Cryoglobulinemic Vasculitis Research Articles

Nonviral cryoglobulinemic vasculitis: an updated review for clinical practice

The clinical spectrum of cryoglobulinemic-associated diseases is broad and heterogeneous, with manifestations ranging from mild symptoms (e.g., isolated palpable purpura) to organ- and life-threatening involvement (e.g., membranoproliferative glomerulonephritis). Cryoglobulins are classified into three types. Type I cryoglobulinemia consists of one monoclonal immunoglobulin (Ig) and is practically always associated with B-cell lymphoproliferative disorders. In contrast, type II/III (mixed) cryoglobulinemia is composed of mono- or polyclonal IgM with rheumatoid factor activity bound to polyclonal IgG. Since the introduction of more efficient therapies for chronic hepatitis C virus (HCV), other diseases such as systemic autoimmune disorders and lymphoproliferative neoplasms have been established as the main causes of mixed cryoglobulinemic vasculitis. The pathogenesis of cryoglobulinemic vasculitis is a complex multifactorial process that involves B-cell aberrant lymphoproliferation and autoantibody production. Therefore, treatment of these patients may involve not only measures aimed to mitigate the severity of clinical manifestation but also those that address the associated underlying disease responsible for Ig production. The treatment of patients with type I cryoglobulinemia is primarily focused on controlling B lymphocyte clones responsible for cryoglobulin production, mostly with chemotherapy drugs. Treatment of mixed cryoglobulinemia syndrome is based on rituximab plus glucocorticoids, which induces remission in the vast majority of cases. In the rare patients that do not respond to rituximab administration, potential rescue approaches include alkylating agents, biologic therapies, conventional immunosuppression, and plasma exchange, although with partial efficacy. This narrative review explores the etiology, pathophysiology, clinical manifestations, treatment, and prognosis of nonviral cryoglobulinemic disease. A special focus is placed on the treatment of type I cryoglobulinemia and rituximab-resistant non-HCV cryoglobulinemic vasculitis.

Mixed cryoglobulinaemia vasculitis secondary to marginal zone lymphoma in a patient with end-stage renal failure on haemodialysis

Cryoglobulinaemia vasculitis can present with a variety of symptoms and there is limited data on the incidence and presentation of cryoglobulinaemia vasculitis in haemodialysis patients. We report a case of a 63-year-old male who had a series of presentations with rash, visual changes, abdominal pain, weight loss, fevers and digital ischaemia. This is on a background of a congenital single kidney with end-stage renal failure secondary to diabetes and hypertension, receiving haemodialysis for nearly 5 years. He initially experienced a leukocytoclastic vasculitis rash confirmed on skin biopsy, followed by multiple hospital presentations for undifferentiated abdominal pain and fever of unknown source. Jejunal biopsy revealed intestinal vasculitis. His peripheral blood flow cytometry and bone marrow biopsy were consistent with marginal zone lymphoma (indolent subtype, IgM kappa clone). Further testing revealed a type II cryoglobulinaemia consisting of an IgM kappa monoclonal band with polyclonal IgG (cryocrit 5%). A diagnosis of cryoglobulinaemia vasculitis was established and he was treated with pulsed methylprednisolone and rituximab therapy. However, after receiving three doses of rituximab the patient developed a presumed vasculitis-associated pulmonary haemorrhage for which he received treatment with five sessions of plasma exchange. His symptoms resolved and cryocrit reduced to < 1% after his final dose of rituximab. The clinical features of cryoglobulinaemia may be difficult to detect in chronic haemodialysis patients and vigilance is required.

Therapy with direct antiviral drugs in patients with HCVassociated cryoglobulinemic vasculitis – is it always possible to achieve complete clinical and immunological responses after the virus eradication?

Background. The use of direct acting antiviral drugs (DAАs) leads to the achievement of a stable virological response (SVR) in 95–100 % of patients with HCV-associated cryoglobulinemic vasculitis (HCV-CV). However, in some patients, despite the eradication of the virus, clinical and immunological markers of vasculitis still remain.The aim: to evaluate clinical and immunological responses in patients with HCV-CV in comparison with patients with "asymptomatic" HCV- associated cryoglobulinemia (HCV- СG) after achieving SVR with the help of DAАs with long-term dynamic observation (12 months).Patients and Methods: The study included 45 patients: 23 with HCV-CV and 22 with "asymptomatic" HCV-CG, who underwent antiviral therapy with DAAs. Clinical-immunological, virological data were evaluated: before treatment, 12 weeks (3 months) and 48 weeks (12 months) after the end of treatment.Results: After a course of DAAs, SVR was diagnosed in all 45 (100 % of patients). In patients with HCV-CV, an immunological response (complete and partial) was observed by week 12 (SVR12) – in 56.5 % and by week 48 (SVR48) – in 73.9 % patients. In 6 patients (26.1 %), the immunological response was not achieved by SVR48. The rate of complete and partial clinical response 12 weeks after the end of treatment at the SVR12 period in patients with HCV-CV was 65.2 %, to the time of SVR48 amounted to 78.3 % patients. In 5 (21.7 %) individual manifestations of CV persisted and/or relapsed. In patients with HCV-CG, the frequency of complete and partial immunological responses after DAAs therapy was 77.3 % – by SVR12 and 86.3 % – by SVR48, respectively. No response was observed in 3 patients and it was characterized by trace-level of cryoglobulinemia.Conclusion: In most patients with HCV-CV eradication of HCV with help of DAAs leads to the achievement of clinical and immunological remission of the disease. However, in 20 % of patients manifestations of HCV-CV persist / recur immediately after the end of treatment or later relapses are observed. Based on these observations, patients with HCV-CV, especially those with severe underlying skin and kidney disease, are required long-term monitoring after SVR is achieved.

Local and systemic autoimmune manifestations linked to hepatitis A infection.

Hepatitis A virus (HAV) represents a global burdening infectious agent causing in the majority of cases a self-limiting acute icteric syndrome, the outcome is related to the hepatic substrate and the potential pre-existing damage, whereas a plethora of extra-hepatic manifestations has also been reported. Despite the absence of post- HAV chronicity it has been associated with an additional burden on existing chronic liver diseases. Moreover, the induced immune response and the antigenic molecular mimicry are considered as triggering factors of autoimmunity with regional and distal impact. Diseases such as autoimmune hepatitis, Guillain-Barré syndrome, rheumatoid arthritis, Still's syndrome, Henoch-Schönlein purpura, autoimmune hemolytic anemia, antiphospholipid syndrome, systematic lupus erythematosus or cryoglobulinemic vasculitis have been described in patients with HAV infection. Although the exact mechanisms remain unclear, this review aims to accumulate and clarify the pathways related to this linkage.

Persistence of monoclonal B-cell expansion and intraclonal diversification despite virus eradication in patients affected by hepatitis C virus-associated lymphoproliferative disorders.

We investigated 23 hepatitis C virus (HCV)-infected patients with overt lymphoproliferative diseases (15 cases) or monoclonal B lymphocytosis (8 cases) treated with direct agent antiviral (DAAs) per clinical practice. DAA therapy yielded undetectable HCV-RNA, the complete response of cryoglobulinemia vasculitis and related signs, whilst the presence of B-cell clones (evaluated by flow cytometry, IGHV, and BCL2-IGH rearrangements), detected in 19/23 cases at baseline, was maintained (17/19). Similarly, IGHV intraclonal diversification, supporting an antigen-driven selection mechanism, was identified in B-cell clones at baseline and end of follow-up. DAA therapy alone, despite HCV eradication and good immunological responses, was less effective on the pathological B-cell clones.

Serological and Molecular Characterization of Hepatitis C Virus-Related Cryoglobulinemic Vasculitis in Patients without Cryoprecipitate.

Prolonged B cells stimulation due to the Hepatitis C virus (HCV) can result in autoimmunity, stigmatized by rising levels of cryoglobulins (CGs), the rheumatoid factor (RF), and free light chains (FLC) of immunoglobulins (Ig) associated with a range of symptoms, from their absence to severe cryoglobulinemic vasculitis and lymphoma. Here, we aimed to identify an immunological signature for the earliest stages of vasculitis when cryoprecipitate is still not detectable. We firstly analyzed the IgG subclasses, FLC, and RF in 120 HCV-RNA-positive patients divided into four groups according to the type of cryoprecipitate and symptoms: 30 asymptomatic without cryoprecipitate (No Cryo), 30 with vasculitis symptoms but without CGs that we supposed were circulating but still not detectable (Circulating), 30 type II and 30 type III mixed cryoglobulinemia (Cryo II and Cryo III, respectively). Our results revealed that patients with supposed circulating CGs displayed a pattern of serological parameters that closely resembled Cryo II and Cryo III, with a stronger similarity to Cryo II. Accordingly, we analyzed the groups of Circulating and Cryo II for their immunoglobulin heavy chain (IgH) and T-cell receptor (TCR) gene rearrangements, finding a similar mixed distribution of monoclonal, oligoclonal, and polyclonal responses compared to a control group of ten HCV-RNA-negative patients recovered from infection, who displayed a 100% polyclonal response. Our results strengthened the hypothesis that circulating CGs are the origin of symptoms in HCV-RNA-positive patients without cryoprecipitate and demonstrated that an analysis of clonal IGH and TCR rearrangements is the best option for the early diagnosis of extrahepatic complications.

#6891 MACHINE LEARNING NEPHROPATHOLOGY DIAGNOSTICS OF THROMBOTIC MICROANGIOPATHIES

Abstract Background and Aims Thrombotic microangiopathies, comprising atypical hemolytic uremic syndrome (aHUS) and other diseases, can present with a broad clinical and histopathological spectrum. On our way to an evidence-base for the nephropathological work-up of TMAs, we have chosen a machine-learning approach, thus eliminating suboptimal reproducibility of descriptors for individual lesions in the three decisive compartments artery, arteriole and glomerulus with human experts. Here, we present our results for an end-to-end diagnostic system. Method We collected 50 random biopsies with TMAs of various etiologies (including aHUS, hypertension-associated, systemic sclerosis, anti-phospholipid antibody syndrome and others) and 50 biopsies with Mimickers (differential diagnoses of TMA), including severe hypertensive nephropathy, necrotising arteritis/arteriolitis, cryoglobulinemic vasculitis from the three participating centers Cologne, Weill-Cornell Medical Center, and Turin. Whole slide images (WSIs) from all four nephropathology stainings HE, PAS, trichrome and Jones were included in this study. We developed an instance segmentation Mask-RCNN model with a Swin Transformer (t) backbone on tissue crops detected using a lightweight variant of the U-Net segmentation architecture. For the classification model we used our own MorphSet++ set transformer architecture to process batches of EfficientNetv2s-encoded tissue crops entered in three separate compartment channels. Batches were chosen with Monte Carlo sampling or using our own soft Markov Chain Monte Carlo (MCMC) approach. Results of the classification model are reported with 5-fold internal cross-validation. Results Segmentation performance measured as mIOU, mAP, mAR, mF1, mAS for artery reached 0.565, 0.739, 0.679, 0.704, 0.995, for arteriole 0.342, 0.531, 0.488, 0.490, 0.996, for glomeruli 0.818, 0.880, 0.919, 0.896, 0.993. Classification accuracy reached 90% with no false positives for TMA. Missed cases of TMA could be salvaged by an experienced nephropathologist on the display of decisive compartment crops, which were selected using model confidence averaged across each sampling iteration. Conclusion We have designed and trained architectures capable of segmenting decisive compartments and diagnosing TMAs on renal biopsy sections. This will enable automatic analysis of clinicopathological datasets with TMA in large cohorts. Our ultimate goal is to use large cohorts from collaborating institutions for weakly supervised, case-level-annotated training of diagnostic, prognostic and theranostic classifiers.

#2533 PROGNOSTIC SIGNIFICANCE OF ARTERIOLAR C4D POSITIVITY AS A MARKER OF MICROANGIOPATHY IN ANCA-ASSOCIATED VASCULITIS

Abstract Background and Aims ANCA-associated vasculitis (AAV) represent a group of systemic autoimmune diseases characterized by necrotizing inflammation of small to medium-size blood vessels frequently associated with anti-neutrophil cytoplasmic antibody (ANCA) positivity. Another term they are commonly referred with is “paucimmune vasculitis”, reflecting the lack of immune complex deposition on histological samples, in contrast with other small vessel vasculitis, e.g. cryoglobulinemic vasculitis. The absence or the paucity of deposition of immunoglobulins and complement components was interpreted in the past as a lack of complement cascade involvement in the pathogenesis of AAV. Only in relatively recent times the possible role of complement in AAV was investigated. A few studies proved the relationship between C3 hypocomplementemia and worse renal outcome[1]. Moreover, the overactivation of the alternative complement pathway (ACP) in AAV could be responsible for thrombotic microangiopathy (TMA). A strong association between low serum C3 and histologic signs of thrombotic microangiopathy on renal biopsy was shown in patients with AAV, with a worse renal prognosis. Currently, there are no clear early histological markers of endothelial damage that allow to identify high-risk patients, other than the seldom not identified or misidentified presence of TMA. The association between renal arteriolar C4d deposition (as a vicariate of TMA) has been already described in several glomerulonephritis, including IgA nephropathy [2], but its prognostic meaning has not yet been explored [3]. Our study aims to explore the predictive role of arteriolar C4d in ANCA-associated GN. Method All patients with ANCA-associated GN who underwent a kidney biopsy between January 1990 and June 2021 at the Renal Unit of Parma University Hospital, Parma, Italy with at least 6 months follow-up data were included. All histology slides were retrieved and reviewed by experienced nephropathologists. Percent IFTA, percent global glomerulosclerosis, Brix score, the presence or absence of TMA, the positivity or negativity of C4d (immunohistochemical staining on paraffin-embedded formalin-fixed slides) were taken note of. C4d positivity was correlated with the presence of TMA and patients outcome (Fig. 1). Results We identified 58 patients who met our criteria. 14 patients were excluded because biopsy specimens were not available for histologic review. Clinical and laboratory baseline and follow-up data for the remaining 44 patients were thus collected. Conclusion C4d and TMA were independently associated (p = 0.003). A tendency towards association between C4d and death-censored ESRD was observed (Fig. 2), although not statistically significant (p = 0.434), likely due to the limited sample size. In order to test our hypothesis, validation on a larger cohort is currently underway.

#5353 THE IDIOPATIC HYPOCRYOGLOBULINEMIA AS AN EMERGING MEMBRANOPROLIPHERATIVE GLOMERULONEPHRITIS

Abstract Background and Aims A considerable number of patients with high clinical suspicion for cryoglobulinaemic vasculitis either show negative results for the detection of cryoglobulins or show only trace amounts which cannot be characterized for composition. We aimed at establishing whether the failure to detect or the detection of trace amounts of cryoglobulin with conventional methods either identifies a peculiar subset of low level cryoglobulinaemia (from now on hypocryoglobulinaemia) or represents a separate entity. Method Using a modified precipitation technique in hypo-ionic medium, we prospectively identified between 2008 and 2021 237 patients (median age 60.8 years [22-97], 137 females) having &amp;lt;0.5% cryocrit and clinical suspicion of autoimmune disorder Results 54 out of 237 patients (22.7%) had a history of HCV infection. 169 out of 237 patients (71%) had an established underlying disease, while 68 patients (28.6%) (median age 62.9 years [29-93], 35 females) did not show either laboratory markers or clinical symptoms consonant with an underlying aetiology. These 68 cases with only trace amounts of cryoglobulins were defined as having a putatively idiopathic hypocryoglobulinaemia. Nineteen of these 68 patients (27.9%) had a history of HCV infection. Twenty-four patients out of 68 (35.3%) were positive for rheumatoid factor (RF), while 25 (36.7%) patients had signs of complement consumption, and 36 (52.9%) had increased inflammatory indexes. Seven patients only had arthralgia and constitutional symptoms while 61 out of 68 (89.7%) presented with at least one of the three cardinal signs of cryoglobulinaemic vasculitis including skin lesions, peripheral nerve involvement, and glomerulonephritis. Seventy-five percent of the subjects had type III hypocryoglobulins. In patients with hypocryoglobulinaemia the histologic features of glomerulonephritis (also examined by electron microscopy) resembled those of mixed cryoglobulinaemia-associated glomerulonephritis Conclusion In conclusion, hypocryoglobulins are often polyclonal and are mainly unrelated to HCV infection. Patients who present high clinical suspicion for vasculitis, especially glomerulonephritis and yet test negative for cryoglobulinaemia detected by standard techniques, could require deeper investigation even in the absence of HCV infection, RF activity or signs of complement consumption.

#5348 THE EFFECTS OF RITUXIMAB IN NON-HCV-RELATED MIXED CRYOGLOBULINEMIC VASCULITIS

Abstract Background and Aims Remarkable results in severe HCV-related cryoglobulinemic vasculitis have been obtained with Rituximab. Details of the clinical characteristics and effective treatment of non HCV-related cryogloulinemic syndromes are presently lacking. Method This paper reports on a prospective single-Center open study aimed at evaluating the clinical presentation and effects of Rituximab administered alone in patients with severe non HCV-related cryoglobulinemic syndrome Results The study group included 11 patients followed for at least 6 months. Three patients had type I cryoglobulinemia, 6 had type II and the remaining 2 patients had type III. Mean cryocrit was 2.5%. Four out of 11 patients had symptomatic sicca complex with anti-SSA (Ro)/anti SSB (La) antibodies. All 11 patients presented with biopsy-proven renal involvement, 4 out of 11 with leukocytoclastic vasculitis, and 8 with involvement of the peripheral nervous system. Renal biopsy revealed diffuse membranoproliferative glomerulonephritis (MPGN) in 9 out of 11 patients. Extracapillary proliferation and necrosis of the glomerular tuft was observed in 1 of these 9 cases. Interstitial nephritis together with mesangial expansion and capillary immune deposits were observed in 1 patient. Prevalent interstitial fibrosis and glomerular sclerosis were detected in the remaining case. Patients underwent treatment with rituximab alone. After 6 months we observed a remarkable improvement in the necrotizing skin ulcers and a substantial amelioration of the electrophysiological parameters of motor and sensory peripheral neuropathy. Improvement in both renal function (from 2.8 to 1.4 mg/dl, p &amp;lt; 0.001) and proteinuria (from 4.2 g/24 to 0.4 g/24 h, p &amp;lt; 0.001) was found in 10 out of 11 patients, while 1 could not be fully treated because of a severe infusion reaction and sudden development of anti-Rituximab antibodies. Good renal response was confirmed at the end of follow-up (38.4 months). Three patients had a relapse at 6, 12, and 48 months, respectively. Conclusion In our cohort the administration of 4 once-weekly infusions of Rituximab followed by 2 more infusions after 1 and 2 months proved to be effective in the management of these rare patients.

Coexistence of cryoglobulinemia and ANCA-associated vasculitis in a chronic brucellosis patient -a case report and literature review

BackgroundThe renal involvement of brucellosis is not common. Here we reported a rare case of chronic brucellosis accompanied by nephritic syndrome, acute kidney injury, the coexistence of cryoglobulinemia and antineutrophil cytoplasmic autoantibodies (ANCA) associated vasculitis (AAV) superimposed on iliac aortic stent implantation. The diagnosis and treatment of the case are instructive.Case presentationA 49-year-old man with hypertension and iliac aortic stent implantation was admitted for unexplained renal failure with signs of nephritic syndrome, congestive heart failure, moderate anemia and livedoid change in the left sole with pain. His past history included chronic brucellosis and he just underwent the recurrence and completed the 6 weeks of antibiotics treatment. He demonstrated positive cytoplasmic/proteinase 3 ANCA, mixed type cryoglobulinemia and decreased C3. The kidney biopsy revealed endocapillary proliferative glomerulonephritis with a small amount of crescent formation. Immunofluorescence staining revealed only C3-positive staining. In accordance with clinical and laboratory findings, post-infective acute glomerulonephritis superimposed with AAV was diagnosed. The patient was treated with corticosteroids and antibiotics and sustained alleviation of renal function and brucellosis was achieved during the course of a 3-month follow-up.ConclusionsHere we describe the diagnostic and treatment challenge in a patient with chronic brucellosis related glomerulonephritis accompanied by the coexistence of AAV and cryoglobulinemia. Renal biopsy confirmed the diagnosis of postinfectious acute glomerulonephritis overlapping with ANCA related crescentic glomerulonephritis, which was not ever reported in the literature. The patient showed a good response to steroid treatment which indicated the immunity-induced kidney injury. Meanwhile, it is essential to recognize and actively treat the coexisting brucellosis even when there are no clinical signs of the active stage of infection. This is the critical point for a salutary patient outcome for brucellosis associated renal complications.

Efficacy of direct-acting antivirals in patients with hepatitis C virus-associated cryoglobulinemic vasculitis: Results of a long-term follow-up

Objective – to evaluate the long-term outcomes of HCV eradication with direct-acting antivirals (DAAs) in patients with hepatitis C-associated cryoglobulinemic vasculitis (HCV-CV)Materials and methods. We retrospectively assessed 48 patients with HCV-CV treated with DAAs. The activity of HCV-CV was assessed by using Birmingham Vasculitis Activity Score version 3 (BVAS v. 3). In patients with HCV-CV the rate of sustained virologic (defined as undetectable HCV-RNA levels 12 weeks after treatment cessation) and immunological (defined as absence of circulating cryoglobulins, rheumatoid factor and normal C4 level) response; and the rate of complete (defined by a BVAS v. 3 score of 0) and partial (defined as BVAS v. 3 score &lt;50% of the baseline score) clinical response were evaluated. Immunosupressants were given before or after DAAs therapy if clinically needed.Results. Median time of follow-up from treatment cessation were 26,5 (11,5–62,3) months. All 48 (100%) patients achieved sustained virologic response. Elimination of cryoglobulins were reported in 20 (41,7%) patients, complete immunological response-in 4 (8,3%) cases. Complete and partial clinical responses were observed in 13 (27,1%) and 19 (39,6%) patients, respectively. BVAS v. 3 score &lt;4 at baseline was independently associated with complete clinical response (ОR=7,58; 95% CI: 1,42–40,48; р=0,018). 3 (6,3%) patients demonstrated HCV-CV relapse.Conclusion. Patients with HCV-CV require a long-term follow-up period even after reaching the SVR. The use of BVAS v. 3 score before the DAAs therapy can facilitate the planning of therapeutic approach, particularly, when identifying the patients in whom the immunosupressive therapy should be considered after viral eradication.

Cryoglobulinemia and Neuromyelitis optica: a case of progressive weakness and neurocognitive decline (P10-5.026)

<h3>Objective:</h3> Describe a case of a woman with mixed cryoglobulinemia who presented with progressive weakness and biopsy proven systemic vasculitis in the setting of Hepatitis C virus (HCV) negative serology. <h3>Background:</h3> The disease expression of mixed cryoglobulinemia vasculitis caused by HCV infection triggers the downstream B-cell arm of autoimmunity. <h3>Design/Methods:</h3> A 61 year old woman with a history of HCV infection, mixed cryoglobulinemia, mononeuritis multiplex secondary to nervous system vasculitis affecting peripheral nerves and hypertension presented with weakness that progressed to quadriparesis and neurocognitive decline over a period of eight months. <h3>Results:</h3> MRI examination of the brain showed bilateral ventral pontine lesions extending into the middle cerebellar peduncles, ventrolateral midbrain and cerebral peduncles as well as bilateral cortical frontal lobe lesions. Also present were intrinsic mixed intensity DWI/ADC lesions of undetermined etiology and extensive subcortical and periventricular white matter hyperintensities. CT angiography of her head and neck showed large vessel intracranial vasculopathy involving the bilateral MCA branches. Conventional angiogram, however, did not show any evidence of angiographic vasculitis. MRI spectroscopy was non-diagnostic. MRI of the neuroaxis showed a small focus of linear non-enhancing hyperintense lesion at the level of C3. EMG demonstrated severe generalized sensory-motor polyneuropathy with severe axonal loss. EEG showed mild to moderate diffuse slowing. CSF evaluation was negative, HCV viral load was undetectable, connective tissue markers (Anti-dsDNA, Anti-SCL70, Anti-CENTR, Anti-RNP, Anti-Smith, Anti-SSA/SSB, ANCA) were negative and the remaining serology was significant for elevated ESR, CRP, low C4 complements, positive anti-AQP4 antibodies titers (1:2560) and positive myelin basic protein. Brain biopsy showed perivascular lymphocytic inflammation, confirming vasculitis. Our patient completed courses of high dose steroids, IVIG and Rituximab with mild improvement in motor strength. <h3>Conclusions:</h3> Although an atypical feature of NMO, cryoglobulinemia with production of anti-AQP4 antibodies may, in part, contribute to development of a demyelinating process. <b>Disclosure:</b> Dr. Esechie has nothing to disclose. Dr. Harazeen has nothing to disclose. Dr. Rivera Vega has nothing to disclose. Dr. Thottempudi has nothing to disclose. Dr. Chhabra has stock in Pfizer. Dr. Chhabra has stock in Biogen. Dr. Chhabra has stock in Johnson and Johnson. Dr. Chhabra has stock in Medtronic. Dr. Shaltoni has nothing to disclose. Muhammad Zeeshan Memon, MD has nothing to disclose. Dr. Patel has nothing to disclose. Dr. Wu has nothing to disclose.

P024 Vasculitis of the female genital tract: is it a single organ or systemic disease?

Abstract Background/Aims Vasculitis of the female genital tract is rare. At one institution, incidence among all gynaecological surgeries was 0.15%. It is usually an incidental finding on histopathological examination after surgery done for another reason. Most commonly, it presents with vaginal bleeding, but can also present with pelvic pain, uterine prolapse, asymptomatic abdominal mass or atypical cervical smear. Constitutional and musculoskeletal symptoms are reported in about a quarter of cases. It can be localised to the female genital tract, most commonly the uterus and cervix. Less commonly, it can be part of a systemic vasculitis, including giant cell arteritis, polyarteritis nodosa, granulomatosis with polyangiitis, microscopic polyangiitis, cryoglobulinaemic vasculitis, lupus and rheumatoid vasculitis. Although data is limited, one review found 31.3% of cases to have systemic involvement. Approximately 60% of patients with vasculitis of the female genital tract and systemic vasculitis had GCA. In this group, about one third do not present with classical cranial, systemic or polymyalgia rheumatica symptoms. In localised disease, anaemia or raised inflammatory markers are unlikely. Histopathology mostly shows non-granulomatous inflammation. With systemic involvement, anaemia, raised inflammatory markers and granulomatous inflammation are more likely to be present. Localised vasculitis of the female genital tract tends not to require treatment. However, it can predate symptoms and signs of systemic disease. Therefore, follow-up for at least 12 months is recommended. Methods Written consent was obtained from the patient. Data was obtained from the patient's case notes, electronic records and histopathology results. Results We describe a 63-year-old lady with no past medical history and on no medications who presented with post-menopausal bleeding and abdominal cramping. Hysteroscopy showed two endometrial polyps. Biopsy showed grade 1A endometrial carcinoma. Total hysterectomy and bilateral salpingo-oophorectomy was performed. Histopathological analysis confirmed endometrial cancer but also showed some foci of granulomatous inflammation with multi-nucleating giant cells surrounding both small and medium calibre vessels. The vessels showed fibrinoid necrosis and disruption of the internal elastic lamina, suspicious for vasculitis. On review by the rheumatology team this lady was found to be well with no history of Raynaud’s; rashes; arthritis; ocular; ear, nose and throat; gastroenterological; respiratory; neurological; or constitutional symptoms. Examination was normal. C-reactive protein and immunoglobulins were normal. Anti-nuclear antibody, anti-neutrophil cytoplasmic antibody, rheumatoid factor and anti-CCP antibody were negative. Urine protein was raised at 0.29 (0-0.1) but protein/creatinine ratio was normal at 11 mg/mmol. Chest x-ray was clear. Conclusion In conclusion, female genital tract vasculitis is rare and is usually an incidental finding on histopathology. In this case, it appeared to be an isolated vasculitis of the female genital tract. It is important to recognise that uncommonly this condition can be associated with systemic involvement and therefore follow up in rheumatology clinic is recommended. Disclosure T. Nadin: None. N. Goadby: None. R. Smith: None.

Systemic Neoplastic Cryoglobulinemic Vasculitis Mimics Large Vessel Occlusion: A Case Report.

We describe a systemic neoplastic cryoglobulinemic vasculitis presenting as a large vessel occlusion (LVO) syndrome. We focus on a rare presentation of a rare condition. A 68-year-old man was admitted to the Stroke Unit of Padova with a right middle cerebral artery syndrome. A cerebrovascular event was suspected and protocol for revascularization treatment was performed. Neuroimaging provided no evidence for infarcted tissue or medium-large vascular occlusion but hypothesized a vasculitic involvement of the small vessels of the right hemisphere. Further diagnostics demonstrated a microangiopathic involvement of the heart, kidneys, and lungs. Blood tests showed circulating cryoglobulins and further hematological investigation identified a chronic lymphatic leukemia-like lymphoproliferative disorder. High-dose steroid therapy improved the patient's clinical status and no neurological symptoms remained at discharge. We discuss the clinical-radiologic presentation of a small vessel vasculitis that mimics an LVO stroke. This case focuses on the relevance of concomitant multiorgan manifestations in the hyper-acute evaluation of LVO stroke, suggesting the clinical neurologist should consider alternative etiologies as these could provide important clinical implications.

Pathophysiology and clinical manifestations of immune complex vasculitides.

Immune complex (IC) vasculitides present inflammations of vessel walls associated with perivascular deposition of immunoglobulins (Igs), mostly ICs. They encompass systemic and skin-limited variants of IgA vasculitis (IgAV), cryoglobulinemic vasculitis (CV), rheumatoid, lupus, and hypocomplementemic vasculitides, serum sickness cutaneous IgM/IgG (non-IgA) vasculitis, and recurrent macular (hypergammaglobulinemic or exertion-induced) vasculitis. Serum sickness and CV fulfill the criteria of a type III hypersensitivity immune reaction as large lattices of the IC precipitate at vessel walls and activate polymorphonuclear neutrophils (PMNs). Immunoglobulin-A vasculitis differs with regard to the causes of perivascular deposition of ICs since here many IgA1 molecules are hypoglycosylated (Gd-IgA1), which appears to facilitate their perivascular deposition in skin and mesangium (via e.g. CD71). The reasons for increased generation of immunoglobulins or formation of IC and their perivascular deposition in either skin or systemic organs are different and not fully explored. A common denominator of OC vasculitides is the activation of PMNs near the vessel wall via Fcy or Fcα receptors. Acute episodes of IgAV additionally require PMNs to become preactivated by IgA1 or by IC already in circulation. This intravascular priming results in increased adherence and subsequently vessel-destructive NETosis when they encounter IgA deposited at the vessel walls. Binding of IgA1 to PMNs in blood stream is associated with increased serum levels of hypogalactosidated IgA1. The characteristic clinical picture of IgAV (and also of so-called IgG/IgM vasculitis) comprises palpable or retiform purpura with a clear predilection for lower legs, probably due to stasis-related reduction in blood velocity, while in other IC vasculitides, additional factors influence the sites of vasculitides. Our knowledge of distinct forms and different pathophysiological pathways of IC vasculitides may lead to in efficacious or targeted therapies. Antibodies to complement components or intestinal budesonide for IgAV are promising agents (the latter suppresses the pathophysiologically related IgA nephropathy by reducing the generation of mucosal IgA.

Cryoglobulinemische vasculitis bij een geriatrische patiënte: een casusbespreking

Cryoglobulinemic vasculitis in an 89-year-old female: a case report Cryoglobulinemic vasculitis is an autoimmune-mediated systemic disorder in which circulating serum immunoglobulins precipitate at a reduced temperature, resulting in inflammation of the small- to medium-sized vessels, which can lead to a wide spectrum of systemic manifestations, including cutaneous, musculoskeletal, renal, neurological, cardiac, hematological, pulmonary and gastrointestinal symptoms. Since there is a broad spectrum of clinical presentations of cryoglobulinemic vasculitis, a correct diagnosis might be delayed or even missed. The overall prevalence of the disease is unknown, but is estimated to be low at approximately 1 per 100,000. This case report describes an 89-year-old female patient presenting with extensive purpura, acronecrosis, neuropathy, muscle weakness, creatine kinase elevation and deterioration of the kidney function. The diagnosis of cryoglobulinemic vasculitis was made. Surprisingly, no underlying infection or malignancy was found, despite extensive investigations.

Hepatitis B virus-infection related cryoglobulinemic vasculitis. Clinical manifestations and the effect of antiviral therapy: A review of the literature.

Hepatitis B virus (HBV) infection causes chronic hepatitis, cirrhosis, and hepatocellular carcinoma. Furthermore, about 20% of the patients develop extrahepatic manifestations such as cryoglobulinemic vasculitis (CV), polyarteritis nodosa, non-rheumatoid arthritis, glomerulonephritis and non-Hodgkin lymphoma. This review analyzed literature data on clinical manifestations of HBV-related CV and the impact of antiviral therapy with analoques nucleotide. A PubMed search was performed to select eligible studies in the literature, up to July 2022. Some studies have analyzed clinical manifestations in HBV-related CV and have investigated the role of antiviral therapy with nucleotides analogues (NAs). Clinical manifestations of CV vary from mild to moderate (purpura, asthenia and arthralgias) to severe (leg ulcers, peripheral neuropathy, glomerulonephritis, and non-Hodking lymphoma). NAs therapy leads to suppression of HBV-DNA; therefore, it is capable of producing clinical response in the majority of patients with mild to moderate symptoms. Antiviral therapy with NAs is the first choice for HBV suppression and control of mild to moderate disease. In severe vasculitis (glomerulonephritis, progressive peripheral neuropathy and leg ulcers), rituximab alone or with plasma-exchange is always indicated in combination with antiviral therapy.

Preventive plasmapheresis for rituximab related flare in cryoglobulinemic vasculitis

IntroductionRituximab monotherapy represents the main therapeutic option for cryoglobulinemic vasculitis (CV) with severe organ involvement. However, initial worsening of the CV, known as rituximab-associated CV flare (=CV flare), has been described and are associated with high mortality rates. The aim of the present study is to evaluate the outcomes of plasmapheresis initiated before or during rituximab treatment, as prevention of CV flare. MethodsWe conducted a retrospecttive study in our tertiary referral center from 2001 to 2020. We have included all patients with CV receiving rituximab and divided them in two groups whether they had flare prevention by plasmapheresis or not. We evaluated rituximab-related CV flare incidence in both groups. CV flare was defined as the onset of a new organ involvement or worsening of the initial manifestations within 4 weeks following rituximab. ResultsAmong the 71 patients included, 44 received rituximab without plasmapheresis (control = CT cohort) and 27 received plasmapheresis before or during rituximab treatment (preventive plasmapheresis = PP cohort). PP was given to patients thought to have a high risk of CV flare, with significantly more severe diseases than patients in the CT cohort. Despite this, no CV flare was observed in the PP group. In the other hand, 5 flares occurred in the CT cohort. ConclusionOur results show that plasmapheresis is efficient and well tolerated to prevent rituximab-associated CV flare. We believe that our data support the use of plasmapheresis in this indication, especially in patients with high risk of CV flare.

Acute kidney injury due to cryoglobulinemic glomerulonephritis as the initial presentation of Chronic Lymphocytic Leukemia

Cryoglobulinemic vasculitis presents with systemic vasculitis including vasculitic rash, fever, peripheral neuropathy and rarely renal involvement. This could be secondary to infections like hepatitis C, malignancies like myeloma, Non Hodgkin’s lymphoma and chronic lymphocytic leukemia. We encountered a patient who presented with fever, anemia, purpuric skin rash and acute kidney injury due to acute glomerulonephritis with nephritic picture and fluid overload that required hemodialysis.Investigations revealed hemolytic anemia, cryoglobulinemia, proliferative glomerulonephritis with Ig M intra-capillary deposits and hyaline thrombi. Bone marrow biopsy clinched the diagnosis of Chronic lymphocytic B cell lymphoma with CD 20 positivity. Treatment was instituted with Rituximab and Bendamustine. Plasmapheresis was done for hyperviscosity syndrome. With treatment, hemodialysis could be discontinued after 10 weeks and renal functions recovered partially with serum creatinine settling at 1.5 mg/dl. We present this case to highlight the presentation of chronic lymphocytic leukemia with cryoglobulinemic vasculitis that presented with purpura and rapidly progressive renal failure that required dialysis.