areata in European patients based on real-world survey data: physician-reported characterization of severity and associated treatment utilization.

Alopecia areata (AA), an autoimmune disease -affecting the hair of the scalp, face, and/or body, can entail substantial psychological and physical burden for patients. There is currently no international agreement on how to treat AA and the approach may vary across countries. This study investigated the management of AA in clinical practice. Data from a point-in-time survey conducted in France, Germany, Italy, Spain, and the United Kingdom, between October 2021-June 2022, were analysed for adults with mild, moderate, and severe AA, based on physician assessment. Dermatologists were surveyed about factors used to assess disease severity, physician-reported treatment goals, and treatment patterns for AA, including the use of wigs. In total, 239 dermatologists reported on 2,083 patients. Physicians' severity assessment and treatment goals were predominantly driven by scalp hair loss. Topical and intralesional corticosteroids were the most prescribed treatments for mild and moderate AA. Conventional immunosuppressants, oral Janus kinase inhibitors, and topical immunotherapy use generally increased with AA severity and therapy line. Wig use was greatest for severe AA. The primary reasons for the last treatment change in the moderate and severe groups were worsening of condition, lack of initial efficacy, and loss of response, and for mild group were improvement in condition, lack of initial efficacy, and worsening of condition. Findings were generally similar across countries. This analysis provides insights into the management of AA in five European countries and confirms the need for more effective therapies, especially for patients with severe AA.

CAR-T Cells for Systemic Lupus Erythematosus

Systemic Lupus Erythematosus (SLE) is an autoimmune disease characterized by an abnormal inflammatory response against nuclear antigens with consequent tissue damage. Autoreactive B cells and auto-antibodies have a fundamental role in SLE pathogenesis. Lupus nephritis (LN) has a great impact on patients' survival and quality of life and still represents and unmet clinical need due to the lack of specific treatments and to the poor response to conventional immunosuppression. Regulatory T cells (Tregs) physiologically maintain the immune tolerance and are impaired in SLE. Polyclonal Treg transfer obtained unsatisfactory results due to the low number of disease-relevant antigen-specific cells. Chimeric Antigen Receptors (CARs) are molecules capable of redirecting T cell specificity. CAR-Tregs proved effective in pre-clinical mouse models of autoimmunity. We aimed at developing a CAR-Treg based product to be employed in SLE in particular in LN. We isolated Tregs from Healthy Donors Peripheral Blood Mononuclear Cells (PBMCs) and expanded them with IL-2 and rapamycin. We transduced Tregs with a Lentiviral Vector encoding for a second-generation anti-CD19 CAR, considering the relevant role of autoreactive B cells and autoantibodies in SLE. Engineered cells retained their immune suppressive capabilities upon polyclonal stimulation. Noticeably, they acquired new antigen-specific suppressive capacities, being able to block autologous B cell proliferation. We set up a humanized mouse model of SLE. In vivo, CAR-Tregs delayed the occurrence of B cell lymphopenia, producing immunomodulatory cytokines and without showing toxicity or reprogramming towards Th17 pro-inflammatory cells. In inflamed organs, CAR-Tregs restored the normal composition of the immune system. In conclusion, we efficiently generated anti-CD19 CAR-Tregs and proved their efficacy both in vitro and in an in vivo humanized mouse model of lupus.

Myositis-associated interstitial lung disease

Introduction/ObjectiveTo review the epidemiology, general clinical aspects and diagnosis, impact on morbidity and mortality, and general treatment approaches for myositis-associated ILD. Materials and methodsThe relevant literature was reviewed. ResultsThe clinical, radiographic, and histopathological features of interstitial lung disease (ILD) in idiopathic inflammatory myopathies (IIM) are similar to idiopathic ILD. Patients with a known diagnosis of myositis require prompt clinical evaluation including the determination of myositis-associated autoantibodies. Patients possessing autoantibodies associated with ILD or those with any pulmonary symptoms should undergo a pulmonary function test and high-resolution CT (HRCT) scanning of their lungs. ConclusionDespite the lack of placebo-controlled trials, systemic glucocorticoids are considered the mainstay of initial treatment of myositis-associated ILD. Glucocorticoid-sparing agents are often concomitantly administered, particularly in patients with severe disease. The first-line conventional immunosuppressive drugs include either mycophenolate mofetil or azathioprine. If these agents fail or if the pulmonary features are severe or rapidly progressive, then more aggressive immunosuppressive or immunomodulatory therapy including cyclophosphamide, tacrolimus or cyclosporine, rituximab, IVIg, or tofacitinib can be considered. Further investigations are required to assess the role of novel therapies in the treatment of myositis-associated ILD.

Practice Patterns and Approach to Childhood Lupus Nephritis in Saudi Arabia.

Renal involvement of systemic lupus erythematosus needs aggressive treatment. Despite the development of multiple international guidelines, differences in practices exist. This study aimed to explore the current practices of pediatric rheumatologists and nephrologists for the diagnosis, management, and monitoring of lupus nephritis (LN) in Saudi Arabia through a survey. Among the 61 respondents, 54.1% were pediatric nephrologists and 49.9% were pediatric rheumatologists. Predominantly, the participating physicians received training either nationally (57%) or in North America (45%). Most of the respondents (77%) did not have a combined rheumatology-nephrology clinic, primarily because of space or time limitations (75%), or a lack of the other specialty (13%). In terms of the decision to request a renal biopsy, the most common factors were nephrotic-range proteinuria (85%) and a lower level of proteinuria associated with hypocomplementemia or elevated anti-double-stranded (ds) DNA (73%). There was marginal agreement over monitoring the disease's activity and treatment response; Complements 3 and 4, anti-dsDNA, protein-creatinine ratio, and estimated glomerular filtration rate were the most popular parameters. The main reason for repeating a renal biopsy was a new renal manifestation that was inconsistent with the previous biopsy. There was considerable variability in the induction therapies used to initiate and taper corticosteroids and conventional immunosuppressive drugs. Most respondents (91%) used angiotensin-converting enzyme agents to control proteinuria. Considerable agreement exists among Saudi physicians managing children with LN but significant variations exist regarding the therapeutic strategies. Additional endeavors are needed to establish a unified national clinical approach for managing LN in children.