Immunomodulatory Drug Therapy Research Articles

Liver involvement with Langerhans cell histiocytosis in adults.

Liver involvement portends poor prognosis in adults. We aimed to characterize the clinical features, liver function tests, radiologic findings, molecular profiles, therapeutic approaches and outcomes of adults patients with Langerhans cell histiocytosis (LCH) with liver involvement. We conducted a retrospective analysis of all adults with LCH (≥ 18 years) seen at Peking Union Medical College Hospital (Beijing, China) between January 2001 and December 2022. Among the 445 newly diagnosed adults with LCH, 90 patients had liver involvement at diagnosis and 22 patients at relapse. The median age was 32 years (range, 18-66 years). Of 112 evaluable patients, 108 had full liver function testing, including alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase (ALP), γ-glutamyl transpeptidase (GGT), and total bilirubin and albumin. Elevated ALP was seen in 63.0% and GGT in 86.1%; 14.8% had elevated bilirubin. Next-generation sequencing of 54 patients revealed frequent BRAFN486_P490 (29.6%), BRAFV600E (18.5%), and MAP2K1 (14.8%). After a median 40 months' follow-up (range 1-168 months), 3-year progression-free survival (PFS) and overall survival were 49.7% and 86.6% respectively. In multivariable analyses, ≥3 abnormal liver function tests (HR 3.384, 95% CI 1.550-7.388, P = .002) associated with inferior PFS; immunomodulatory drug therapy (HR 0.073, 95% CI, 0.010-0.541, P = .010) correlated with superior PFS versus chemotherapy. In summary, elevated GGT and ALP were common in adults with LCH liver involvement. Greater than equal to 3 abnormal liver function tests predicted poor outcomes. Immunomodulatory drug therapy was associated with favorable progression-free survival compared to chemotherapy.

Risks of Cancer Associated with Therapeutic Drugs for Inflammatory Bowel Disease

Crohn's disease and ulcerative colitis are lifelong chronic inflammatory conditions, with many patients requiring ongoing immunomodulatory drug therapy for maintenance treatment. Recent therapeutic goals in inflammatory bowel disease (IBD) are not only aimed at symptomatic remission but also at achieving mucosal healing to improve the natural course of the disease. In this context, therapeutic approaches are being applied in clinical settings that involve early and appropriate use of drugs, such as immunomodulators or biologics, that have the potential to induce healing of the inflamed intestine before irreversible intestinal damage occurs. All drugs that continuously control intestinal inflammation in IBD can heal the mucosa and potentially reduce the incidence of colitis-associated bowel cancer; however, the continuous use of immunosuppressants can potentially increase the risk of malignancies. The safety issues of the drugs used in clinical practice are partly confirmed during their development processes or shortly after initial marketing, but in other cases, they are estimated through post-marketing case reports or epidemiological studies, sometimes decades after drug approval. This review explores the risks associated with malignancies related to the treatment of IBD, focusing on drugs currently approved in Republic of Korea.

A Comprehensive Exploration of Therapeutic Strategies in Inflammatory Bowel Diseases: Insights from Human and Animal Studies.

Inflammatory bowel disease (IBD) is a collective term for a group of chronic inflammatory enteropathies which are characterized by intestinal inflammation and persistent or frequent gastrointestinal signs. This disease affects more than 3.5 million humans worldwide and presents some similarities between animal species, in particular, dogs and cats. Although the underlying mechanism that triggers the disease is not yet well understood, the evidence suggests a multifactorial etiology implicating genetic causes, environmental factors, microbiota imbalance, and mucosa immune defects, both in humans and in dogs and cats. Conventional immunomodulatory drug therapies, such as glucocorticoids or immunosuppressants, are related with numerous adverse effects that limit its long-term use, creating the need to develop new therapeutic strategies. Mesenchymal stromal cells (MSCs) emerge as a promising alternative that attenuates intestinal inflammation by modulating inflammatory cytokines in inflamed tissues, and also due to their pro-angiogenic, anti-apoptotic, anti-fibrotic, regenerative, anti-tumor, and anti-microbial potential. However, this therapeutic approach may have important limitations regarding the lack of studies, namely in veterinary medicine, lack of standardized protocols, and high economic cost. This review summarizes the main differences and similarities between human, canine, and feline IBD, as well as the potential treatment and future prospects of MSCs.

Maintenance therapy for chronic lymphocytic leukaemia.

Maintenance therapy for chronic lymphocytic leukaemia.

Small intestinal perforation manifesting as post-transplant lymphoproliferative disorder occurring 23 years after living lung transplantation: a case report

A Japanese female patient underwent a living lung transplant at age 29 and has been on immunomodulatory drug therapy since then. At age 52, she presented with sudden hematochezia. Despite abdominal computed tomography scan, esophagogastroduodenoscopy, and colonoscopy, no definitive source of bleeding was identified. Considering the possibility of small bowel bleeding, video capsule endoscopy was performed, which revealed a suspected ulcerative lesion in the jejunum. Subsequent per-oral double-balloon endoscopy confirmed the presence of an ulcerative lesion in the jejunum. A potential pathological diagnosis of post-transplant lymphoproliferative disorder (PTLD) was considered based on endoscopic biopsy specimens from the jejunal lesion. However, before the pathologic biopsy results were available, the patient experienced small intestinal perforation, necessitating emergency partial resection. Pathologic examination revealed a dense proliferation of medium-to-large atypical lymphocytes with neutrophilic infiltration in the perforated area of the small intestinal wall. Immunostaining showed lymphoid cells positive for CD20 but negative for CD3. Epstein-Barr virus (EBV) -encoded RNA was detected by in situ hybridization, and Ki-67 staining demonstrated a higher percentage of positive cells. Consequently, an EBV-positive diffuse large B-cell lymphoma, developed as PTLD, was diagnosed. Complete remission was achieved with a reduced immunomodulatory drug dosage and rituximab therapy. She has been alive for 8 months postoperatively without recurrence. This case suggests that PTLD should be considered in assessing patients presenting with abdominal symptoms following organ transplantation.

External Validation of PRISM Score in Multiple Myeloma Patients in a Community Setting: A Retrospective Cohort Study

Background: Newly diagnosed Multiple Myeloma (MM) patients have a 10 to 20 times higher risk of developing venous thromboembolism (VTE) than the general population. The pathogenesis may involve several factors such as activation of procoagulant factors, acquired activated protein C resistance, and inflammation. In addition to the general risk factors for venous thromboembolism such as older age, immobility, and surgery, some MM treatment-related factors such as the use of immunomodulatory drug therapy and abnormal cytogenetics contribute to the increased risk. The PRISM score (Prior VTE, Race, IMiD, Surgery, Metaphase Cytogenetics) is a risk prediction tool for VTE in MM and was published in 2022. The score ranges from 0 to 18 and patients were stratified into three groups: low (0), intermediate (1-6), and high risk (≥ 7). Our primary objective was to assess the external validity of the PRISM score in our community hospital setting. Methods: All consecutive newly diagnosed MM treated at Saint Vincent Hospital from 1/1/2008 to 12/22/2022 were included in our analysis. Patients receiving therapeutic anticoagulation for other indications or a diagnosis of VTE within 6 months preceding the MM diagnosis were excluded. Variables were collected through a retrospective chart review during MM treatment initiation. Model discrimination was assessed by calculating the area under the receiver operating characteristic curve (AUROC). Logistic regression was used to calculate the odds ratio (OR) of VTE occurrence in the risk prediction model. Results: A total of 214 patients with newly diagnosed MM and available data on VTE occurrence were included. The median age of our cohort at treatment initiation was 74 years (range 31- 96). The median BMI was 27.8. 56% were male, and 44% were female. The mean PRISM score was 2.9, and 73% of MM were IgG/IgA subtype. IMiD-based induction regimen was used in 63 % of patients. A total of 24 patients (11.2%) were diagnosed with VTE after treatment initiation, of which 8 (3.7%) patients had a previous history of VTE. Prophylactic aspirin was used in 53.8% and abnormal metaphase cytogenetics was identified in 13% of MM cases. The median time to VTE from induction therapy was 4.8 months. The PRISM score was low in 116 patients, intermediate in 89, and high in 9 patients. The AUROC of the model was 0.759 (95% CI, 0.644-0.874) (1). The cumulative incidence of VTE at 6 months, 12 months, and more than 1 year was 6%, 7%, and 11.2% of the patients respectively. Each 1-point increase in the score was associated with a significantly higher chance of VTE occurrence in the model [ HR= 1.53, 95% CI (1.27-1.85), P<0.001]. Among the parameters, patients with a history of VTE [ HR= 1.55, 95% CI (1.26-1.91), P<0.001] and with abnormal metaphase cytogenetics [HR= 2.35, 95% CI (1.37-4.05), P<0.001] had a higher strength of association with the development of VTE after induction (2). Furthermore, among 9 patients with a high-risk PRISM score (≥ 7), 7 (77%) developed VTE within the first 6 months after treatment initiation. Conclusions: Our findings suggest that PRISM [AUROC=0.75, 95% CI (0.644-0.874), P<0.001] score could statistically predict VTE outcomes in our patient population. Abnormal metaphase cytogenetics was a significant predictor of VTE in the validation cohort. Abnormal cytogenetics has been well established to be an indicator of aggressive tumor biology and proliferation in stroma-independent MM. It has been established to be a predictor of VTE in acute myeloid leukemia as well. Also, high-risk scores were predictive of earlier development of VTE after treatment induction. Our study strengthens the evidence of using PRISM as a predictive tool. Further studies are needed to enhance the sensitivity of our existing tool.

First results from the RedirecTT-1 study with teclistamab (tec) + talquetamab (tal) simultaneously targeting BCMA and GPRC5D in patients (pts) with relapsed/refractory multiple myeloma (RRMM).

8002 Background: Tec is the first BCMA-directed bispecific antibody approved for the treatment of triple-class exposed RRMM. Tal, a bispecific antibody targeting the novel myeloma antigen GPRC5D, has shown promising efficacy in pts with RRMM. Simultaneously targeting 2 validated myeloma target antigens, using tec + tal in combination may lead to improved outcomes by overcoming resistance mechanisms, such as antigen escape. Here, we report the first results from the phase 1b RedirecTT-1 trial (NCT04586426) in pts with RRMM. Methods: Enrolled pts had MM per International Myeloma Working Group 2016 criteria; were RR or intolerant to the last line of therapy (LOT); were exposed to a proteasome inhibitor, immunomodulatory drug, and anti-CD38 therapy; and had measurable disease. The primary objectives are to evaluate safety and to identify a recommended phase 2 regimen (RP2R) for the combination. Responses were investigator assessed. AEs were graded per CTCAE v5.0. Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) were graded per ASTCT criteria. Results: As of Dec 12, 2022, 63 pts received tec + tal. Median (range) age was 67 y (39–81); median (range) prior LOT was 5 (1–11); 33% (15/45) had high-risk cytogenetics; 78% (49/63) were triple-class refractory; 63% (40/63) were penta-drug exposed; and 43% (27/63) had extramedullary disease (EMD; all bone independent). Median (range) duration of follow-up was 14.4 mos (0.5–21.9). The most common treatment-emergent AEs were CRS (81%; grade [gr] 3, 3%, no gr 4), neutropenia (76%; gr 3/4, 75%), and anemia (60%; gr 3/4, 43%). Dose-limiting toxicities (DLTs) were reported at dose level 1 (gr 3 herpetic stomatitis) and dose level 3 (gr 3 AST/ALT elevation). One ICANS event was reported at dose level 3. No DLTs were reported at the RP2R. Across all dose levels, overall response rate (ORR) was 84% (52/62) among all evaluable pts and 73% (19/26) among evaluable pts with EMD; rate of CR or better (≥CR) was 34% (21/62) and 31% (8/26), respectively. At the RP2R, ORR was 92% (12/13) among all evaluable pts and 83% (5/6) among evaluable pts with EMD; rate of ≥CR was 31% (4/13) and 33% (2/6), respectively. Median duration of response has not been reached. Updated data, with 19 additional pts at the RP2R, will be presented. Conclusions: In this first combination study of a BCMA- and GPRC5D-targeted bispecific antibody, tec + tal at the RP2R has a manageable safety profile consistent with each of the monotherapies. A 92% ORR was observed in pts with advanced RRMM at the RP2R, and an ORR of 83% was achieved in pts with EMD, a high-risk population with unmet need, supporting further evaluation of the combination. Clinical trial information: NCT04586426 .

SOHO State-of-the-Art Updates and Next Questions | BCMA-Directed CAR T-Cells: Early Results and Future Directions.

Despite continued advances that have led to improved survival of patients with multiple myeloma (MM) over the years, MM remains largely incurable with overall survival in patients who have progressed after proteasome inhibitor, immunomodulatory drug, and anti-CD38 monoclonal antibody therapy measured in months. Better understanding of the immunopathology of MM has led to the discovery of newer treatment targets like B-cell maturation antigen (BCMA). BCMA is a tumor necrosis factor receptor superfamily expressed on normal B-lymphocytes and malignant plasma cells with a vital role in proliferation, maturation, and differentiation of normal and malignant plasma cells. Antibody drug conjugates, chimeric antigen receptor (CAR) T-cells and bispecific T-cell engagers targeting the BCMA antigen are now available within and outside of clinical trials for treatment of triple class refractory MM. This review article focuses on the evolution, safety, efficacy, and limitations of BCMA-directed CAR T-cell therapies. It also discusses the challenges unveiled by the incorporation of these CAR T-cells in the treatment paradigm of MM and deliberates on the future of CAR T-cell therapy within MM.

Characterization of Three Variants of SARS-CoV-2 In Vivo Shows Host-Dependent Pathogenicity in Hamsters, While Not in K18-hACE2 Mice.

Animal models are used in preclinical trials to test vaccines, antivirals, monoclonal antibodies, and immunomodulatory drug therapies against SARS-CoV-2. However, these drugs often do not produce equivalent results in human clinical trials. Here, we show how different animal models infected with some of the most clinically relevant SARS-CoV-2 variants, WA1/2020, B.1.617.2/Delta, B.1.1.529/Omicron, and BA5.2/Omicron, have independent outcomes. We show that in K18-hACE2 mice, B.1.617.2 is more pathogenic, followed by WA1, while B.1.1.529 showed an absence of clinical signs. Only B.1.1.529 was able to infect C57BL/6J mice, which lack the human ACE2 receptor. B.1.1.529-infected C57BL/6J mice had different T cell profiles compared to infected K18-hACE2 mice, while viral shedding profiles and viral titers in lungs were similar between the K18-hACE2 and the C57BL/6J mice. These data suggest B.1.1.529 virus adaptation to a new host and shows that asymptomatic carriers can accumulate and shed virus. Next, we show how B.1.617.2, WA1 and BA5.2/Omicron have similar viral replication kinetics, pathogenicity, and viral shedding profiles in hamsters, demonstrating that the increased pathogenicity of B.1.617.2 observed in mice is host-dependent. Overall, these findings suggest that small animal models are useful to parallel human clinical data, but the experimental design places an important role in interpreting the data. Importance: There is a need to investigate SARS-CoV-2 variant phenotypes in different animal models due to the lack of reproducible outcomes when translating experiments to the human population. Our findings highlight the correlation of clinically relevant SARS-CoV-2 variants in animal models with human infections. Experimental design and understanding of correct animal models are essential to interpreting data to develop antivirals, vaccines, and other therapeutic compounds against COVID-19.

Lenalidomide induced pneumonitis.

Iatrogenic lung injury is a very rare, albeit serious complication with antineoplastic therapy, including immunomodulatory drugs. Pneumonitis typically presents clinically with symptoms such as cough, dyspnea, fever, and hypoxemia. Radiographic evaluation often demonstrates diffuse, patchy infiltrates and ground-glass opacities. We present a case in which therapy from an immunomodulatory drug, lenalidomide, elicited a pneumonitis in the form of a 9 cm lung mass. An exhaustive workup was completed to rule out viral, bacterial, and fungal infections as well as malignant causes. Lenalidomide-induced lung injury was suspected. Lenalidomide was discontinued and corticosteroid therapy was initiated. This resulted in a complete clinical and radiographic resolution of symptoms. Several case reports of pneumonitis have been associated with immunomodulatory drug therapy, and while most of these exhibit diffuse ground-glass opacities radiographically, our patient presented with a 9 cm lung mass. Our findings stress the importance of a thorough medication review while ruling out other potential causes of lung injury.

Population pharmacokinetic/pharmacodynamic joint modeling of ixazomib efficacy and safety using data from the pivotal phase III TOURMALINE-MM1 study in multiple myeloma patients.

Ixazomib is an oral proteasome inhibitor approved in combination with lenalidomide and dexamethasone for the treatment of relapsed/refractory multiple myeloma (MM). Approval in the United States, Europe, and additional countries was based on results from the phase III TOURMALINE‐MM1 (C16010) study. Here, joint population pharmacokinetic/pharmacodynamic time‐to‐event (TTE) and discrete time Markov models were developed to describe key safety (rash and diarrhea events, and platelet counts) and efficacy (myeloma protein [M‐protein] and progression‐free survival [PFS]) outcomes observed in TOURMALINE‐MM1. Models reliably described observed safety and efficacy results; prior immunomodulatory drug therapy and race were significant covariates for diarrhea and rash events, respectively, whereas M‐protein dynamics were sufficiently characterized using TTE models of relapse and dropout. Moreover, baseline M‐protein was identified as a significant covariate for observed PFS. The developed framework represents an integrated approach to describing safety and efficacy with MM therapy, enabling the simulation of prospective trials and potential alternate dosing regimens.

Ciltacabtagene Autoleucel, an Anti-B-cell Maturation Antigen Chimeric Antigen Receptor T-Cell Therapy, for Relapsed/Refractory Multiple Myeloma: CARTITUDE-1 2-Year Follow-Up.

CARTITUDE-1, a phase Ib/II study evaluating the safety and efficacy of ciltacabtagene autoleucel (cilta-cel) in heavily pretreated patients with relapsed/refractory multiple myeloma, yielded early, deep, and durable responses at 12 months. Here, we present updated results 2 years after last patient in (median follow-up [MFU] approximately 28 months), including analyses of high-risk patient subgroups. Eligible patients had relapsed/refractory multiple myeloma, had received ≥ 3 prior lines of therapy or were double refractory to a proteasome inhibitor and immunomodulatory drug and had received prior proteasome inhibitor, immunomodulatory drug, and anti-CD38 therapy. Patients received a single cilta-cel infusion 5-7 days after lymphodepletion. Responses were assessed by an independent review committee. At a MFU of 27.7 months (N = 97), the overall response rate was 97.9% (95% CI, 92.7 to 99.7); 82.5% (95% CI, 73.4 to 89.4) of patients achieved a stringent complete response. Median duration of response was not estimable. Median progression-free survival (PFS) and overall survival (OS) were not reached; 27-month PFS and OS rates were 54.9% (95% CI, 44.0 to 64.6) and 70.4% (95% CI, 60.1 to 78.6), respectively. Overall response rates were high across all subgroups (95.1%-100%). Duration of response, PFS, and/or OS were shorter in patients with high-risk cytogenetics, International Staging System stage III, high tumor burden, or plasmacytomas. The safety profile was manageable with no new cilta-cel-related cytokine release syndrome and one new case of parkinsonism (day 914 after cilta-cel) since the last report. At approximately 28 months MFU, patients treated with cilta-cel maintained deep and durable responses, observed in both standard and high-risk subgroups. The risk/benefit profile of cilta-cel remained favorable with longer follow-up.

Real-World Treatment Patterns and Clinical, Economic, and Humanistic Burden in Triple-Class Refractory Multiple Myeloma: Analysis of the Connect ® Multiple Myeloma (MM) Disease Registry

Real-World Treatment Patterns and Clinical, Economic, and Humanistic Burden in Triple-Class Refractory Multiple Myeloma: Analysis of the Connect ® Multiple Myeloma (MM) Disease Registry

BCMA-Directed CAR T-Cells: Early Results and Future Directions

Introduction Despite continued advances that have led to improved survival of patients with multiple myeloma (MM) over the years,1 MM remains largely incurable with overall survival in patients who have progressed after proteasome inhibitor (PI), immunomodulatory drug (IMID), and anti-CD38 monoclonal antibody (MoAb) therapy measured in months.2 Chimeric antigen receptor T cell (CAR-T) therapy has yielded early impressive results in the relapsed/refractory setting, with B cell maturation antigen (BCMA) as the most studied target. This review will summarize the evolution of this therapy, early results, and future directions that incrementally continue to move us closer toward that elusive cure.

Effects of refractory status to lenalidomide on safety and efficacy of selinexor, bortezomib, and dexamethasone (XVd) versus bortezomib and dexamethasone (Vd) in patients with previously treated multiple myeloma.

8024 Background: Lenalidomide (LEN) is typically a frontline therapy for newly diagnosed MM. Patients (pts) with MM refractory to LEN are less likely to repond to other IMiDs and represent a signification area of unmet medical need. In the BOSTON study in the ITT population, XVd was associated with significant improvements in median progression-free survival (PFS), overall response rate (ORR), and rates of peripheral neuropathy, with trends in overall survival (OS) favoring XVd. Methods: The BOSTON trial (NCT03110562) is a Phase 3 randomized, controlled, open-label study of once weekly XVd vs twice weekly Vd in pts with MM and 1-3 prior therapies. We performed post-hoc analyses on two different subgroups to compare outcomes based on refractory status to LEN and immunomodulatory drug (IMiD) therapy. These post hoc analyses evaluated if PFS, overall response rate (ORR), time to next treatment (TTNT) and safety was influenced by prior treatment with LEN when comparing XVd with Vd. Results: Amongst the 402 pts in BOSTON, 160 had MM refractory to any IMiD (XVd = 74, Vd = 86). Of those, 106 were documented to be refractory to LEN (XVd = 53, Vd = 53) and 296 were not refractory to LEN (XVd = 142, Vd = 154). Baseline characteristics were generally well balanced between subgroups. In these subgroups based on refractory status to IMiD or LEN, median PFS was significantly longer in the XVd arm as compared to Vd (IMiD refractory, 13.9 vs. 8.4 months (mo), p = 0.005; LEN refractory, 10.2 vs. 7.1 mo, p = 0.012; not LEN refractory, 15.4 vs 9.6 mo, p = 0.014). Significant increases in TTNT were observed with XVd treatment in pts that were IMiD refractory (14.8 vs. 10.2 mo, p = 0.003), LEN refractory (13.0 vs. 7.6 mo, p = 0.015), and not refractory to LEN (19.1 vs 12.9 mo, p = 0.005). ORR was improved with XVd compared to Vd regardless of refractory status (IMiD refractory, 68.9% vs 55.8%, p = 0.045; LEN refractory, 67.9% vs. 47.2%, p = 0.016; and not refractory to LEN, 79.6% vs 67.5%, p = 0.010). The most common treatment-emergent AEs for the XVd/Vd arms for all subgroups were thrombocytopenia (66.2/30.6%; 71.7/40.4%; 55.6/22.4%), nausea (48.6/11.8%; 50.9/11.5%; 50.0/9.2%), and fatigue (40.5/20.0%; 45.3/21.2%; 40.8/17.1%) for IMiD, LEN, and not LEN refractory, respectively. Incidence of PN AEs of any grade were reduced compared to pts treated with Vd (IMiD refractory, 27% vs. 42.4%; LEN refractory, 30.2% vs 36.5%; not refractory, LEN 33.1% vs 50.7%). Conclusions: In pts with previously treated MM, PFS, ORR, and TTNT were significantly improved regardless of documented refractory status to any IMiD or to LEN-specifically. These analyses support the use of the XVd combination for pts with disease refractory to LEN and likely to any IMiD. Clinical trial information: NCT03110562.

Immunomodulatory drug therapy for the disease caused by SARS-CoV-2 infection (COVID-19)

This systematic review focuses on the state-of-the-art pharmacotherapy of immune disorders in the novel coronavirus infection (COVID-19), leading to a cytokine storm and uncontrolled inflammatory response that causes severe tissue damage and multiple organ failure. A lot of theoretical, experimental and clinical data support the need for immunomodulatory (immunosuppressive) therapy for this disease. It should be emphasized that all immunomodulatory drugs for COVID-19 are prescribed off label, and the evidence base of the results of randomized trials is just being accumulated. We review the immunomodulatory therapy for COVID-19 with the following agents: glucocorticoids, hydroxychloroquine and chloro-quine, type 1 interferons, interleukin-6 antagonists (tocilizumab, sarilumab, olokizumab), interleukin-1 p inhibitor canakinumab, tumour necrosis factor inhibitors (infliximab), Janus kinase (JAK) inhibitors (tofacitinib, baricitinib, ruxolitinib), as well as drugs with other mechanisms of action (abatacept, nivolumab, tacrolimus, sirolimus, fingolimod, melphalan, cyclosporine, methotrexate). At the moment, the most reasonable is the use of interleukin-6 receptor inhibitors, intermediate and high dose glucocorticoids, and JAK inhibitors. Based on the latest data from clinical studies, especially the "Solidarity” trial, the use of hydroxychloroquine and chloroquine seems to have insufficient evidence. There are significant pathophysiological overlaps in the development of immunopathology in COVID-19 and in rheumatic diseases, and the strategy of early aggressive immunosuppressive therapy proposed by a number of researchers almost completely coincides with the current strategies for rheumatoid arthritis.

Collaborative Physician-Pharmacist-Managed Multiple Myeloma Clinic Improves Guideline Adherence and Prevents Treatment Delays.

We hypothesized that a multidisciplinary collaborative physician-pharmacist multiple myeloma clinic would improve adherence to treatment and supportive care guidelines as well as reduce delays in receiving oral antimyeloma therapy. From March 2014 to February 2015, an oncology pharmacist provided consultation for all patients in a specialist myeloma clinic. This included reviewing medications, ensuring physician adherence to supportive care guidelines, managing treatment-related adverse effects, and navigating issues involving access to oral specialty medications (collaborative clinic). Outcome measures were retrospectively compared with those of patients being treated by the same physician during the previous year, in which ad hoc pharmacist consultation was available upon request (traditional clinic). The collaborative clinic led to significant improvements in adherence to supportive medications, such as bisphosphonates (96% v 68%; P < .001), calcium and vitamin D (100% v 41%; P < .001), acyclovir (100% v 58%; P < .001), and Pneumocystis jirovecii pneumonia prophylaxis (100% v 50%; P < .001). Appropriate venous thromboembolism prophylaxis in immunomodulatory drug-treated patients was prescribed in 100% versus 83% of cases ( P = .0035). The median time to initiation of bisphosphonate (5.5 v 97.5 days; P < .001) and P jirovecii pneumonia prophylaxis after autologous transplantation was shortened in the collaborative clinic (11 v 40.5 days; P < .001). Furthermore, the number (85% v 21%; P < .001) and duration (7 v 15 days; P = .002) of delays in obtaining immunomodulatory drug therapy were also significantly reduced. Our collaborative clinic model could potentially be applied to other practice sites to improve the management of patients with multiple myeloma. Prospective studies analyzing clinical outcomes, patient satisfaction, and cost effectiveness of this approach are warranted.

Neutral tumor evolution in myeloma is associated with poor prognosis

Recent studies suggest that the evolutionary history of a cancer is important in forecasting clinical outlook. To gain insight into the clonal dynamics of multiple myeloma (MM) and its possible influence on patient outcomes, we analyzed whole exome sequencing tumor data for 333 patients from Myeloma XI, a UK phase 3 trial and 434 patients from the CoMMpass study, all of which had received immunomodulatory drug (IMiD) therapy. By analyzing mutant allele frequency distributions in tumors, we found that 17% to 20% of MM is under neutral evolutionary dynamics. These tumors are associated with poorer patient survival in nonintensively treated patients, which is consistent with the reduced therapeutic efficacy of microenvironment-modulating IMiDs. Our findings provide evidence that knowledge of the evolutionary history of MM has relevance for predicting patient outcomes and personalizing therapy.

Uncommon presentation of postcardiac injury syndrome induced by radiofrequency catheter ablation for atrial fibrillation: Only pulmonary parenchymal inflammation

Postcardiac injury syndrome (PCIS) is characterized by the appearance of pericardial, pleural, or pulmonary parenchymal inflammation following a cardiac operation. The autoimmune disorder is characterized by eosinophilia, pleuritic chest pain, pleural, and pericardial effusion. It is a troublesome complication, which may prolong hospital stay and lead to severe and life-threatening conditions. Recently, its incidence appears to be declining, owing to modern immunomodulatory drug therapies. Here we report an uncommon case of PCIS, which occurred following a pulmonary vein isolation for atrial fibrillation. The patient suffered from pulmonary parenchymal inflammation but no pleuropericarditis after the operation. We describe with detailed clinical information, laboratory, and imaging tests, treatment processes, and a favorable prognosis in the content. This case illustrates that even after initially uneventful radiofrequency catheter ablation, careful, long-term follow-up is necessary to recognize the potential development of postcardiac injury syndrome.<Learning objective: Although uncommon, physicians should keep postcardiac injury syndrome in mind following radiofrequency catheter ablation. The pattern does not always resemble the classical picture described by Dressler, but may take many forms and should be sought. Diagnosis is based on the clinical signs and symptoms and is mostly confirmed after excluding other diseases. Prognosis is usually benign, and therapeutic response to anti-inflammatory drugs and corticosteroids can aid in the diagnosis.>

CLINICAL FEATURES AND INCIDENCE RATE OF OCULAR COMPLICATIONS IN PUNCTATE INNER CHOROIDOPATHY

To study the clinical features and incidence rate of ocular complications in patients with punctate inner choroidopathy. This is a retrospective cohort study conducted in a single-center academic practice setting. Patients diagnosed with punctate inner choroidopathy at the Wilmer Eye Institute, Johns Hopkins University from 1984 to 2012 were identified. Demographics and clinical features including the presence of choroidal neovascularization (CNV) and structural complications were collected. Main outcome measures, including visual impairment and incidence rate of ocular complications, were analyzed. Thirty-one patients (59 eyes) were included in the study. Follow-up data were available for 24 patients (47 eyes) with a mean follow-up time of 3.4 years (range, 2 months to 8.7 years). In the affected eyes with follow-up, the incidence rate of visual impairment to 20/50 or worse was 0.06 per eye-year (EY) (95% confidence interval, 0.022/EY-0.114/EY). The incidence rate of visual loss to 20/200 or worse was 0.006/EY (95% confidence interval, 0.0001/EY-0.034/EY). Thirty-six eyes (77%) had an ultimate visual acuity of 20/40 or better. All of the 13 patients with more than ≥ 3 years of follow-up had a visual acuity of ≥ 20/40 in at least 1 eye at 3 years after presentation. Two thirds of the follow-up patients (67%) on immunomodulatory drug therapy did not have new or recurrent CNV. However, this was not a statistically significant difference. Three eyes with follow-up had recurrence of CNV for an incidence rate of 0.04/EY (95% confidence interval, 0.008/EY-0.12/EY). Two eyes developed new CNV during follow-up for an incidence rate of 0.02/EY (95% confidence interval, 0.002/EY-0.066/EY). The visual prognosis in most cases of punctate inner choroidopathy is very good. The incidence rate of new CNV and recurrent CNV was 0.02/EY and 0.04/EY, respectively.