Mantle cell lymphoma is a rare and aggressive form of non-Hodgkin lymphoma that often begins with slow growth in lymph nodes before progressing to rapid growth and widespread disease. Diagnosis frequently occurs at an advanced stage, potentially involving the gastrointestinal tract, spleen, and bone marrow, and most patients are diagnosed between 60 and 70 years of age. The retrospective study used linked Ontario health administrative records from the Institute for Clinical Evaluative Sciences, including data from the Ontario Cancer Registry, to examine patients who were at least 65 at diagnosis and had not received an autologous stem cell transplant.

Among the 754 included patients, the median age was 76 years, with an interquartile range of 71 to 82, and 56.4% were at least 75. Men represented 71.1% of the cohort, and 22.4% of patients with recorded collaborative staging had Stage IV disease at diagnosis. Collaborative stage was missing for 64.1% of the cohort, so the available stage distribution does not describe the entire population. Mean follow-up was 36.1 months, with a standard deviation of 31.1 months. The analysis excluded patients younger than 65, those who received an autologous stem cell transplant, and those with incomplete or invalid administrative records. The design therefore describes a population generally considered ineligible for intensive chemotherapy and transplantation in Ontario practice, rather than directly measuring the clinical decision for every individual participant.

Annual diagnoses remained relatively steady, ranging from 76 to 91 new cases between 2013 and 2021. As Ontario’s population aged 65 and older increased, the estimated crude incidence fell from 0.0425 cases per 1,000 people in 2013 to 0.0332 per 1,000 in 2021. The 2013 estimate had a 95% confidence interval of 0.0344 to 0.0524 per 1,000, while the 2021 estimate had an interval of 0.0269 to 0.0408. This pattern describes a population-rate change over the study period rather than a demonstrated reduction in the underlying number of new diagnoses. The retrospective design could not establish why the rates changed, and the confidence intervals overlapped across annual estimates.

Systemic treatment was initiated in 540 patients, or 71.6% of the cohort, while 214 received no systemic therapy during follow-up. Among treated patients, 391 received only first-line therapy, 125 received second-line therapy without a third line, and 24 reached third-line treatment. Bendamustine plus rituximab was the most common first-line regimen, used in 414 patients, or 76.7% of those treated. R-CHOP accounted for 10.0%, R-CVP for 4.3%, and other first-line regimens for 7.6%. Rituximab maintenance after first-line induction was given to 277 patients, representing 51.3% of the treated group, while 168 patients, or 22.3% of the full cohort, received local radiotherapy. Because these were descriptive counts, the study did not test whether the use of maintenance rituximab improved survival.

The first-line regimen was generally initiated soon after diagnosis: median time from diagnosis to treatment was 1.64 months, with an interquartile range of 0.99 to 3.88 months. Median recorded treatment duration was 12.8 months for patients receiving rituximab maintenance and 4.70 months for those without maintenance. Among the 149 patients who received second-line treatment, ibrutinib was used in 109 cases, or 73.2%, and bortezomib-based therapy in 8, or 5.4%. Median time from diagnosis to second-line treatment was 21.6 months, with an interquartile range of 11.1 to 38.9 months. Recorded second-line treatment lasted a median of 2.14 months, including 2.07 months for ibrutinib. These durations represent the interval between the first and last recorded treatment within each line and do not by themselves establish why treatment ended.

Following first-line treatment, 212 patients died before beginning second-line therapy, accounting for 39.3% of those receiving first-line systemic treatment. Of the 149 patients who reached second-line treatment, 102 died before third-line treatment, or 68.5%. Seven of the first-line deaths were classified as COVID-19-related, as were six deaths after second-line treatment. The investigators estimated median time to next treatment or death at 2.62 years, with a 95% confidence interval of 2.24 to 3.01 years. Patients whose first-line treatment was bendamustine plus rituximab had the longest estimated time to next treatment or death, at 2.85 years with a 95% confidence interval of 2.54 to 3.62, compared with 1.74 years for R-CHOP and 0.90 years for R-CVP. These unadjusted comparisons describe observed outcomes and do not establish that any regimen caused the differences.

Median overall survival after first-line treatment initiation was longest among patients receiving bendamustine plus rituximab, at 4.02 years with a 95% confidence interval of 3.23 to 4.72, compared with 2.67 years for R-CHOP, whose confidence interval was wide at 1.52 to 5.17 years. Median survival across all first-line treatments was 3.51 years, with a 95% confidence interval of 2.89 to 4.03. Age was associated with survival: patients aged 65 to 74 had a median of 5.95 years after first-line treatment, with a 95% confidence interval of 4.26 to 8.01, whereas those aged 75 or older had a median of 2.49 years, with an interval of 2.11 to 2.82. In second-line treatment, median survival was 0.50 years for ibrutinib and 0.60 years across all second-line regimens. Because the study was retrospective and unadjusted, differences cannot be attributed solely to age, regimen selection, disease severity, comorbidity, or other clinical factors.

The findings also illustrate how administrative data were used to assess outcomes in a population with limited treatment options. Progression-free survival could not be measured reliably because health administrative records do not consistently capture progression, so time to next treatment or death served as a pragmatic surrogate. This endpoint combines subsequent treatment with death and therefore differs from progression-free survival. Censoring at the end of the study may have limited assessment of patients diagnosed near 2021, and Ontario-specific funding and clinical practices may limit generalizability to other provinces. Administrative data also may not capture every treatment delivered through compassionate programs, although the investigators expected that omission to have little effect on the analysis. The linked population-level data nevertheless captured nearly all registry-diagnosed cases, providing a broad view of care delivered in routine practice. The study identifies an unmet need for more effective treatments for older patients with mantle cell lymphoma who are ineligible for autologous stem cell transplantation.

Subject of Research: Real-world treatment patterns and survival in older transplant-ineligible mantle cell lymphoma patients in Ontario

Article Title: Real‐World Treatment Patterns, Burden of Illness, and Survival of Autologous Stem Cell Transplant‐Ineligible Patients With Mantle Cell Lymphoma in Ontario, Canada

Article References: George, S., Seung, S. J., Thibault, S., Wong, A., Hamilton, M. A., & Prica, A. (2026). Real‐World Treatment Patterns, Burden of Illness, and Survival of Autologous Stem Cell Transplant‐Ineligible Patients With Mantle Cell Lymphoma in Ontario, Canada. eJHaem, 7(5), Article e70384. https://doi.org/10.1002/jha2.70384

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DOI: 10.1002/jha2.70384

Keywords: mantle cell lymphoma, Ontario, older adults, autologous stem cell transplant, ibrutinib, bendamustine, rituximab, real-world evidence, population-based study, overall survival, Real, World

Primary testicular lymphoma is an uncommon entity, but among lymphomas that arise primarily in the testis, diffuse large B-cell lymphoma is by far the most common subtype. It tends to affect older men, behaves aggressively, and carries a well-known propensity to spread to the central nervous system, which is why standard care has evolved into a multimodal package. That package typically begins with radical orchiectomy, the surgical removal of the affected testis, followed by rituximab-based chemotherapy, prophylactic radiotherapy to the contralateral testis, and intrathecal or systemic central nervous system prophylaxis. Each element was adopted at a different time and on the basis of different bodies of evidence, which is precisely what makes isolating the contribution of any single component so difficult.

Rituximab itself is one of the most successful targeted therapies in oncology. The monoclonal antibody binds CD20, a surface molecule found on normal and malignant B cells, and recruits the immune system to destroy them. Its addition to chemotherapy transformed outcomes in diffuse large B-cell lymphoma generally, and it is a cornerstone of modern treatment for the disease. But primary testicular DLBCL is a distinct clinical scenario: an extranodal site with unique pharmacological challenges, since the blood-testis barrier may limit drug penetration, and a pattern of relapse that favors the opposite testis and the brain. Whether the survival gains demonstrated in nodal DLBCL translate cleanly to this niche has remained an open question that no randomized trial has answered.

To address that gap, the Qingdao team, led by Kaiyue Liu and corresponding authors Zhihe Liu and Xia Zhao, conducted a comprehensive search across English and Chinese databases, including PubMed, Embase, Web of Science, the Cochrane Library, ClinicalTrials.gov, CNKI, VIP, Wanfang, SinoMed, and ChiCTR, covering the literature from database inception through June 19, 2024. The search identified eleven retrospective comparative studies encompassing 663 patients with PT-DLBCL. The study was prospectively registered in PROSPERO under registration number CRD42024567721, and the authors report no funding and no competing interests.

The quantitative core of the meta-analysis rested on a much smaller foundation than the headline numbers suggest. Only three of the eleven studies, covering 454 patients, provided extractable hazard ratios for overall survival and progression-free survival, and only these three contributed to the pooled survival estimates. Using random-effects models, the researchers calculated a pooled hazard ratio of 0.74 for overall survival, with a 95 percent confidence interval spanning 0.45 to 1.21 and a p-value of 0.23. For progression-free survival, the pooled hazard ratio was 0.78, with a 95 percent confidence interval of 0.44 to 1.37 and a p-value of 0.38. In both cases, the confidence intervals cross the null value of 1.0, meaning the data cannot exclude either a meaningful benefit or a meaningful harm.

The direction of the point estimates is mildly encouraging for rituximab, and the authors do not dismiss that signal. But they are unusually explicit about how little weight it can bear. The pooled estimates were derived from limited retrospective evidence and were largely based on unadjusted hazard ratios, meaning they were not corrected for differences between treated and untreated patients in age, disease stage, or the intensity of the other treatment modalities they received. The authors state plainly that the results should be interpreted as descriptive summaries rather than evidence of an independent association between rituximab and survival.

This caution reflects a deeper methodological problem with retrospective comparisons in oncology. Patients treated in the rituximab era also received, on average, more refined radiotherapy techniques, more consistent central nervous system prophylaxis, and better supportive care. Survival differences between cohorts separated by calendar time may therefore reflect the broader evolution of multimodal treatment strategies rather than any rituximab-specific contribution. Disentangling the antibody from its era requires either adjustment for confounders at the individual-patient level or, ideally, randomization, neither of which the existing literature provides. The meta-analysis also evaluated complete response as an exploratory secondary endpoint, but the survival outcomes remain the primary focus of the work.

The authors’ conclusion is deliberately measured: given the limitations of the available evidence, the meta-analysis found insufficient evidence to determine the independent association between rituximab-containing frontline therapy and overall survival or progression-free survival in PT-DLBCL. Importantly, they add that these findings do not exclude a potentially clinically meaningful association. The absence of proof, in other words, is not proof of absence, and clinicians should not read the null result as a reason to abandon a drug that has reshaped lymphoma care worldwide.

What the study does provide is a roadmap for fixing the evidence base. The authors call for further well-designed studies, including multicenter registries and unified reporting standards, to clarify the association. Because PT-DLBCL is rare, no single institution will ever accumulate enough patients for a definitive trial; coordinated registries that record treatment components, stage, age, and central nervous system prophylaxis in a standardized way are the most realistic path to adjusted, multivariable estimates of each therapy’s contribution. Until such data exist, the role of rituximab in this disease rests on biological plausibility and extrapolation from other lymphoma subtypes rather than on direct evidence.

For patients and clinicians, the practical takeaway is continuity rather than change. Standard multimodal therapy for primary testicular DLBCL, including rituximab-based chemotherapy alongside surgery, prophylactic radiotherapy, and CNS prophylaxis, remains the accepted approach, and nothing in this meta-analysis argues for altering it. What the study changes is the epistemic status of that practice: the survival benefit of rituximab in this specific site, long assumed by analogy, is now formally documented as unproven. In a field where rare cancers often inherit their treatment standards from better-studied cousins, that kind of honest accounting is a small but genuine contribution, marking exactly where the evidence ends and where the next decade of research should begin.

Subject of Research: Association of rituximab-containing frontline therapy with survival outcomes in primary testicular diffuse large B-cell lymphoma

Article Title: Association of rituximab with survival outcomes in primary testicular diffuse large B-cell lymphoma: a systematic review and meta-analysis of retrospective studies

Article References: Liu, K., Liu, Z., Zhang, Y., Wang, W., & Zhao, X. (2026). Association of rituximab with survival outcomes in primary testicular diffuse large B-cell lymphoma: a systematic review and meta-analysis of retrospective studies. BMC Cancer. https://doi.org/10.1186/s12885-026-16658-z

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DOI: 10.1186/s12885-026-16658-z

Keywords: rituximab, primary testicular lymphoma, diffuse large B-cell lymphoma, meta-analysis, overall survival, progression-free survival, retrospective studies, CNS prophylaxis, orchiectomy, PROSPERO, BMC Cancer, lymphoma treatment

The syndrome at the center of the Norwegian case series, hemophagocytic lymphohistiocytosis, is best understood as a runaway positive feedback loop in the immune system rather than a discrete disease entity. In its normal state, the immune response to infection or cellular stress is self-limiting: activated macrophages and cytotoxic T cells eliminate infected or malignant targets, then recede as regulatory signals reassert control. In HLH, this braking mechanism fails. Cytotoxic cells — whether defective through inherited mutations in primary HLH or overwhelmed by persistent antigenic stimulation in secondary HLH — fail to clear their targets, and the sustained activation of macrophages and T cells floods the circulation with inflammatory cytokines such as interferon-gamma, interleukin-6, and tumor necrosis factor. The name of the syndrome describes its histological signature: hemophagocytosis, the engulfment of red cells and other blood elements by activated macrophages in the bone marrow, spleen, and lymphoid tissues. Clinically, the result is persistent fever, cytopenias, hepatosplenomegaly, coagulopathy, and, in severe cases, progressive multiorgan failure. Untreated, the mortality of the syndrome approaches one hundred percent, and even with modern therapy, survival in high-risk adult populations remains poor.

Ferritin, the iron-storage protein that served as the screening tool in the Norwegian study, deserves particular attention because of its unusual role in this syndrome. Hyperferritinemia is not specific to HLH — it rises in sepsis, liver failure, adult-onset Still disease, and many other inflammatory states — but the magnitude of elevation is informative. Values above 10,000 micrograms per liter carry a meaningful probability of HLH, and the patients in the Oslo series far exceeded this threshold, with a median of 107,500 micrograms per liter and a maximum of 326,000. Ferritin in HLH is not merely a passive marker of inflammation; it is thought to reflect macrophage activation directly, since activated macrophages secrete ferritin into the plasma. The investigators chose an arbitrary cutoff of 20,000 micrograms per liter precisely because it is high enough to be highly suggestive of hyperinflammatory syndromes in a transplant population, where moderate elevations are common and nonspecific. Their screening strategy — extracting every transplant recipient with EBV reactivation and ferritin above this level — illustrates both the promise and the limits of biomarker-driven case finding in a condition that lacks a gold-standard diagnostic test.

The diagnostic instrument most widely used for secondary HLH, the H-score, was developed in French cohorts of immunocompetent adults and assigns points for fever, organomegaly, cytopenias, ferritin levels, triglycerides, fibrinogen, and evidence of hemophagocytosis on bone marrow examination. In the Oslo series, the eight patients in whom the score could be calculated retrospectively all exceeded 200 points, corresponding to a probability of HLH above ninety percent — a striking validation that these were genuine cases rather than diagnostic overreach. Yet the authors are careful to note the caveat that the score was never validated in immunocompromised hosts. Bone marrow hemophagocytosis, one scored variable, is notoriously insensitive and often absent early in the disease course, and three of the eight scored patients lacked marrow sampling entirely. In a transplant recipient, fever and cytopenias are ambiguous findings that could equally signal graft failure, drug toxicity, sepsis, or graft-versus-host disease, and the treating physician’s judgment — which served as the diagnostic standard in this series — remains the operative reality in most centers. The absence of validated diagnostic tools for this population is not a bureaucratic gap but a genuine obstacle to early intervention, since every day of diagnostic uncertainty in a syndrome that killed its victims within weeks of diagnosis is a day of untreated cytokine storm.

The relationship between EBV reactivation and HLH in this setting is mechanistically coherent. EBV infects B cells and establishes lifelong latency in memory lymphocytes, kept in check by cytotoxic T cells that recognize viral antigens. When T-cell depletion removes this surveillance, infected B cells can proliferate unchecked, producing the spectrum of post-transplantation lymphoproliferative disease, from polymorphic lesions to monomorphic lymphomas. In the Oslo series, all ten patients had histologically confirmed PTLD, and nine of the ten had monomorphic disease — the more aggressive end of that spectrum. The massive antigenic load presented by uncontrolled EBV-infected B cells, combined with the cytokine milieu of the post-transplant period, provides exactly the kind of persistent, unresolvable stimulation that drives secondary HLH. The very high viral loads observed — with median whole-blood EBV DNA exceeding one million international units per milliliter, the ceiling of the assay — underscore the degree of uncontrolled viral replication these patients experienced. The temporal pattern is also telling: reactivation occurred at a median of fifty-two days post-transplant, a window consistent with the waning of pharmacologic immunosuppression from the conditioning period and the slow reconstitution of donor T-cell immunity, which typically takes months after ATG-conditioned transplantation.

The therapeutic dilemma the authors describe is one of the most difficult in transplant medicine. The standard approach to PTLD after allogeneic transplantation is twofold: reduction of immunosuppression to allow recovered T cells to attack the EBV-infected B cells, and rituximab, a monoclonal antibody against CD20, to deplete the B-cell compartment directly. But in a patient simultaneously developing HLH, reduction of immunosuppression risks pouring fuel on the hyperinflammatory fire, while intensifying anti-inflammatory therapy risks further impairing the T-cell recovery needed for viral control. The Oslo patients received rituximab and corticosteroids in all cases, with additional agents — chemotherapy, intravenous immunoglobulin, the interleukin-1 receptor antagonist anakinra, the interleukin-6 receptor antibody tocilizumab, and the JAK inhibitor ruxolitinib — deployed in various combinations. That none survived despite this arsenal reflects both the aggressiveness of the syndrome and the absence of an established treatment algorithm for EBV-HLH in this population. Anakinra and ruxolitinib, which target specific cytokine pathways implicated in HLH pathogenesis, represent a newer generation of rational therapy, and small series in other HLH contexts have suggested benefit, but controlled data in transplant-associated EBV-HLH do not exist. EBV-specific cytotoxic T lymphocyte therapy, which could in principle restore viral control without broad immunosuppression, is an attractive theoretical solution but remains logistically complex and unavailable at most centers, including the authors’ own institution.

The preventive strategies the authors propose deserve scrutiny in light of broader trends in transplantation. Post-transplantation cyclophosphamide, which selectively depletes proliferating alloreactive T cells while sparing regulatory and memory populations, has gained substantial ground as graft-versus-host disease prophylaxis and is associated with lower rates of viral reactivation than T-cell-depleting serotherapy, precisely because it preserves more antiviral immune competence. Its adoption as an alternative to ATG-based prophylaxis in appropriate settings could plausibly reduce the incidence of the syndrome described here. Prophylactic rituximab, meanwhile, acts by a different mechanism: by depleting B cells before EBV reactivation occurs, it removes the target cell population in which the virus replicates. The retrospective study the authors cite, in which a single peritransplant dose reduced EBV reactivation and PTLD compared with a preemptive strategy, is suggestive but not definitive, and the finding that long-term survival was similar between groups tempers enthusiasm — preventing PTLD episodes does not necessarily translate into preventing death when competing risks such as relapse and graft-versus-host disease remain. Both strategies, in any case, address the trigger rather than the hyperinflammatory response itself, and it remains unknown whether any intervention can reliably interrupt the transition from EBV-driven PTLD to fulminant HLH once it has begun.

The incidence figure of 1.1 percent among ATG-exposed patients should be interpreted with appropriate caution. The authors themselves note that underdiagnosis is very likely, since milder cases may resolve when treatment of the EBV trigger proves sufficient, and the retrospective design, the reliance on an arbitrary ferritin cutoff, and the exclusion of four probable cases with incomplete data all suggest the true burden may be higher. The denominator — 930 ATG-containing transplants over nearly sixteen years — is large enough to establish that this is not an isolated curiosity, but small enough that the confidence interval around any incidence estimate is wide. What the series establishes unambiguously is the phenotype: early onset within three months of transplant, exclusive occurrence in ATG-treated recipients of EBV-seropositive grafts, universal progression to histologically confirmed PTLD, and uniform fatality within weeks of diagnosis. For clinicians managing ATG-conditioned transplant recipients, the practical implication is concrete: EBV reactivation in this population should prompt ferritin measurement alongside viral load monitoring, and a markedly elevated ferritin in a febrile, cytopenic patient should trigger a full HLH work-up without waiting for the classical diagnostic constellation to complete itself. The syndrome described here is rare, but its rarity is precisely what makes it dangerous — few clinicians encounter it often enough to recognize it early, and by the time the diagnosis is secure, the therapeutic window has usually closed.

Subject of Research: Hematology

Article Title: Epstein-barr virus-associated hemophagocytic lymphohistiocytosis after antithymocyte globulin-conditioned allogeneic hematopoietic stem cell transplantation: a single-center case series

Article References: Abrahamsen, I. W., Myhre, A. E., Vo, C. D., Gedde-Dahl, T., & Tvedt, T. H. (2026). Epstein-barr virus-associated hemophagocytic lymphohistiocytosis after antithymocyte globulin-conditioned allogeneic hematopoietic stem cell transplantation: a single-center case series. Annals of Hematology, 105(11), Article 461. https://doi.org/10.1007/s00277-026-07307-3

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DOI: 10.1007/s00277-026-07307-3

Keywords: Epstein-Barr virus, hemophagocytic lymphohistiocytosis, stem cell transplantation, ATG, PTLD, graft-versus-host disease, rituximab, ferritin, Epstein-barr, virus-associated, hemophagocytic, lymphohistiocytosis

Antineutrophil cytoplasmic antibody-associated vasculitis, abbreviated as AAV, is a systemic autoimmune disease characterized by necrotizing inflammation of small blood vessels. When it strikes both the lungs and the kidneys, clinicians call it pulmonary-renal syndrome, and it ranks among the most lethal presentations of any autoimmune disease. Patients typically develop rapidly progressive glomerulonephritis, in which the kidney’s filtering units are destroyed within days or weeks, alongside pulmonary infiltrates or diffuse alveolar hemorrhage that can suffocate the patient from within. Without aggressive immunosuppressive treatment, mortality is high and kidney failure is often irreversible.

The patient in this case had been in good health until early 2023, with a medical history notable only for kidney stones. In January 2023, routine laboratory tests revealed persistent leukocytosis, an elevated white blood cell count. Over the following months he developed abdominal pain, muscle and joint aches, low-grade fever, fatigue, and swelling of the lower limbs. Multiple courses of empirical antibiotics were administered without any improvement, a pattern that should raise suspicion of a non-infectious cause. His condition then deteriorated dramatically: urine output fell to oliguria and progressed to complete anuria, accompanied by laboratory evidence of severe systemic inflammation.

On admission to the Department of Nephrology at St. George University Hospital in Plovdiv in May 2023, the man was in poor general condition, with arterial hypertension, peripheral edema, pallor, pulmonary congestion, and clinical signs of fluid overload. Laboratory investigations revealed extreme leukocytosis reaching 41 × 10⁹ per liter, thrombocytosis up to 850 × 10⁹ per liter, markedly elevated inflammatory markers, severe acute kidney injury, electrolyte disturbances, and hypoalbuminemia. Serum creatinine, a key marker of kidney failure, reached 700 µmol/L, while potassium climbed to 6.6 mmol/L, a level that threatens fatal cardiac arrhythmia.

Immunological testing provided the diagnostic turning point. The patient tested positive for proteinase 3-ANCA with a cytoplasmic staining pattern, the immunological signature of this form of vasculitis. Critically, antibodies against the glomerular basement membrane were negative, ruling out Goodpasture’s disease, and microbiological cultures showed no infection. Computed tomography of the chest and abdomen revealed bilateral pulmonary infiltrates, pleural and pericardial effusions, pleural-based pulmonary lesions, and enlarged paraaortic lymph nodes, findings that initially kept both severe infection and malignancy in the differential diagnosis.

A percutaneous kidney biopsy settled the question. Light microscopy showed pauci-immune necrotizing crescentic glomerulonephritis, a pattern in which inflammatory cells form crescent-shaped crescents around the glomeruli while immunofluorescence shows little or no immune complex deposition. This histopathological picture is consistent with PR3-ANCA-associated rapidly progressive glomerulonephritis and, importantly, indicated advanced active disease with an unfavorable prognosis for renal recovery. The extent of crescent formation meant that even with perfect treatment, the kidneys were unlikely to regain function.

Treatment began with the standard induction regimen: high-dose corticosteroids and cyclophosphamide, an alkylating chemotherapy agent that has anchored vasculitis therapy for decades. The patient also received hemodialysis, broad-spectrum antimicrobials including meropenem, vancomycin, and metronidazole, thromboembolic prophylaxis with enoxaparin, and human albumin to correct low blood protein levels. Despite this intensive combination, renal recovery was not achieved, and concerns grew about cumulative cyclophosphamide toxicity, which limits prolonged use particularly in critically ill patients already at high risk of infection.

A multidisciplinary team therefore made the decision to escalate to rituximab, an anti-CD20 monoclonal antibody marketed as MabThera. The pharmaceutical rationale was compelling on several fronts. Rituximab works by selectively depleting CD20-positive B lymphocytes, the cells responsible for producing the ANCA antibodies that drive the inflammatory attack. It has demonstrated efficacy comparable to cyclophosphamide for remission induction, with particular effectiveness in PR3-ANCA-positive disease. Crucially for this dialysis-dependent patient, rituximab is not significantly eliminated through the kidneys and is not effectively removed by hemodialysis, so no dose adjustment was necessary. Before initiating the biologic, the team screened for hepatitis B, hepatitis C, and HIV because of the risk of viral reactivation under immunosuppression.

The outcome demonstrated both the power and the limits of modern therapy. Following rituximab administration, systemic inflammatory activity stabilized and the pulmonary involvement regressed, with no new manifestations outside the kidneys during follow-up. However, renal recovery never occurred, and the patient remained chronically dependent on dialysis, a consequence the authors attribute to the advanced crescentic glomerular injury and the delayed diagnosis. The case underscores a sobering reality: controlling the immune attack cannot always reverse damage already done to organs destroyed before treatment began.

Beyond the individual outcome, the report carries broader lessons for the management of severe vasculitis. Delayed diagnosis and high inflammatory burden are associated with irreversible renal damage and increased mortality, making early recognition of ANCA-associated disease essential when patients present with unexplained kidney failure and lung infiltrates. The authors emphasize that careful pharmaceutical monitoring, including complete blood counts, inflammatory markers, electrolytes, immunoglobulin levels to detect hypogammaglobulinemia, and vigilant surveillance for opportunistic infections, remains essential during biologic immunosuppressive therapy. The successful coordination among nephrologists, clinical pharmacists, pathologists, and intensive care specialists in this case illustrates that multidisciplinary care is not an administrative nicety but a determinant of survival in these complex, rapidly evolving diseases.

Subject of Research: Rituximab therapy for severe PR3-ANCA-associated pulmonary-renal syndrome

Article Title: Rituximab therapy in severe PR3 – ANCA pulmonary–renal syndrome: A clinical and pharmaceutical case report

Article References: Nikolov, D., Nikolov, G., Kitova, L., Kitov, S., Kitova, M.-F., & Mihaylova, A. A. (2026). Rituximab therapy in severe PR3-ANCA pulmonary–renal syndrome: A clinical and pharmaceutical case report. Pharmacia, 73, Article e201634. https://doi.org/10.3897/pharmacia.73.e201634

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DOI: 10.3897/pharmacia.73.e201634

Keywords: rituximab, ANCA-associated vasculitis, pulmonary-renal syndrome, PR3-ANCA, glomerulonephritis, case report, autoimmune disease, kidney failure, hemodialysis, immunosuppression, B-cell depletion, clinical pharmacology

The therapeutic armamentarium at the center of the article acts at different levels of the pathogenic cascade. The neonatal Fc receptor antagonists efgartigimod alfa and rozanolixizumab promote the degradation of circulating pathogenic IgG antibodies, giving them a rapid onset of action and a favorable safety profile. Ravulizumab, a long-acting terminal C5 complement inhibitor, acts downstream by preventing formation of the membrane attack complex and complement-mediated injury at the postsynaptic membrane; the CHAMPION MG trial confirmed rapid and lasting improvement in acetylcholine receptor antibody-positive generalized myasthenia gravis with maintenance dosing every eight weeks. Rituximab, by contrast, acts upstream by depleting CD20-positive B cells and may provide long-term immunosuppressive effect; in the RINOMAX randomized trial, rituximab given within twelve months of diagnosis increased the probability of achieving minimal disease manifestations and reduced the need for rescue treatment compared with placebo.

The Athens team retrospectively described seven purposively selected adults managed between February 2025 and July 2026, distinguishing therapies that had actually been administered from those merely planned at the data cutoff. Treatment selection was guided by disease severity, corticosteroid-related risks, presence of thymoma, comorbidities, peripheral venous access, vaccination requirements and the need for rapid improvement or sustained disease management. During the study period, efgartigimod alfa and rozanolixizumab were the only FcRn antagonists and ravulizumab the only C5 complement inhibitor commercially available in Greece, a practical constraint that shaped the pathways. Follow-up under the targeted strategy ranged from one to twelve months, and no treatment-related side effects, relevant infections or rescue therapies for worsening disease were recorded.

Three of the cases involved recent-onset disease, defined as diagnosis within the preceding twelve months. A 72-year-old man with a four-month history and advanced chronic glaucoma, for which corticosteroid escalation was contraindicated, received four cycles of efgartigimod alfa as a rapidly acting bridging therapy; prednisolone was halved from 15 to 7.5 milligrams per day while clinical stability was maintained, and rituximab was planned as the longer-term non-steroidal strategy. A 71-year-old man with recently diagnosed early-stage prostate cancer and hypertension received two cycles of rozanolixizumab, whose subcutaneous route was clinically practical, with prednisolone reduced from 15 to 12.5 milligrams per day while he completed the vaccinations required before planned rituximab. A 59-year-old man with type 2 diabetes and cardiovascular comorbidities worsened by steroids received a single efgartigimod cycle and reached a Myasthenia Gravis Activities of Daily Living score of 0, with prednisolone reduced from 20 to 17.5 milligrams per day.

A fourth profile involved very-late-onset disease, defined as onset at age 65 or older. An 80-year-old man with two months of predominantly bulbar dysfunction requiring a nasogastric tube received prednisolone, intravenous immunoglobulin and two rituximab infusions of 500 milligrams each, achieving enough improvement to remove the tube. Because dysarthria and dysphagia persisted and his peripheral venous access was poor, rozanolixizumab was initiated nine weeks after the second rituximab infusion as continuing, symptom-guided FcRn inhibition with the practical advantage of subcutaneous administration. After four cycles with intercycle intervals of three to six weeks determined by clinical need, his status improved from class IIIB to IIB, prednisolone fell from 10 to 7.5 milligrams per day, and immunophenotyping six months after rituximab showed CD19-positive cells at 0.5 percent, confirming sustained B-cell depletion.

Two thymoma-associated cases illustrate the bridging logic most vividly. A 46-year-old woman referred eighteen months after diagnosis with severe ocular-cervical-bulbar weakness received prednisolone, intravenous immunoglobulin, plasma exchange and four weekly rituximab infusions, yet disabling neck flexor weakness, nasal speech and dysarthria persisted. Efgartigimod was started eleven months after the rituximab course; after three cycles at seven-week intervals, prednisolone was reduced from 20 to 10 milligrams per day, and ravulizumab was intended as long-term therapy once required vaccinations were completed. A 48-year-old woman whose thymoma was removed incidentally, and who also carried a history of HPV-associated cervical adenocarcinoma, had poor venous access that precluded further plasma exchange; two efgartigimod cycles improved her from class IVB to IIA with an MG-ADL score of 1, while meningococcal vaccination proceeded toward planned ravulizumab. The choice is supported by growing real-world evidence, including an Italian multicenter ravulizumab cohort of 14 thymoma patients showing greater early Quantitative Myasthenia Gravis response in this subgroup, and a separate cohort of 23 patients confirming complement inhibitor effectiveness in thymoma-associated disease.

The seventh case involved chronic, corticosteroid-dependent disease with prominent ocular relapse. A 71-year-old man with a seven-year history had achieved pharmacological remission on mycophenolate mofetil and low-dose alternate-day prednisolone, then developed an unprovoked ocular-bulbar relapse with severe bilateral ptosis and diplopia. Prednisolone was raised to 25 milligrams per day, and symptom recurrence during tapering indicated inadequate control despite mycophenolate. Three efgartigimod cycles improved his MG-ADL score from 7 to 2 and his class from IIIB to IIB, but residual ptosis tended to recur as each cycle approached, precluding steroid reduction. Ravulizumab was therefore planned for sustained control, a rationale reinforced by a post hoc analysis of CHAMPION MG showing benefit across individual MG-ADL items, with particularly notable improvements in ocular symptoms including eyelid ptosis and diplopia.

The article also highlights practical pharmacology that determines sequencing. Clinically meaningful improvement with efgartigimod may appear as early as one week after the first administration, with maximal benefit generally around week four, while rozanolixizumab improvement has been detected from day eight, the first post-baseline assessment. FcRn antagonists require no pre-treatment vaccinations, allowing immediate initiation, whereas C5 complement inhibition demands meningococcal vaccination against serogroups A, C, W, Y and B completed at least two weeks before the first ravulizumab dose, with antibacterial prophylaxis required if treatment must begin sooner. This vaccination delay is precisely why FcRn antagonists served as immediately available bridging therapies in the thymoma and relapsing cases. For planned rituximab transitions, the team uses an interval of at least two to three weeks after the last FcRn dose, reflecting efgartigimod pharmacokinetics and serum IgG recovery preferably above 5 grams per liter, while stressing that no evidence-based interval has been established.

A subtle pharmacokinetic consideration runs through the discussion: because FcRn inhibition enhances IgG catabolism and ravulizumab is an IgG-based monoclonal antibody, FcRn blockade increases ravulizumab clearance, which is why the pathways were sequential rather than concomitant. Japanese clinicians have recently reported two refractory patients treated with combined subcutaneous efgartigimod and zilucoplan, a macrocyclic peptide C5 inhibitor that, not being an IgG antibody, escapes FcRn-mediated catabolism; zilucoplan was not commercially available in Greece during the study period. The authors are candid about limitations, including the retrospective single-center design, very small and heterogeneous sample, potential selection bias and the fact that several planned transitions had not yet been implemented, making the observations descriptive and hypothesis-generating rather than proof of comparative efficacy. Still, the seven pathways assign distinct but complementary clinical roles to each agent, rapid IgG reduction, long-term B-cell depletion and sustained terminal complement inhibition, and argue that treatment sequence should be tailored to disease phenotype, therapeutic objective, comorbidities, vaccination requirements and route of administration, with prospective studies needed to establish optimal intervals and biomarkers capable of guiding individualized selection.

Subject of Research: Neurology

Article Title: Individualized sequencing of targeted immunotherapies in generalized myasthenia gravis across distinct patient profiles

Article References: Zouvelou, V., Tzavella, D., Strataki, E., & Vakrakou, A. G. (2026). Individualized sequencing of targeted immunotherapies in generalized myasthenia gravis across distinct patient profiles. Frontiers in Neurology, 17, Article 1989043. https://doi.org/10.3389/fneur.2026.1989043

Image Credits: AI Generated

DOI: 10.3389/fneur.2026.1989043

Keywords: myasthenia gravis, immunotherapy, FcRn antagonists, rituximab, ravulizumab, neuromuscular disorders, targeted therapy, Individualized, sequencing, targeted, immunotherapies, generalized

The biological logic behind B-cell depletion in lupus is compelling. At the heart of the disease lies a breakdown of self-tolerance, with polyclonal activation of B cells that differentiate into plasmablasts and plasma cells churning out autoantibodies. These antibodies bind self-antigens to form immune complexes, which deposit in the kidneys, joints, and skin, activating the complement cascade and driving progressive organ damage. Lupus B cells are also quantitatively and qualitatively abnormal: they overproduce pro-inflammatory cytokines such as tumor necrosis factor, interleukin-6, and interferon-gamma, present autoantigens to T cells in a self-perpetuating activation loop, and are further stimulated when their toll-like receptors engage nucleic acid-protein complexes, the most prominent autoantigens in the disease. Striking at this cellular linchpin, the authors argue, is a rational therapeutic strategy.

Rituximab itself is a chimeric monoclonal antibody, part murine variable region and part human constant region, assembled as an immunoglobulin G1 molecule directed against CD20, a surface marker found on pre-B and mature B cells. Its principal killing mechanism is complement-dependent cytotoxicity, which classifies it as a type I anti-CD20 antibody. Recent structural work has added molecular texture to that picture: researchers solved the structure of CD20 bound to rituximab, revealing a compact double-barrel dimer gripped by two antibody antigen-binding fragments. That architecture suggests rituximab cross-links CD20 into circular assemblies within lipid rafts, a clustering event thought to supercharge complement activation at the cell surface.

The clinical record, however, is more complicated than the biology. Two pivotal randomized, placebo-controlled trials, EXPLORER in extrarenal lupus and LUNAR in lupus nephritis, both missed their primary endpoints, casting a long shadow over the drug. The review’s authors dissect why those trials may have failed on design rather than biology. EXPLORER lumped together heterogeneous disease manifestations, making uniform improvement hard to demonstrate, and both trials layered rituximab on top of intensive background immunosuppression, including high-dose corticosteroids and, in LUNAR, 3 grams per day of mycophenolate mofetil, regimens robust enough to mask any added benefit. The endpoints were also stringent and arguably ill-suited to capturing partial responses, and both trials judged efficacy at 52 weeks, an early timepoint in a disease where clinical responses often take longer to mature. Both trials did confirm that rituximab reliably depletes peripheral B cells, even when that depletion did not translate into measured clinical improvement.

Real-world experience tells a very different story. Observational studies and registries, encompassing cohorts from 18 to 261 patients, have consistently reported response rates between roughly 60 and 85 percent when rituximab is added to standard care in refractory disease. Follow-up periods in these studies range from six months to five years, with only one study extending beyond a decade, a small real-world analysis that documented disease activity improvements persisting at ten years or more. The evidence base is admittedly messy: endpoints vary from clinician judgment to BILAG and SELENA-SLEDAI activity scores, dosing schemes differ across and even within studies, and most analyses lack control groups. Yet the consistency of benefit across so many heterogeneous settings has made rituximab a mainstay for patients whose disease has shrugged off conventional therapy, and scientific society guidelines now sanction its use in refractory SLE.

Nowhere is that benefit clearer than in lupus nephritis, the kidney complication that afflicts roughly 60 percent of patients and can progress to end-stage kidney disease. A Bayesian meta-analysis found that ESKD risk in lupus nephritis fell from the 1970s to the mid-1990s, plateaued, and then paradoxically rose again in the late 2000s despite escalating immunosuppression. Against that trend, the steroid-sparing RITUXILUP protocol stands out: 50 patients received two 1-gram rituximab infusions with limited methylprednisolone and mycophenolate maintenance but no oral steroids, achieving complete and partial renal responses in 52 and 34 percent at 52 weeks. Long-term follow-up of that regimen showed preserved renal function beyond five years. A pooled European analysis of 164 patients with biopsy-proven nephritis found the highest complete response rates in class III and mixed disease, roughly 62 and 50 percent, and the lowest in class IV and pure class V, while nephrotic syndrome and renal failure at treatment initiation predicted worse outcomes. A network meta-analysis ranked rituximab and tacrolimus as the most efficacious induction agents for lupus nephritis.

The stakes of achieving renal response are enormous. Ten-year renal survival reaches 95 percent in patients who achieve a complete response, 45 percent with partial response, and just 19 percent with no response; at 15 years, chronic kidney disease-free survival is 95.2, 87.6, and 55.4 percent respectively. An early proteinuria drop below 0.8 grams per day at 12 months is the best predictor of seven-year renal survival, and each renal flare adds to irreversible damage. Intriguingly, a small biopsy study in membranous lupus nephritis showed that immune complex resorption increased significantly after rituximab but not after conventional immunosuppression, with all seven rituximab-treated patients responding compared with 53 percent of conventionally treated controls, hinting at histological benefit beyond proteinuria numbers.

Perhaps the review’s most provocative thread concerns timing. Data from 131 patients showed that those needing only a single rituximab cycle had multi-organ but non-refractory disease and far less prior immunosuppressive exposure, while patients previously treated with azathioprine or methotrexate were significantly more likely to require repeated cycles. A multicenter study of 147 patients found treatment failure in 27 percent at six months, with fewer prior immunosuppressants and higher complement C4 levels protecting against failure. In newly diagnosed patients, early rituximab plus cyclophosphamide produced dramatic BILAG score reductions and slashed cumulative prednisolone doses, with seven-year follow-up showing 2.63 mean flares versus 4 in controls and cumulative steroid exposure of roughly 4,746 milligrams versus 12,554. A retrospective study of newly diagnosed patients found modified lupus low disease activity state in 76 percent of first-line rituximab recipients versus 45.8 percent on conventional first-line therapy. A dedicated clinical trial, FIRST, now underway in 128 patients aged five and older with new moderate-to-severe lupus, will randomize early rituximab against placebo on top of standard care to test whether prompt B-cell depletion can genuinely rewrite the disease trajectory.

Safety data offer reassurance with caveats. Infusion reactions range from 3.5 to 16.4 percent in most cohorts, though some report up to 44 percent; infections occur in 40 to 57 percent of patients, with serious infections requiring hospitalization in 7 to 20 percent, most commonly respiratory and urinary tract infections and herpes zoster. Mortality is low, 0 to nearly 3 percent, mostly from severe infection. A network meta-analysis found rituximab carried the lowest serious adverse event rate among B-cell-targeting biologics, with anifrolumab showing the lowest infection likelihood at 78.7 percent ranking probability followed by rituximab at 72.6. Hypogammaglobulinemia after repeated cycles remains uncommon, affecting 21 percent for IgM and 7 percent for IgG, though rituximab-treated patients face heightened COVID-19 severity and mortality. Low-dose regimens, two 200-milligram infusions or 100 milligrams weekly for four weeks, have shown encouraging response rates in lupus-related thrombocytopenia and lupus enteritis, potentially trimming both toxicity and cost.

The therapeutic landscape around rituximab is shifting rapidly. Obinutuzumab, a glycoengineered type II anti-CD20 antibody that kills B cells through antibody-dependent cellular phagocytosis rather than complement, has been FDA-approved for active lupus nephritis after the REGENCY trial, and small series show it rescuing patients with secondary non-response to rituximab, with median SLEDAI-2K scores falling from 16 to 5 at six months. Ofatumumab and ocrelizumab offer fully human or humanized alternatives with lower immunogenicity, though their phase III lupus programs stumbled on infections and lack of efficacy. Belimumab after rituximab eliminates severe flares and works best, exploratory data suggest, in patients with high baseline serum IgA2 anti-dsDNA antibody concentrations, a potential biomarker for personalized sequencing. And at the frontier, allogeneic CD19-targeted CAR-T cell therapy has induced durable, drug-free remission in refractory lupus, albeit at enormous cost and with risks including cytokine release syndrome and prolonged B-cell aplasia. For now, the review concludes, rituximab’s accessibility, two decades of safety experience, and biosimilar-driven affordability keep it central to lupus care, even as deeper depletion strategies wait in the wings.

Subject of Research: The role of rituximab, an anti-CD20 B-cell-depleting antibody, in therapeutic strategies for systemic lupus erythematosus

Article Title: Positioning rituximab in the therapeutic strategies for SLE

Article References: Staveri, C., & Liossis, S.-N. C. (2026). Positioning rituximab in the therapeutic strategies for SLE. Frontiers in Lupus, 4, Article 1877692. https://doi.org/10.3389/flupu.2026.1877692

Image Credits: AI Generated

DOI: 10.3389/flupu.2026.1877692

Keywords: rituximab, systemic lupus erythematosus, lupus nephritis, B-cell depletion, anti-CD20, belimumab, obinutuzumab, CAR-T therapy, autoimmunity, refractory disease, biologic therapy, rheumatology

The patient arrived with a constellation of symptoms that would puzzle many clinicians: intermittent jaw pain, headache, tenderness over the left temple, blurred vision in the left eye, and intermittent binocular diplopia, the medical term for double vision arising from misalignment of the two eyes. Her history included seropositive rheumatoid arthritis, meaning her blood carried the characteristic autoantibodies such as rheumatoid factor, along with atrial arrhythmia, breast cancer, and osteoporosis. Notably, she was a one-pack-per-day cigarette smoker, a habit the authors highlight as a known risk factor for rheumatoid vasculitis and one that adversely influences the expression of the p53 proto-oncogene in the disease.

Examination revealed measurable deficits. Her visual acuity was 20/40 in the right eye and 20/30 in the left, and Humphrey visual field testing showed a mean deviation of minus 0.50 decibels on the right and minus 3.03 decibels on the left, with an inferior arcuate defect corresponding to the worse left eye. A relative afferent pupillary defect, in which the affected pupil paradoxically dilates when light swings to it, pointed to dysfunction of the left optic nerve pathway. Ocular motility testing showed a minus 2 limitation of both adduction and abduction in the left eye, meaning the eye could not fully turn inward or outward, while the right eye moved normally. Optical coherence tomography measured retinal nerve fiber layer thicknesses of 91 and 96 microns, values within a range that would later prove useful for tracking stability.

The decisive diagnostic tool was magnetic resonance imaging of the brain and orbits with contrast. The scans showed asymmetric enhancement of the left orbital apex, the narrow posterior gateway where the eye’s nerves and vessels pass into the skull, with extension through the left superior orbital fissure into the cavernous sinus, a venous channel flanking the pituitary that carries multiple cranial nerves, and into Meckel’s cave, a dural pocket housing the trigeminal ganglion. This anatomic triad, orbital apex, superior orbital fissure, and cavernous sinus, explains the patient’s combination of eye movement restriction, vision loss, and facial pain, because each structure houses distinct nerve populations vulnerable to inflammatory compression.

Before attributing the syndrome to rheumatoid arthritis, the team systematically excluded competing diagnoses, a critical step because orbital inflammatory syndrome is a diagnosis of exclusion. A temporal artery biopsy returned negative for giant cell arteritis, the dangerous vascular inflammation that mimics this presentation in older patients. Serologic testing for angiotensin-converting enzyme and lysozyme ruled against sarcoidosis, while negative myelin oligodendrocyte glycoprotein and neuromyelitis optica antibodies excluded demyelinating disease. Tuberculosis and Lyme disease testing was negative, serum immunoglobulin G4 was normal, and lumbar puncture showed unremarkable cerebrospinal fluid. Granulomatosis with polyangiitis was considered unlikely given the absence of sinonasal disease, bone destruction, or ANCA positivity, and the multiyear stability of the findings argued against lymphoma.

Treatment began with intravenous high-dose methylprednisolone followed by high-dose oral prednisone with a slow taper, the standard first-line approach for orbital inflammatory disease. Three months later, repeat imaging showed near resolution of the left orbital apex enhancement, though persistent enhancement remained at the right Meckel’s cave, and the patient was started on maintenance infliximab infusions, a tumor necrosis factor inhibitor already part of her rheumatoid regimen. But the story did not end there. Thirteen months after the initial presentation, she developed chemosis, pain, ophthalmoplegia, ptosis, and lid edema in the right eye, the previously unaffected side. Repeat MRI revealed new enhancement of the right orbital apex, cavernous sinus, foramen ovale, and superior orbital fissure, confirming that the inflammatory process had migrated across the midline.

The relapsing course became the defining feature of the case. The patient again improved with intravenous methylprednisolone and high-dose prednisone, but she experienced recurrent diplopia with each attempt to taper the steroid, notably at around 10 milligrams of prednisone. Elevated serum rheumatoid factor of 88 and a C-reactive protein of 1.05 accompanied the flares. Ultimately, stability was achieved with leflunomide and hydroxychloroquine, with stable orbital and cranial imaging and preserved visual function in both eyes at last follow-up. The authors emphasize that this steroid-dependent, relapsing trajectory distinguishes their patient from most previously reported cases, in which glucocorticoids produced partial or complete short-term improvement and sustained remission.

The treatment landscape for orbital inflammatory disease is evolving, and the report situates the case within that evidence base. In a tertiary cohort of orbital inflammatory disease, corticosteroids achieved full remission in roughly half of patients, while rituximab, a B-cell-depleting antibody, achieved full remission in more than 80 percent, giving it the strongest evidence in refractory orbital inflammation. Only one prospective interventional trial exists in this field, a phase 1/2 randomized trial of rituximab, and the authors call for validated orbital disease grading systems and corticosteroid-sparing endpoints to enable the multicenter trials needed to study individually rare presentations like this one. Prior case reports, including migratory orbital inflammation treated with rituximab and adalimumab, and orbital pseudotumor managed with prednisolone alone, illustrate the heterogeneity of responses.

The authors are candid about the limitations of their report. No biopsy was performed because the lesion’s location made tissue sampling unfeasible, leaving the diagnosis presumptive rather than histologically confirmed, the most definitive means of excluding entities such as IgG4-related disease. Serial MRI scans were acquired using non-identical protocols across time points, limiting direct quantitative comparison of inflammation over time, and the authors argue that standardized orbital MRI protocols would strengthen future longitudinal assessment. These caveats matter because treatment decisions in orbital inflammation hinge on distinguishing steroid-responsive inflammation from lymphoma, which can masquerade as the same radiographic pattern.

For clinicians, the message is that rheumatoid arthritis belongs on the differential for painful ophthalmoplegia and orbital apex syndromes, alongside the far more common ocular manifestations such as scleritis and episcleritis. Patients at highest risk of rheumatoid vasculitis and severe extra-articular disease include those with high-titer rheumatoid factor or anti-CCP antibodies, long-standing erosive disease with nodules, prior exposure to disease-modifying antirheumatic drugs, and male sex. Because extra-articular rheumatoid arthritis tracks with more active systemic disease, tighter inflammatory control and earlier immunomodulatory therapy may reduce the incidence of these devastating complications over time. The case also underscores the importance of counseling rheumatoid patients that their disease can progress in unexpected directions, and that symptoms such as double vision, eye pain, or vision loss warrant urgent neuro-ophthalmic evaluation rather than attribution to routine joint disease.

Subject of Research: A rare case of rheumatoid arthritis-associated orbital and intracranial inflammatory disorder affecting the orbital apex, cavernous sinus, and Meckel's cave

Article Title: Case Report: Orbital and intracranial inflammatory syndrome in rheumatoid arthritis

Article References: Mans, C., Ibrahim, S., Abdelsalam, D., & Lee, A. G. (2026). Case Report: Orbital and intracranial inflammatory syndrome in rheumatoid arthritis. Frontiers in Ophthalmology, 6, Article 1929961. https://doi.org/10.3389/fopht.2026.1929961

Image Credits: AI Generated

DOI: 10.3389/fopht.2026.1929961

Keywords: rheumatoid arthritis, orbital inflammatory disease, cavernous sinus, Meckel's cave, neuro-ophthalmology, autoimmune disease, rituximab, corticosteroids, diplopia, vasculitis, MRI, case report

Systemic lupus erythematosus is a chronic autoimmune disease in which the immune system attacks multiple organ systems, affecting an estimated 5.14 per 100,000 person-years worldwide. Women of childbearing age are disproportionately affected, being ten times more likely than men to develop the disease, and prevalence is highest among Black, Hispanic, and Asian populations. Pulmonary involvement occurs in a striking 20 to 90 percent of lupus patients, ranging from pleuritis and pleural effusion to acute pneumonitis, interstitial lung disease, and pulmonary hypertension. Against this backdrop, shrinking lung syndrome stands out as an uncommon but clinically important entity, estimated to affect between 0.5 and 1.53 percent of all lupus patients.

First described in 1965 by Hoffbrand and Beck, shrinking lung syndrome is characterised by progressive breathlessness, pleuritic chest pain, reduced lung volumes, and elevated hemidiaphragms on chest imaging, all in the absence of identifiable parenchymal lung disease. The syndrome has also been reported in other connective tissue diseases, including Sjögren’s syndrome, scleroderma, and rheumatoid arthritis, though it remains most strongly associated with lupus. What has made the condition so difficult to study is its rarity and the absence of standardised diagnostic criteria, forcing clinicians to diagnose it largely by excluding pneumonia, pulmonary embolism, heart failure, interstitial lung disease, and other more common causes of restrictive lung physiology.

The researchers, led by Nandini Bindal of Queen Mary University of London and Debasish Pyne of the Barts Health Lupus UK Centre of Excellence, conducted a systematic search of MEDLINE and Embase databases covering publications from January 1946 through December 2025. They identified 107 records, of which 34 met their inclusion criteria: 19 case reports, nine case series, five case series with literature reviews, and one cross-sectional cohort study. From these, they pooled data on 120 patients. The demographic profile mirrored that of lupus itself, with 86 percent of patients being female and ages ranging from 12 to 67 years, including several paediatric cases. The mean age across studies was approximately 33 years.

Clinically, the syndrome announced itself most often through breathlessness. Dyspnoea was present in 98 percent of patients for whom symptom data were available, while pleuritic chest pain affected 81 percent. Orthopnoea, fever, fatigue, arthralgia, and cough were also described, though less consistently quantified. In 22 percent of cases, shrinking lung syndrome was the initial manifestation of lupus, meaning that for some patients, respiratory symptoms were the first clue that they had an autoimmune disease at all. Among those who developed the syndrome after an established lupus diagnosis, the median interval from lupus diagnosis to syndrome onset was 48 months, with a remarkable range extending from concurrent onset to 38 years later. Symptom onset itself varied widely, from gradual progression over months to years to abrupt deterioration, including one case triggered by prednisolone withdrawal after two months of medication non-compliance.

Imaging findings reinforced the syndrome’s characteristic signature. Chest radiographs were performed in 88 percent of patients and computed tomography in 68 percent. Elevated hemidiaphragms were identified in 78 percent of the pooled cohort, reduced lung volumes in 43 percent, and basal or laminar atelectasis in 34 percent. Pleural effusions or pleural thickening appeared in 31 percent of patients. Importantly, lung parenchyma was generally preserved, with no evidence of significant fibrosis or diffuse interstitial changes, distinguishing the syndrome from interstitial lung disease. Some patients had entirely normal baseline imaging, with serial chest radiographs later revealing progressive diaphragmatic elevation, highlighting the dynamic nature of the condition. Diaphragmatic fluoroscopy and ultrasound, performed in a subset of patients, confirmed reduced diaphragmatic excursion in 19 patients and complete absence of movement in one.

Pulmonary function testing provided perhaps the most diagnostically useful pattern. A restrictive ventilatory defect was present in 91 percent of the 117 patients with available data. Forced vital capacity values ranged from 15 to 99 percent of predicted, with most patients showing moderate to severe restriction, and total lung capacity was similarly reduced. Yet the diffusing capacity for carbon monoxide, while reduced in the majority, was preserved or elevated in the transfer coefficient (KCO) in 90 percent of the 33 patients in whom it was measured. This disproportionate reduction in lung volumes relative to preserved gas transfer efficiency points to an extrapulmonary cause of restriction, offering clinicians a valuable clue that separates shrinking lung syndrome from interstitial lung disease, where both lung volumes and gas transfer are typically reduced together.

The pathophysiology of the syndrome remains contested, and the pooled data reflect this uncertainty. Phrenic nerve conduction studies, available in only four patients, yielded heterogeneous results: one patient had normal nerve potentials, another showed normal diaphragm twitch pressures on magnetic stimulation, and a third displayed absent electrical activity on the left hemidiaphragm with delayed responses on the right, consistent with a demyelinating phrenic neuropathy that improved after corticosteroid treatment. One patient underwent dynamic magnetic resonance imaging, which revealed normal movement of both diaphragms and all accessory respiratory muscles during forced ventilation, suggesting that diaphragmatic dysfunction may not always explain the restriction. Muscle biopsy findings from two other cases pointed instead to a myopathic mechanism, with one showing an endomysial T-lymphocytic infiltrate and another describing a CD20-positive B-cell-predominant myositis responsive to mycophenolate mofetil. These scattered observations suggest that shrinking lung syndrome may not be a single entity but rather the convergent clinical expression of several distinct immune-mediated mechanisms.

Treatment in the pooled cohort was dominated by corticosteroids, given to 93 percent of patients, typically as oral prednisolone at doses of 15 to 60 milligrams per day or as intravenous methylprednisolone pulses. Conventional immunosuppressants were frequently added, including azathioprine in 28 percent, cyclophosphamide in 19 percent, mycophenolate mofetil in 18 percent, and methotrexate in 8 percent. Rituximab, a B-cell-depleting monoclonal antibody, was used in 10 percent of patients, and belimumab in 2 percent, generally in refractory cases. Theophylline appeared in 10 percent of treatment regimens, though one patient developed paroxysmal supraventricular tachycardia and atrial flutter that persisted after discontinuation, underscoring the cardiac risks of this adjunct. Supportive measures such as inhaled beta-2 agonists and pulmonary physiotherapy were occasionally employed, and a structured inspiratory muscle training programme has shown promise in improving respiratory muscle strength and diaphragm thickness on ultrasound.

Outcomes were broadly favourable. Among 104 patients with reported symptomatic outcomes, 77 percent improved, 17 percent remained stable, and only 6 percent showed no improvement or worsened. Follow-up pulmonary function data in 85 patients demonstrated partial recovery in 64 percent, stabilisation of the restrictive pattern in 22 percent, and complete normalisation in just 7 percent. Notably, patients often reported symptomatic relief before measurable improvements in lung function, reinforcing the idea that the restriction reflects a reversible, functional process rather than fixed structural damage. Follow-up periods ranged from three weeks to 20 years, and one death was attributed to the syndrome across the entire cohort. The authors caution that the evidence base remains limited by its reliance on case reports and small series, with inconsistent reporting of investigations, treatments, and long-term follow-up. Nevertheless, the review makes a compelling case that early recognition of shrinking lung syndrome, combined with tailored immunosuppressive therapy, can achieve good outcomes for most patients, and that greater clinical awareness is essential to reduce the diagnostic delays that have historically plagued this rare but treatable complication of lupus.

Subject of Research: Shrinking lung syndrome as a rare pulmonary manifestation of systemic lupus erythematosus

Article Title: Shrinking lung syndrome in systemic lupus erythematosus: a systematic review

Article References: Bindal, N., & Pyne, D. (2026). Shrinking lung syndrome in systemic lupus erythematosus: a systematic review. Frontiers in Lupus, 4, Article 1845359. https://doi.org/10.3389/flupu.2026.1845359

Image Credits: AI Generated

DOI: 10.3389/flupu.2026.1845359

Keywords: shrinking lung syndrome, systemic lupus erythematosus, systematic review, diaphragmatic dysfunction, restrictive lung disease, corticosteroids, rituximab, pulmonary function tests, autoimmune disease, dyspnoea, immunosuppression, rare disease

The woman, who had been treated years earlier for low-grade B-cell non-Hodgkin lymphoma with a rituximab-based regimen, arrived at the hospital with dangerously low blood pressure — 86/58 — and severe swelling in both legs. Lab tests revealed massive protein leakage into her urine, a condition known as nephrotic-range proteinuria, along with acute kidney injury. Her creatinine, a marker of kidney function, was elevated at 1.8 mg/dL, and her urine protein-to-creatinine ratio exceeded 10 g/g, a level indicating profound kidney damage. She was diagnosed with nephrotic syndrome of uncertain origin and scheduled for a renal biopsy to find the cause.

What the biopsy revealed was light chain (AL) amyloidosis — a rare protein misfolding disorder in which abnormal immunoglobulin light chains, produced by a clonal population of plasma cells or B cells, fold incorrectly and aggregate into insoluble fibrils that deposit in organs, disrupting their structure and function. In this patient, the amyloid deposits were composed of lambda light chains and had infiltrated the glomeruli, interstitium, arteries, and arterioles of her kidneys. Light microscopy showed 52% global glomerulosclerosis, moderate interstitial fibrosis, and moderate acute tubular injury — evidence that the deposits had already caused substantial, though not yet irreversible, damage.

AL amyloidosis is uncommon, with an estimated incidence of 9 to 14 cases per million person-years in the United States. It typically arises from plasma cell dyscrasias such as multiple myeloma or monoclonal gammopathy of undetermined significance (MGUS). But in rare instances, it can originate from B-cell lymphomas — a distinctly less prevalent pathogenic subtype that reflects an alternative lymphoid origin of the misfolded light chains. The clinical consequences depend on where the amyloid accumulates: in the heart, it causes restrictive cardiomyopathy; in the kidneys, it produces nephrotic-range proteinuria and progressive renal failure; and systemically, it can cause fatigue, hypotension, and unintentional weight loss.

To identify the source of the amyloid, the team performed a bone marrow biopsy. The results were striking: low-grade B-cell non-Hodgkin lymphoma had infiltrated 85% of the marrow. Immunophenotyping revealed a lambda-restricted clonal B-cell population that was positive for CD20 — a surface marker targeted by rituximab — and negative for CD5, CD10, and CD11c. The immunophenotypic profile raised the possibility of lymphoplasmacytic lymphoma or Waldenström macroglobulinemia, but MYD88 L265P mutation testing was not performed, leaving the precise subtype unresolved. PET imaging confirmed lymphomatous involvement without additional abnormal uptake or lymphadenopathy.

The connection between the two diagnoses was an IgM monoclonal lambda gammopathy detected on serum immunofixation, along with mildly elevated serum lambda free light chains and a decreased kappa-to-lambda ratio of 0.11. These findings indicated that the lymphoma cells were producing the very light chains that were misfolding and depositing as amyloid in her kidneys. The patient was also found to have a positive hepatitis C antibody, though HCV RNA was undetectable and cryoglobulins were absent, making an infectious cause of her kidney disease unlikely.

Treatment was initiated with rituximab and bendamustine, a combination targeting the underlying clonal B-cell disorder driving the amyloid production. The patient tolerated therapy well, and within four weeks her creatinine had improved to 1.15 mg/dL, a sign of recovering kidney function. Her proteinuria also decreased, though it remained elevated at 7.9 g/g. She was simultaneously treated for adrenal insufficiency with hydrocortisone and fludrocortisone, and she reported significant improvement in her peripheral edema.

The case, published in Frontiers in Nephrology, highlights a diagnostic challenge that nephrologists and hematologists rarely encounter. AL amyloidosis is attributed to non-Hodgkin lymphoma in only 1% to 4% of cases, and the overlap in symptoms — fatigue, edema, renal dysfunction — makes it easy to miss. Moreover, nephrotic syndrome in patients with lymphoma has a broad differential diagnosis, including minimal change disease, membranous nephropathy, focal segmental glomerulosclerosis, light-chain deposition disease, cast nephropathy, cryoglobulinemic glomerulonephritis, and immune complex membranoproliferative glomerulonephritis. Distinguishing among these entities requires careful integration of clinical features, serologic testing, complement levels, and definitive renal biopsy findings, because treatment differs significantly depending on the underlying pathology.

Prognosis in AL amyloidosis is primarily determined by the extent of organ involvement and disease stage. Cardiac involvement is the most significant predictor of poor outcomes, with heart failure accounting for approximately 50% of amyloidosis-related deaths. Renal failure and infection each contribute roughly 15% of mortality. In untreated patients, progression to dialysis-dependent renal failure occurs in an estimated 60% to 75% within three years. Earlier studies reported median survival as low as six months, though advances in immunomodulatory therapies and earlier diagnosis have substantially improved outcomes.

The authors acknowledge several limitations, including the absence of definitive amyloid typing by laser microdissection with mass spectrometry and the lack of MYD88 L265P mutation testing, which precluded definitive subclassification of the lymphoma. The relatively short follow-up also limits assessment of long-term remission and renal recovery. Nevertheless, the case adds to a limited body of literature on renal AL amyloidosis associated with low-grade B-cell non-Hodgkin lymphoma and reinforces a critical clinical message: persistent nephrotic-range proteinuria in a patient with B-cell lymphoma — particularly when accompanied by IgM lambda monoclonal gammopathy — should prompt urgent evaluation for amyloidosis with renal biopsy and hematologic assessment, because early clone-directed therapy can alter the trajectory of both diseases.

Subject of Research: Renal light chain amyloidosis secondary to low-grade B-cell non-Hodgkin lymphoma

Article Title: Case Report: Light chain amyloidosis in a patient with low-grade B-cell lymphoma

Article References: Matthaeus, A., Thomas, D., & Toka, H. R. (2026). Case Report: Light chain amyloidosis in a patient with low-grade B-cell lymphoma. Frontiers in Nephrology, 6, Article 1959759. https://doi.org/10.3389/fneph.2026.1959759

Image Credits: AI Generated

DOI: 10.3389/fneph.2026.1959759

Keywords: AL amyloidosis, light chain amyloidosis, non-Hodgkin lymphoma, renal amyloidosis, nephrotic syndrome, IgM monoclonal gammopathy, rituximab, bendamustine, kidney biopsy, B-cell lymphoma, proteinuria, amyloid fibrils

Thrombotic thrombocytopenic purpura is an uncommon but potentially deadly form of thrombotic microangiopathy, a family of disorders in which small blood vessels become obstructed by clots. In its classic form, TTP produces a constellation of findings: microangiopathic hemolytic anemia, in which red blood cells are sheared apart as they squeeze through partially blocked vessels; severe depletion of platelets, the cell fragments that form clots; neurological abnormalities; kidney injury; and fever. The immune-mediated variant of the disease, known as iTTP, arises when the body produces autoantibodies that either inhibit or clear ADAMTS13, an enzyme whose job is to trim oversized strands of von Willebrand factor (VWF), a protein that helps platelets stick together.

When ADAMTS13 is knocked out of commission, these oversized VWF strands accumulate unchecked in the bloodstream. Platelets bind to them indiscriminately, forming microthrombi that clog capillaries throughout the body. Red blood cells are forced through the narrowed passages and are physically torn apart, producing the fragmented cells — schistocytes — that pathologists recognize under the microscope. The result is a cascade of anemia, platelet depletion, and oxygen starvation of vital organs, particularly the brain, kidneys, and heart. Without urgent treatment, mortality rates historically approached 90 percent.

For the 45-year-old African-American woman at the center of this report, the diagnosis unfolded with textbook speed but devastating severity. She arrived at the emergency department with several hours of transient expressive aphasia — difficulty producing speech — along with blurred vision and dizziness. Initial bloodwork revealed a hemoglobin level of 6.3 grams per deciliter, far below the normal range, and a platelet count of just 21,000 per microliter, roughly one-twentieth of normal. Her haptoglobin, a protein that binds free hemoglobin released from destroyed red cells, was undetectable, and her lactate dehydrogenase, a marker of cell damage, was markedly elevated at 1,078 units per liter. A peripheral blood smear confirmed the presence of schistocytes, sealing the diagnosis of microangiopathic hemolytic anemia.

Clinicians calculated a PLASMIC score — a validated tool for estimating the likelihood of TTP in patients with unexplained hemolysis and thrombocytopenia — and it came back at 6 points, placing the patient in the high-probability category. Two days later, confirmatory testing revealed an ADAMTS13 activity level below 5 percent of normal, alongside a positive inhibitor screen with a Bethesda titer of 4.2 Bethesda units per milliliter, confirming that autoantibodies were actively neutralizing the enzyme. The diagnosis of immune-mediated TTP was definitive. Treatment with high-dose intravenous methylprednisolone, a potent corticosteroid, was initiated immediately, and the hematology team strongly recommended urgent plasma exchange, the traditional cornerstone of TTP therapy that physically removes the offending antibodies from the bloodstream while replacing ADAMTS13-rich donor plasma.

But the patient and her husband, devout Jehovah’s Witnesses, declined plasma exchange on religious grounds. Their faith, as they understand it, prohibits the transfusion of whole blood, red blood cells, white blood cells, platelets, and plasma. While certain fractionated blood products such as albumin, clotting factors, and immunoglobulins are matters of personal conscience rather than absolute prohibition, the couple declined both conventional plasma exchange and an alternative approach using albumin-based plasmapheresis. The medical team was forced to chart an entirely different course.

On day three of hospitalization, the patient received rituximab, a monoclonal antibody that depletes the B cells responsible for producing the autoantibodies against ADAMTS13. Urgent efforts were made to obtain caplacizumab, a humanized antibody fragment that binds to the A1 domain of von Willebrand factor, physically blocking platelets from attaching to it and thereby preventing the formation of new microvascular thrombi. The drug, approved by the FDA in 2019 for use in combination with plasma exchange, had never before been tested in a patient with TTP this severe — with neurological compromise requiring intubation and hemoglobin levels this profoundly depressed.

By day four, the patient’s condition had deteriorated dramatically. Her hemoglobin had fallen to 5.4 grams per deciliter and would eventually bottom out at 3.8, her platelet count dropped to 9,000 per microliter, and she became unresponsive, requiring emergency intubation and transfer to the intensive care unit. Elevated troponin levels signaled cardiac injury, and her kidneys and liver were showing signs of compromise. Caplacizumab was administered immediately upon arrival — 11 milligrams intravenously, followed by 11 milligrams subcutaneously daily. A trial of plasmapheresis with albumin replacement was attempted but abandoned when the machine began alarming due to the patient’s critically low hematocrit, which had fallen to between 11 and 16 percent, and the effluent became turbid with hemolytic debris. The patient also began oozing significantly from the access site, raising concerns that continued albumin-based plasma exchange would worsen bleeding.

The clinical turnaround was striking. On day five, the medical team added intravenous folic acid and subcutaneous epoetin alfa, an erythropoiesis-stimulating agent that prompts the bone marrow to produce new red blood cells, along with intravenous immune globulin at 1,000 milligrams per kilogram daily for two doses, which the patient’s husband consented to. By day six, her platelet count had rebounded to 48,000 per microliter, her haptoglobin had risen to 10 milligrams per deciliter, and her neurological status improved so dramatically that she was successfully extubated. By day seven, her neurological symptoms had completely resolved. On day nine — after just six doses of caplacizumab and without any plasma exchange — she achieved clinical remission, defined as two consecutive days with a normal platelet count and a continued downward trend in lactate dehydrogenase. She was discharged from the hospital on day fourteen, continuing daily subcutaneous caplacizumab at home alongside a gradual six-week taper of oral corticosteroids.

Yet the underlying autoimmune attack had not been fully extinguished. One month after caplacizumab initiation, despite corticosteroids, four weekly doses of rituximab, and intravenous immune globulin, the patient’s ADAMTS13 activity remained stubbornly below 5 percent. The medical team escalated to intravenous cyclophosphamide, a powerful chemotherapy agent that suppresses the immune system more broadly. After a single dose of 600 milligrams per square meter, her ADAMTS13 activity normalized to 79 percent. Caplacizumab was discontinued on day fifty of therapy. Cyclophosphamide was stopped after four doses once laboratory values fully normalized — ADAMTS13 activity above 100 percent, platelets at 164,000 per microliter, hemoglobin at 11.9 grams per deciliter, and lactate dehydrogenase at 221 units per liter — with no recurrence of neurological symptoms. She remains in both clinical and immunological remission.

The case, reported by physicians at North Memorial Health in Robbinsdale, Minnesota, and the University of Minnesota, is the first documented use of caplacizumab in a Jehovah’s Witness patient with TTP this severe — with neurological compromise necessitating intubation and hemoglobin levels this low. It adds to a growing body of evidence suggesting that caplacizumab, when initiated early, may be sufficient on its own to manage acute iTTP episodes without plasma exchange. A 2024 study of 42 iTTP episodes in 41 patients from Germany and Austria found no difference in outcomes between those treated with caplacizumab alone and those treated with plasma exchange. More recently, the Phase 3 MAYARI trial, a single-arm open-label study, reported that 93.5 percent of participants achieved remission without plasma exchange, with 97.8 percent achieving remission overall.

What makes this case particularly instructive is the mechanism. Caplacizumab binds to the A1 domain of von Willebrand factor but does not displace platelets that have already attached. It functions more as an anticoagulant than a thrombolytic — preventing new clots from forming rather than dissolving existing ones. Resolving established platelet-rich thrombi likely still requires ADAMTS13, which in conventional therapy is supplied through donor plasma. For patients with milder symptoms and presumably a smaller burden of existing microvascular thrombi, caplacizumab alone may suffice. That this patient, with severe neurological injury and profound anemia, recovered so rapidly suggests that even in advanced disease, blocking new thrombus formation can buy the body enough time to clear existing clots and regenerate damaged tissue — without a single unit of plasma.

The authors emphasize that earlier initiation of caplacizumab might have prevented the most dangerous phase of this patient’s illness, as TTP is fundamentally a time-dependent disease in which every hour of untreated microvascular thrombosis translates into additional organ damage. Current guidelines from the International Society on Thrombosis and Haemostasis recommend starting caplacizumab as early as possible once the diagnosis is confirmed. For patients who cannot or will not undergo plasma exchange — whether for religious convictions, hemodynamic instability, or logistical barriers — this case offers compelling evidence that a targeted antibody strategy, layered with escalating immunosuppression, can achieve complete recovery even in the face of life-threatening disease.

Subject of Research: Treatment of severe immune-mediated thrombotic thrombocytopenic purpura with caplacizumab without plasma exchange

Article Title: Case report: Caplacizumab without plasma exchange for severe thrombotic thrombocytopenic purpura

Article References: Hayes, S. M., Pease, D. F., Wiese, C. M., & Mazepa, M. (2026). Case report: Caplacizumab without plasma exchange for severe thrombotic thrombocytopenic purpura. Frontiers in Drug Delivery, 6, Article 1894135. https://doi.org/10.3389/fddev.2026.1894135

Image Credits: AI Generated

DOI: 10.3389/fddev.2026.1894135

Keywords: caplacizumab, thrombotic thrombocytopenic purpura, plasma exchange, ADAMTS13, von Willebrand factor, rituximab, cyclophosphamide, Jehovah's Witness, microangiopathic hemolytic anemia, immunosuppression, case report, hematology