Flemish network on rare connective tissue diseases (CTD): patient pathways in systemic sclerosis. First steps taken.

Despite the low prevalence of each rare disease, the total burden is high. Patients with rare diseases encounter numerous barriers, including delayed diagnosis and limited access to high-quality treatments. In order to tackle these challenges, the European Commission launched the European Reference Networks (ERNs), cross-border networks of healthcare providers and patients representatives. In parallel, the aims and structure of these ERNs were translated at the federal and regional levels, resulting in the creation of the Flemish Network of Rare Diseases. In line with the mission of the ERNs and to ensure equal access to care, we describe as first patient pathways for systemic sclerosis (SSc), as a pilot model for other rare connective and musculoskeletal diseases. Consensus was reached on following key messages: 1. Patients with SSc should have multidisciplinary clinical and investigational evaluations in a tertiary reference expert centre at baseline, and subsequently every three to 5 years. Intermediately, a yearly clinical evaluation should be provided in the reference centre, whilst SSc technical evaluations are permissionably executed in a centre that follows SSc-specific clinical practice guidelines. In between, monitoring can take place in secondary care units, under the condition that qualitative examinations and care including interactive multidisciplinary consultations can be provided. 2. Patients with early diffuse cutaneous SSc, (progressive) interstitial lung disease and/or pulmonary arterial hypertension should undergo regular evaluations in specialised tertiary care reference institutions. 3. Monitoring of patients with progressive interstitial lung disease and/or pulmonary (arterial) hypertension will be done in agreement with experts of ERN LUNG.

Etiological spectrum and outcome of fever and inflammation of unknown origin. Does symptom duration matter?

OBJECTIVE: Evidence suggests that the symptom duration may affect the occurrence of certain fever (FUO) and inflammation (IUO) of unknown origin associated conditions. It is unclear if this could potentially guide diagnostic evaluations. We examined the association between symptom duration and diagnostic and prognostic outcomes in FUO/IUO. METHODS: We retrospectively analyzed a cohort of adult patients meeting criteria for FUO/IUO from a tertiary care center in Belgium between 2000 and 2019. The association between symptom duration and outcomes of interest were estimated by Cox proportional hazards models. RESULTS: Among 602 patients who met criteria for FUO/IUO (mean age 54 years, 43% female), 132 (22%) and 68 (11%) had symptoms for 3-12 months and >12 months, respectively. There were no significant differences in diagnosis or all-cause mortality between a symptom duration of <3 months and 3-12 months. In contrast, those who had a symptom duration of >12 months were less likely to receive a final diagnosis (aHR 0.42, 95% CI 0.30-0.60), in particular a diagnosis of infectious disorders (aHR 0.29, 95% CI 0.12-0.74), malignancies (aHR 0.11, 95% CI 0.03-0.46), and miscellaneous conditions (aHR 0.22, 95% CI 0.07-0.71), but no significant differences were seen in noninfectious inflammatory disorders (aHR 0.74, 95% CI 0.48-1.15) or all-cause mortality (aHR 0.55, 95% CI 0.19-1.54). CONCLUSIONS: The symptom duration may be used to guide the diagnostic workup among patients with FUO and IUO, in particular those with longstanding symptoms.

Rheumatic disorders among patients with fever of unknown origin: A systematic review and meta-analysis.

OBJECTIVES: To conduct a systematic literature review and meta-analysis to estimate the proportion of fever of unknown origin (FUO) and inflammation of unknown origin (IUO) cases that are due to rheumatic disorders and the relative frequency of specific entities associated with FUO/IUO. METHODS: We searched PubMed and EMBASE between January 1, 2002, and December 31, 2021, for studies with ≥50 patients reporting on causes of FUO/IUO. The primary outcome was the proportion of FUO/IUO patients with rheumatic disease. Secondary outcomes include the association between study and patient characteristics and the proportion of rheumatic disease in addition to the relative frequency of rheumatic disorders within this group. Proportion estimates were calculated using random-effects models. RESULTS: The included studies represented 16884 patients with FUO/IUO. Rheumatic disease explained 22.2% (95%CI 19.6 - 25.0%) of cases. Adult-onset Still's disease (22.8% [95%CI 18.4-27.9%]), giant cell arteritis (11.4% [95%CI 8.0-16.3%]), and systemic lupus erythematosus (11.1% [95%CI 9.0-13.8%]) were the most frequent disorders. The proportion of rheumatic disorders was significantly higher in high-income countries (25.9% [95%CI 21.5 - 30.8%]) versus middle-income countries (19.5% [95%CI 16.7 - 22.7%]) and in prospective studies (27.0% [95%CI 21.9-32.8%]) versus retrospective studies (20.6% [95%CI 18.1-24.0%]). Multivariable meta-regression analysis demonstrated that rheumatic disease was associated with the fever duration (0.011 [95%CI 0.003-0.021]; P=0.01) and with the fraction of patients with IUO (1.05 [95%CI 0.41-1.68]; P=0.002). CONCLUSION: Rheumatic disorders are a common cause of FUO/IUO. The care of patients with FUO/IUO should involve physicians who are familiar with the diagnostic workup of rheumatic disease.

Pneumocystis jirovecii pneumonia in patients treated for systemic autoimmune disorders: a retrospective analysis of patient characteristics and outcome.

Objectives: Pneumocystis jirovecii is an opportunistic fungus. Pneumocystis jirovecii pneumonia (PJP) is well known in the human immunodeficiency virus (HIV)-infected population, but in non-HIV-related immunosuppressed patients, risk factors are largely unknown. We studied the characteristics and outcome of patients treated for systemic autoimmune disorders infected with P. jirovecii, aiming to clarify risk stratification to guide prophylaxis. Method: Clinical charts collected between 2010 and 2016 at the University Hospital of Leuven (Belgium) were reviewed. Information on type of systemic disorder, organ involvement, immunosuppressant use, and comorbidity was collected, and laboratory results were consulted. Results: In total, 39 cases of non-HIV PJP were retrieved, 24 of whom had pre-existing pulmonary disease. All were on immunosuppressant medication at the time of infection, the majority (36/39) taking glucocorticoids, with a median dose of 16 mg methylprednisolone over the past 3 months. Of the 39 cases, 21 were admitted to the intensive care unit and mortality reached 35%. Age and pulmonary disease correlated positively and methotrexate use negatively with mortality. When applying current prophylactic strategies to our cohort, 50% of infections could theoretically have been prevented. Conclusion: PJP is a rare but relevant clinical problem when caring for immunosuppressed patients with autoimmune systemic disorders. Pulmonary disease and age are risk factors for acquiring the infection and carry a worse prognosis. More studies are needed to further define prophylactic criteria.

Rituximab prescription patterns and efficacy in the induction treatment of ANCA-Associated Vasculitis in a Belgian multicenter cohort.

Introduction: The RAVE trial has revolutionized induction treatment of anti-neutrophil cytoplasmic antibodies (ANCA)-Associated Vasculitis (AAV)by demonstrating the non-inferiority of rituximab (RTX) compared with cyclophosphamide.Objectives: We studied AAV patients' characteristics, RTX prescription practices and efficacy in AAV induction treatment in four Belgian university hospitals. The patient population, selected according to the Belgian reimbursement criteria, was relatively homogeneous and comparable to the one of RAVE trial.Methods: 57 patients, receiving RTX as AAV induction therapyfrom May 2014 to June 2017 were enrolled in an observational retrospective multicenter trial involving four Belgian university hospitals. We focused on the type of AAV, ANCA specificity, prescriber's specialty, used reimbursement criteria, organ involvements, severity of the flares and finally RTX efficacy in AAV induction treatment by considering the RAVE primary (complete remission without prednisone) and secondary (complete remission with prednisone <10 mg) outcomes at 6, 12, 18 and 24 months.Results: 66.7% of the patients reached complete remission with prednisone <10 mg at 6 months, 55.3% at 12 months, 40% at 18 months and 25% at 24 months. The rates of complete remission without steroids were very low at 6, 12, 18 and 24 months. The rates of relapses were high between 18 and 24 months. Conclusions: Our results confirm those of RAVE regarding complete remission rates with prednisone <10 mg/day, in a 'real-life' cohort of patients selected according to data of RAVE trial. The high prevalence of relapses - especially after 18 months - underlines the need to optimize maintenance treatment after an induction treatment with RTX..

Outcome of patients with systemic diseases admitted to the medical intensive care unit of a tertiary referral hospital: a single-centre retrospective study.

OBJECTIVES: Systemic diseases form a rare heterogeneous group of diseases, with important morbidity caused by disease evolution and/or treatment. We describe the clinical features and outcome of patients with these diseases admitted to a referral hospital intensive care unit (ICU). METHOD: We conducted a retrospective case review of all patients with systemic diseases (n = 86) admitted to the medical ICU of Leuven University Hospital between May 2007 and September 2012. RESULTS: The most frequent diagnoses were systemic vasculitis (n = 31), sarcoidosis (n = 15), systemic sclerosis (n = 9), and systemic lupus erythematosus (SLE) (n = 7). The main reason for admission was infection (60%), followed by disease-related organ failure (48%). Respiratory failure was the most common organ dysfunction. The mean APACHE II (Acute Physiology and Chronic Health Evaluation II) score was 28 ± 10. Mortality was 19% during ICU admission, 39% during hospital stay, and 58% at the end of follow-up. Death was caused by infection in the majority of cases (56%), and by evolution of the underlying disease in 32%. Only age and APACHE II score were associated with mortality. CONCLUSIONS: The mortality of patients with systemic diseases admitted to an ICU is high, both during their stay in the ICU and afterwards. Age and APACHE II score, but not infection or immunosuppressive therapy, were associated with mortality.

Comparison between classical polyarteritis nodosa and single organ vasculitis of medium-sized vessels: a retrospective study of 25 patients and review of the literature.

BACKGROUND: Polyarteritis nodosa (PAN) is a rare form of systemic vasculitis, characterized by necrotizing inflammation of medium-sized vessels. In clinical practice, the distinction is made between a limited, mostly cutaneous, form and a generalized form. The Chapel Hill Consensus Conference of 2012 on the classification of the vasculitides classifies PAN as a medium vessel vasculitis, whereas the limited forms fall under the heading 'single-organ vasculitis' (SOV), with subdivions such as 'cutaneous arteritis' (formerly called cutaneous PAN) and 'others'. In this last category, forms of PAN limited to a single organ (e.g. testicle, gall bladder or appendix) should be categorized. The relation between classical and limited forms of PAN remains enigmatic. OBJECTIVE: To compare demographics, clinical characteristics and prognosis between SOV and generalized PAN. METHODS: Clinical files of all patients with a diagnosis of classical or limited PAN made in the departments of general internal medicine and dermatology between 1983 and 2013 in a tertiary care university hospital were reviewed. RESULTS: The patients of the SOV group tend to be younger, with a female predominance, while we observed a male predominance in the generalized PAN group. Relapses were more common in SOV than in classical PAN. None of the patients initially diagnosed with cPAN/SOV progressed to generalized disease. DISCUSSION: Though SOV and classical PAN share a lot of similarities, they are probably different disease entities, based on their different demographical, clinical and prognostic characteristics. The 1990 ACR-criteria for classical PAN are too broad since they allow patients with limited disease to be classified as classic PAN.

There is no benefit in routinely monitoring ANCA titres in patients with granulomatosis with polyangiitis.

OBJECTIVES: To analyse the link between antineutrophil cytoplasmic antibody (ANCA) levels and risk of relapse in patients with granulomatosis with polyangiitis (GPA), as the clinical benefit of monitoring ANCA levels is uncertain. METHODS: A retrospective analysis was made of all charts available from 43 patients diagnosed with GPA, fulfilling The American College of Rheumatology 1990 criteria, and followed between 1994 and 2012 at a general internal medicine department of a university hospital. Clinical and biochemical data (i.e. anti-proteinase 3 (PR3) levels) were collected and correlated. RESULTS: 43 relapses occurred in 25 patients (58.1% of 43 patients). When blood samples are routinely taken at a follow-up visit (i.e. low pre-test probability, ± 5.5%) in the GPA-population, a 75%-increase in the PR3-level or its reappearance has only limited positive predictive value (PPV 15.0% and 22.5% respectively) for predicting relapse. Adversely, when clinical suspicion of relapse is high (i.e. high pre-test probability, for example 50%), an increase of 75% or reappearance of PR3 makes relapse even more likely (PPV 77.5%, 81.6% respectively). Conversely, a high negative predictive value (NPV) of 99.3% and a negative likelihood ratio (LR-) of 0.12 suggest that, in the absence of PR3, relapse is unlikely if patients had detectable ANCAs at diagnosis. CONCLUSIONS: Routine ANCA monitoring in patients diagnosed with GPA has limited value. However, targeted determination of ANCA levels may be useful if a relapse is clinically suspected (i.e. high pre-test probability).

Living related intestinal transplantation for Churg-Strauss syndrome: a case report.

Exceptionally, gastrointestinal involvement of Churg-Strauss syndrome (CSS) may require extensive bowel resection resulting in a short bowel syndrome. Living related intestinal transplantation (IT) has emerged as an alternative to deceased-donor IT in the management of patients with irreversible short bowel syndrome. Herein, we have presented a 35-year-old patient with isolated intestinal involvement of CSS lesions refractory to steroids and azathioprine requiring multiple abdominal resections resulting in an ultrashort bowel syndrome. A living related IT (from the mother) was performed. She underwent several acute rejection episodes treated with additional immunosuppressive therapy. Despite higher doses of immunosuppression, these repeated acute rejection episodes eventually evolved into a syndrome of chronic allograft rejection. Eventually, owing to her poor general condition and to avoid life-threatening infections, transplantectomy was inevitable. Recent immunologic studies indicate that peripheral mononuclear cells from patients with CSS secrete large amounts of T-helper type 1 and 2 cytokines. It is likely that patients with CSS are at higher risk for acute and chronic rejection after transplantation.

Anti-PM/Scl-100 and anti-RNA-polymerase III antibodies in scleroderma.

BACKGROUND: Systemic sclerosis (SSc) is a rare autoimmune disease characterized by the presence of various autoantibodies, including anti-centromere, anti-topoisomerase (Scl-70), anti-PM/Scl-100, and anti-RNA-polymerase III (RNA Pol-III) antibodies. Recently, new ELISA based immunoassays have become available for the detection of anti-PM/Scl and anti-RNA Pol-lII antibodies. OBJECTIVE: We studied the prevalence and clinical association of anti-PM/Scl-100 (PM1-Alpha) and anti-RNA Pol-III antibodies. METHODS: Antibodies to PM1-Alpha and RNA Pol-III were measured by ELISA (DR. Fooke Laboratories and Inova Diagnostics, respectively) in 242 patients with various connective tissue diseases (CTD) (including 70 SSc patients) and in 36 non-CTD controls. RESULTS: Low levels of PM1-Alpha antibodies were found in various CTDs, whereas high levels were exclusively found in SSc, dermatomyositis and polymyositis, albeit at low frequency (4.7%). Anti-RNA Pol-III antibodies were found in 7% of SSc and in 1% of non-CTD and CTD controls. Anti-centromere and anti-Scl-70 antibodies were found in 37% and 21% of SSc patients, respectively. Anti-centromere antibodies were associated with limited cutaneous SSc and anti-Scl-70 antibodies with diffuse cutaneous SSc and interstitial lung disease. Because of the low number of samples positive for anti-PM/Scl-100 or RNA Pol-III antibodies, no clinical feature was statistically correlated with the presence of either reactivity, but taken together the presence of either antibody was correlated with interstitial lung disease. Anti-PM1-Alpha and anti-RNA Pol-III antibodies were mutually exclusive with anti-Scl-70 antibodies. CONCLUSIONS: At high levels, anti-PM/Scl-100 antibodies were associated with SSc, PM, and DM, albeit at low frequency. Anti-RNA Pol-III antibodies were associated with SSc (in 7%) with high specificity.

The 10-year follow-up data of the Euro-Lupus Nephritis Trial comparing low-dose and high-dose intravenous cyclophosphamide.

OBJECTIVE: To update the follow-up of the Euro-Lupus Nephritis Trial (ELNT), a randomised prospective trial comparing low-dose (LD) and high-dose (HD) intravenous (IV) cyclophosphamide (CY) followed by azathioprine (AZA) as treatment for proliferative lupus nephritis. PATIENTS AND METHODS: Data for survival and kidney function were prospectively collected during a 10-year period for the 90 patients randomised in the ELNT, except in 6 lost to follow-up. RESULTS: Death, sustained doubling of serum creatinine and end-stage renal disease rates did not differ between the LD and HD group (5/44 (11%) vs 2/46 (4%), 6/44 (14%) vs 5/46 (11%) and 2/44 (5%) vs 4/46 (9%), respectively) nor did mean serum creatinine, 24 h proteinuria and damage score at last follow-up. Most patients in both groups were still treated with glucocorticoids, other immunosuppressant agents and blood pressure lowering drugs. After 10 years of follow-up, the positive predictive value for a good outcome of an early drop in proteinuria in response to initial immunosuppressive therapy was confirmed. CONCLUSION: The data confirm that a LD IVCY regimen followed by AZA-the "Euro-Lupus regimen"-achieves good clinical results in the very long term.

Common variable immunodeficiency (CVID): case report and review of the literature.

Common variable immunodeficiency (CVID) is an immunodeficiency disease characterized by diminished ability to produce immunoglobulins. CVID has an estimated incidence of 1:10,000 to 1:200,000 (male:female 1:1) and usually presents in the second and third decade, although it also has a peak of incidence in childhood. The exact pathophysiology remains unclear. CVID can be associated with autoimmune, granulomatous and gastrointestinal diseases and patients have a predisposition to malignancies (especially non-Hodgkin lymphoma). Since different organ systems can be affected, all clinicians need to be aware of this entity, especially when confronted with patients with recurrent infections and/or multiple autoimmune diseases.

Usefulness of FDG-PET to diagnose intravascular lymphoma with encephalopathy and renal involvement.

Intravascular lymphoma (IVL) is a rare subtype of extranodal diffuse large B-cell lymphoma. It is characterized by proliferation of neoplastic Lymphoid cells almost exclusively within the lumina of small blood vessels. It can affect virtually every organ system. Due to its rarity and its diverse and heterogeneous clinical presentation, diagnosis is difficult and often made post-mortem. When diagnosed early, it is, however, potentially treatable. We present a young woman with longstanding constitutional symptoms, positive antinuclear antibody, elevated LDH levels and rapidly progressive encephalopathy. FDG-PET scan showed intense uptake in the renal cortex, which prompted us to perform a kidney biopsy which was compatible with IVL. The value of PET in establishing the diagnosis of this rare disease will be discussed.

Case reports: testicular pain as a manifestation of polyarteritis nodosa.

Polyarteritis nodosa (PAN) is a necrotising vasculitis of medium-sized vessels of unknown origin. This type of vasculitis is usually systemic, but restriction to a single organ, for example the testis, the appendix or the gall bladder, can occur. Testicular pain or tenderness are frequent clinical features. In this report, we present three cases of PAN. In every patient, testicular pain was the main symptom or first sign of systemic disease. We state that a thorough history taking, clinical examination and biochemical analyses are obligatory in patients presenting with acute or chronic scrotal pain. Polyarteritis nodosa should always be taken into account, and a search for systemic spread is mandatory. We emphasize that before initiation of systemic therapy with corticosteroids and/or cyclophosphamide, a Five Factor Score should be obtained, which also gives crucial prognostic information.

Relationship between fluorodeoxyglucose uptake in the large vessels and late aortic diameter in giant cell arteritis.

OBJECTIVE: GCA carries an increased risk of developing thoracic aortic aneurysms. Previous work with fluorodeoxyglucose (FDG)-PET has shown that the aorta is frequently involved in this type of vasculitis. We wanted to investigate whether there is a correlation between the extent of vascular FDG uptake during the acute phase of GCA and the aortic diameter at late follow-up. METHODS: All patients with biopsy-proven GCA who ever underwent an FDG-PET scan in our centre were asked to undergo a CT scan of the aorta. The diameter of the aorta was measured at six different levels (ascending aorta, aortic arch, descending aorta, abdominal suprarenal, juxtarenal and infrarenal aorta) and the volumes of the thoracic and of the abdominal aorta were calculated. RESULTS: Forty-six patients agreed to participate (32 females, 14 males). A mean of 46.7 +/- 29.9 months elapsed between diagnosis and CT scan. All aortic dimensions were significantly smaller in women than in men, except for the diameter of the ascending aorta. Patients who had an increased FDG uptake in the aorta at diagnosis of GCA, had a significantly larger diameter of the ascending aorta (P = 0.025) and descending aorta (P = 0.044) and a significantly larger volume of the thoracic aorta (P = 0.029). In multivariate analysis, FDG uptake at the thoracic aorta was associated with late volume of the thoracic aorta (P = 0.039). CONCLUSION: GCA-patients with increased FDG uptake in the aorta may be more prone to develop thoracic aortic dilatation than GCA patients without this sign of aortic involvement.