Continuous Immunosuppressive Therapy Research Articles

OA24 Extended oligoarthritis with proximal muscle weakness and antinuclear antibody positivity associated with a novel genetic variant of uncertain significance in lipopolysaccharide-responsive and beige-like anchor protein (LRBA) gene

Abstract Introduction LRBA deficiency is associated with recurrent infections and immune dysregulation, particularly autoimmune cytopenias, enteropathy and intestitial lung disease, and in a few cases chronic polyarthritis and uveitis. Case description A girl presented at three years old with history of not walking for two months with no history of trauma or fever. Examination revealed arthritis in her ankles and knees. Ultrasound showed synovial thickening in both knees and small effusion to hips. There was no evidence of uveitis at presentation. Her bloods showed raised C-Reactive Protein (CRP) 33 mg/L and Erythrocyte Sedimentation rate (ESR) 45 mm/h. Anti-nuclear and anti-centromere antibodies were positive. Diagnosis was made of oligoarticular JIA and she was treated with intra-articular steroids in both knees and ankles and was started on oral prednisolone, weekly oral methotrexate. On subsequent clinic review, she had started to walk with mild restriction to internal rotation of hips and difficulty in getting up from sitting. She was started on regular hydrotherapy, physiotherapy and occupational therapy. From five to 11 years old, she had four flares of uveitis, treated with prednisolone eye drops; and two flares of arthritis, treated with steroids. Her methotrexate was changed to subcutaneous and at eight years of age she was also started on subcutaneous adalimumab fortnightly. Due to prolonged proximal muscle weakness, abnormal gait and chronic pain in leg joints without clinical or radiological evidence of synovitis during clinic reviews, she underwent thorough neurological work up which was inconclusive for myopathies. Her creatinine kinase levels, thyroid profile, MRI brain and spine were normal. Genetic work up showed two variants in the LRBA gene, one pathogenic and the other was variant of uncertain significance (VUS). Her CTLA4 expression was normal by flow cytometry. Discussion Three case reports have previously associated homozygous LRBA deficiency with polyarthritis. Compound heterozygous LRBA deficiency may present with various phenotypes including autoimmune disease affecting multiple organs, immune cytopenia and immune dysregulations including CTLA-4 expression. This report potentially widens the clinical spectrum of LRBA deficiency and given that it is a novel variant, prompts us to screen for this gene mutation in patients with JIA where remission is challenging and there is a need for continuous immunosuppressive or immune-modulatory therapy. Three case reports have previously associated homozygous LRBA deficiency with polyarthritis. Compound heterozygous LRBA deficiency may present with various phenotypes including autoimmune disease affecting multiple organs, immune cytopenia and immune dysregulations including CTLA-4 expression. This report potentially widens the clinical spectrum of LRBA deficiency and given that it is a novel variant, prompts us to screen for this gene mutation in patients with JIA where remission is challenging and there is a need for continuous immunosuppressive or immune-modulatory therapy. Three case reports have previously associated homozygous LRBA deficiency with polyarthritis. Compound heterozygous LRBA deficiency may present with various phenotypes including autoimmune disease affecting multiple organs, immune cytopenia and immune dysregulations including CTLA-4 expression. This report potentially widens the clinical spectrum of LRBA deficiency and given that it is a novel variant, prompts us to screen for this gene mutation in patients with JIA where remission is challenging and there is a need for continuous immunosuppressive or immune-modulatory therapy. Key learning points • There is no single diagnostic investigation for JIA as the aetiology is complex and there are currently no specific clinical guidelines of when to consider genetic testing in patients with JIA. With the mainstreaming of genetic services and improved access to cheaper, advanced next-generation sequencing, we should consider looking into monogenic conditions that mimic JIA. • The case illustrates the challenges of determining whether VUS are pathogenic in causing arthritis, or just incidental findings. Compound heterozygous LRBA may present within a spectrum of clinical features, further analysis with CTLA4 expression by flow cytometry and genetic analysis of siblings and parents will be helpful. • Compound heterozygous LRBA variation has different clinical manifestation which needs personalised treatment. Treatment with abatacept (a soluble CTLA4 immunoglobulin fusion protein) which is reported in a case series of LRBA deficiency. Risks of continuous immunosuppressive treatment need to be balanced with more definitive hematopoietic stem cell transplantation (HSCT) previously used to achieved complete remission in LRBA deficiency.

Renal cell carcinoma in a transplanted kidney: a retrospective evaluation

IntroductionKidney transplantation is the optimal treatment modality for patients with end-stage chronic kidney disease. The long-term mortality of kidney recipients is 48–82% lower than that of patients on the waiting list. However, the risk of developing malignancies in these patients is twice as high as in the healthy population. Specifically, the incidence of renal cell carcinoma (RCC) in transplant recipients is 10–30 times higher than in non-transplanted patients. The reason for the increased risk is poorly understood, but is most likely related to continuous immunosuppressive therapy. The problem of kidney graft neoplasia has not been adequately addressed in the medical literature.ObjectiveTo determine the incidence of renal cell carcinoma in transplanted kidneys, enhance the efficacy of its treatment, and study the etiology of RCC development.Materials and methodsA retrospective analysis of RCC incidence in kidney grafts was conducted in 3,270 patients who underwent kidney transplantation between 2013 and 2023. We evaluated the effectiveness of surgical interventions for these complications. Patients with histologically confirmed RCC of the transplanted kidney underwent genetic study to determine the etiology of the neoplasm.ResultsThe incidence of RCC in transplanted kidneys was found to be 0.95% (n = 31), 28 patients underwent laparoscopic resection of the renal transplant tumor, 2 patients were treated with radiofrequency ablation of the tumor. Transplantectomy was performed in 1 patient.ConclusionLaparoscopic resection is an effective and safe method for the treatment of RCC in kidney transplants. Transplanted kidney cancer originates from the donor tissue. The clear cell variant of transplanted kidney cancer is a genetically determined disease.

Narrative Review on the Use of Cladribine Tablets as Exit Therapy for Stable Elderly Patients with Multiple Sclerosis.

The number of ageing people with relapsing multiple sclerosis (RMS) is increasing. The efficacy of disease-modifying therapies (DMTs) for RMS declines with age. Also, older persons with MS may be more susceptible to infections, hospitalisations and malignancy. Aging people with MS have higher rates of comorbidities versus aged-matched controls, increasing the individual risk of disability. We review the therapeutic properties of cladribine tablets (CladT) in ageing people with RMS, with regard to their utility for allowing these individuals to cease continuous administration of a DMT (i.e. to act as an "exit therapy"). CladT is thought to be an immune reconstitution therapy, in that two short courses of oral treatment 1year apart provide suppression of MS disease activity in responders that far outlasts the duration of treatment and post-treatment reductions in lymphocyte counts. Post hoc analyses, long-term follow-up of populations with RMS in randomised trials, and real-world evidence suggest that the efficacy of CladT is probably independent of age, although more data in the elderly are still needed. No clear adverse signals for lymphopenia or other adverse safety signals have emerged with increasing age, although immunosenescence in the setting of age-related "inflammaging" may predispose elderly patients to a higher risk of infections. Updating vaccination status is recommended, especially against pneumococci and herpes zoster for older patients, to minimise the risk of these infections. CladT may be a useful alternative treatment for ageing people with MS who often bear a burden of multiple comorbidities and polypharmacy and who are more exposed to the adverse effects of continuous immunosuppressive therapy.

Quantification of Torque Teno Virus Load to Monitor Short-term Changes in Immunosuppressive Therapy in Kidney Transplant Recipients.

Quantification of torque teno virus (TTV) has been proposed as a surrogate parameter to monitor immunocompetence in kidney transplant recipients (KTRs) early after transplantation. However, its use in monitoring short-term changes of immunosuppression in KTRs late after transplantation requires further investigation. In this post hoc analysis, we quantified TTV load in sera of 76 KTRs, with 43 pausing mycophenolic acid (MPA) 1 wk before to 4 wk after COVID-19 vaccination to increase vaccine response. TTV load was quantified before, 4 wk, and 3 mo postvaccination. Results were compared to 33 KTRs with continued standard immunosuppressive therapy and with 18 hemodialysis as well as 18 healthy control subjects. TTV load before vaccination was with a median (interquartile range) of 1.39 × 10 4 copies/milliliter (c/mL) (9.17 × 10 1 -2.66 × 10 5 c/mL) highest in KTRs compared to 1.73 × 10 3 c/mL (1.07 × 10 3 -1.31 × 10 4 c/mL) in hemodialysis patients and 1.53 × 10 2 c/mL (6.38-1.29 × 10 3 c/mL) in healthy controls. In KTRs with MPA withdrawal, TTV load decreased significantly from a median (interquartile range) of 1.11 × 10 4 c/mL (4.75 × 10 2 -1.92 × 10 5 c/mL) to 5.24 × 10 3 c/mL (6.92 × 10 2 -6.91 × 10 4 c/mL) 4-5 wk after initiation of MPA withdrawal ( P = 0.003). In patients with MPA withdrawal, TTV load was significantly inversely correlated with COVID-19 or SARS-CoV-2-specific antibodies 4 wk and 3 mo postvaccination ( P = 0.009 and P = 0.004). TTV load reflects changes in immunosuppressive therapy even late after transplantation, supporting its use to monitor immunocompetence in KTRs.

A clinical case of Streptococcus equi subsp. ruminatorum infection in a 9-year-old child

Streptococcus equi subsp. ruminatorum is a zoonotic disease that can cause serious morbidity in immunocompromised people. The first case of infection in human was described in 2007. We describe a case of infection in a 9-year-old child with a history of liver transplantation, who was hospitalized for differential diagnosis of high fever on continuous immunosuppressive therapy with Tacrolimus. The examination revealed an increase in the level of systemic inflammatory response markers, cholestasis and cytolysis syndrome markers, which indicated cholangitis. Acute graft rejection was excluded. Streptococcus. equi subsp. ruminatorum was identified in the patient’s blood cultures, which made it possible to diagnose a generalized zoonotic infection (the child was often in contact with horses) with a possible focus in the bile ducts, which required antibiotic therapy in combination with short-term, within 1 day, withdrawal and then a lower dose of immunosuppressive therapy (temporary adjustment of tacrolimus dosage). During the treatment, clinical and laboratory signs of the infectious process improved, and the functional state of the liver graft normalized. Therapy was stopped after negative blood cultures were obtained. This case confirms that S. equi subsp. ruminatorum can cause human disease. We emphasize the utility of molecular biological tests and MALDI-TOF mass spectrometry to be performed in patients with infections caused by group C streptococci.

Стоматологический статус пациентов на фоне иммуносупрессивной терапии после операций по трансплантации органов

Immunosuppressive therapy – therapy to suppress undesirable immune reactions of the body, is mandatory and lifelong after an organ transplantion. The risk of oral diseases increases against the background of continuous immunosuppressive therapy. The article presents the most common complications of immunosuppressive treatment in the oral cavity. These are, first of all, diseases of the oral mucosa caused by a fungal, bacterial or viral factor, such as oral hairy leukoplakia, stomatitis, erosive-ulcerative lesions, hyperkeratosis, exudative multiform erythema as well as diseases of marginal periodontium, xerostomia and dental caries. To ensure a high level of dental health after the organ transplantation operation, dispensary observation and timely diagnosis of diseases of the oral cavity are necessary.

Variables Associated With Response to Therapy in Patients With Interstitial Pneumonia With Autoimmune Features.

Background/ObjectiveWe have limited knowledge regarding characteristics of patients with interstitial pneumonia with autoimmune features (IPAF) that are associated with response to immunosuppression. In this study, we used published IPAF criteria to characterize features associated with response to treatment.MethodsWe conducted a single-center medical records review study of 63 IPAF patients to evaluate for serological, clinical, and morphological characteristics that are associated with response to immunosuppression. Response was defined as % relative functional vital capacity decline of less than 10% and absence of death or lung transplant within the first year of continuous immunosuppressive therapy. Nonparametric measures of association and multivariate logistic regression were used to evaluate the relationship between baseline characteristics and immunosuppressive response.ResultsThere was a trend of greater progression among men, ever smokers, those negative for antisynthetase antibodies, and those with usual interstitial pneumonia radiographic pattern, but no statistically significant relationship was found between baseline serological, clinical, or morphological features and response to immunosuppression. Patients on combination therapy with mycophenolate mofetil and prednisone had less disease progression (p = 0.018) than those on regimens that did not include both of these medications.ConclusionsIn our cohort, baseline clinical assessment did not identify which patients with IPAF will respond to immunosuppressive therapy. Combination therapy with mycophenolate mofetil and prednisone was associated with lack of disease progression in our IPAF patients, including in IPAF–usual interstitial pneumonia. Further studies are needed to evaluate which IPAF patients would benefit from immunosuppressive therapy, antifibrotic therapy, or a combination of both.

Returning to PD after kidney transplant failure is a valuable option.

There is a paucity of data on the prognosis for patients returning to peritoneal dialysis (PD) after a failed transplant. PD has an advantage over hemodialysis in preserving residual renal function, which is associated with better outcomes. We have reviewed the electronic charts of patients on PD in a tertiary academic hospital for the last 8years. We have compared technique survival, peritonitis-free survival, and residual diuresis in two groups: patients with graft failure which returned to PD (PD-KTx, N = 18) and patients starting PD for other causes (PD-not KTx, N = 163). The median follow-up was similar between groups [42(16,71) in PD-not KTx vs. 48(22,90) months in PD-KTx, p = 0.293]. Kaplan-Meier survival comparing PD-KTx and PD-not KTx showed no difference in technique survival (p = 0.196), and peritonitis-free survival (log-rank 0.238), which were confirmed in a fully adjusted Cox regression. Diuresis at baseline and at the end of the first year was similar between groups (p = 0.799 and p = 0.354, respectively). Six out of 18 patients from the PD-KTx group had the immunosuppression maintained and none of those had peritonitis. The reduction of diuresis across the first year of PD was significant for all patients, except for those on continued immunosuppressive therapy. PD is a worthy dialysis alternative after a failed kidney transplant, providing similar outcomes when compared to patients who started PD for other reasons.

COVID-19 Pneumonia in Patients with Chronic Myocarditis (HBV-Associated with InfarctLike Debute): Specifics of the Diseases Course, the Role of the Basic Therapy (Part II)

Chronic infectious-immune myocarditis of severe course can potentially be considered as a factor that aggravates the course of new coronavirus disease (COVID-19) and increases the risk of adverse outcomes. The interaction of chronic myocarditis and COVID-19 during long-term immunosuppressive therapy has not been studied. We present a description of a 35-year-old female patient with chronic infectious-immune myocarditis (morphologically confirmed, with a history of infarction-like onset and thromboembolic complications), who had continuous immunosuppressive therapy with methylprednisolone and mycophenolate mofetil. The patient also received new oral anticoagulants and tenofovir (for chronic HBV infection). COVID-19 (SARS-Cov-2 RNA+) was diagnosed in May 2020. Risk factors for the adverse course of coronavirus infection included severe obesity, heart failure, and life-threatening ventricular arrhythmias. Correction of immunosuppressive therapy (withdrawal of the cytostatic agent, administration of hydroxychloroquine) and therapy with levofloxacin, an interleukin-17 inhibitor (netakimab) were performed. The severity of pneumonia and respiratory failure was moderate despite high fever and high levels of inflammatory markers in the blood (including interleukin-6). Signs of exacerbation of myocarditis, increased levels of troponin T and anticardial antibodies (compared with the initial ones) were not found. It can be assumed that supportive immunosuppressive therapy for myocarditis has a positive effect on the course of coronavirus pneumonia and avoids exacerbation of myocarditis. Careful continuation of immunosuppressive therapy with temporary withdrawal of aggressive cytostatics can be recommended in chronic myocarditis. Further study of the features of the course of previous myocarditis and COVID-19 pneumonia is necessary.

Trained immunity in organ transplantation.

Consistent induction of donor‐specific unresponsiveness in the absence of continuous immunosuppressive therapy and toxic effects remains a difficult task in clinical organ transplantation. Transplant immunologists have developed numerous experimental treatments that target antigen‐presentation (signal 1), costimulation (signal 2), and cytokine production (signal 3) to establish transplantation tolerance. While promising results have been obtained using therapeutic approaches that predominantly target the adaptive immune response, the long‐term graft survival rates remain suboptimal. This suggests the existence of unrecognized allograft rejection mechanisms that contribute to organ failure. We postulate that trained immunity stimulatory pathways are critical to the immune response that mediates graft loss. Trained immunity is a recently discovered functional program of the innate immune system, which is characterized by nonpermanent epigenetic and metabolic reprogramming of macrophages. Since trained macrophages upregulate costimulatory molecules (signal 2) and produce pro‐inflammatory cytokines (signal 3), they contribute to potent graft reactive immune responses and organ transplant rejection. In this review, we summarize the detrimental effects of trained immunity in the context of organ transplantation and describe pathways that induce macrophage training associated with graft rejection.

MANAGEMENT OF PREGNANCY AND LABOUR AFTER KIDNEY TRANSPLANTATION: CLINICAL CASE

Aim. To present a clinical case of pregnancy and childbirth in a woman with a kidney transplant with a favourable outcome for the mother and the fetus. Materials and methods. We studied all medical documents — the pregnancy record, observations and delivery record — of a woman with a transplanted kidney. Clinical case. The article describes the clinical observation of a pregnant woman, who is intended for continuous immunosuppressive therapy after the operation on cadaveric kidney allotransplantation. Conclusion. Pregnancy management in patients with a transplanted kidney should be carried out under the supervision of an obstetrician-gynecologist, nephrologist and urologist, as well as under the permanent clinical and laboratory monitoring of all indicators of the mother’s body (blood and urine tests, blood pressure control) and the fetus (ultrasound, Doppler). This category of patients belongs to a high-risk group in terms of complications for the mother and fetus.

Intestinal Cryptosporidiosis in Renal Transplant Recipients: Prevalence, Species Detection and Comparative Evaluation of SSU rRNA and Cryptosporidium Oocyst Wall Protein Genes

Context: Cryptosporidiosis is intestinal opportunistic infection commonly occurring in immunocompromised patients including renal transplant (RT) recipients receiving continuous immunosuppressive therapy. Knowledge about species of Cryptosporidium-infecting RT recipients is necessary to know about mode of its transmission (anthroponotic or zoonotic). Various genes such as small subunit rRNA (SSU rRNA) and Cryptosporidium oocyst wall protein (COWP) genes may help in species identification though their sensitivity and specificity are highly variable. Subjects and Methods: A total of 993 and 575 stool samples were examined for Cryptosporidium by microscopy from 358 RT recipients and 200 healthy controls, respectively. Stool samples of RT recipients and healthy controls were subjected to polymerase chain reaction (PCR) followed by restriction fragment length polymorphism (RFLP) for species identification. Results:Cryptosporidium was more commonly detected amongst RT recipients than healthy controls (30/358, 8.4% vs. 0/200, respectively; P < 0.001). The infection was more common amongst patients with diarrhoea than those without (26/162, 16.1% vs. 4/145, 2.8%; P < 0.001). Cryptosporidium parvum was identified in 10/30 (33.3%) and Cryptosporidium hominis in 20/30 (66.7%) samples. SSU gene PCR-RFLP proved to be more sensitive (100%) than COWP (90%); however, specificity of both was same (100%). Conclusions: Cryptosporidiosis is common amongst RT recipients, particularly those with diarrhoea. C. hominis is the most common species in the studied population. SSU rRNA PCR was more sensitive molecular method for the differentiation of Cryptosporidium species.

Polymyositis in solid organ transplant recipients receiving tacrolimus

Tacrolimus, also known as FK506, is an immunosuppressive agent widely used for the prevention of acute allograft rejection in organ transplantation and for the treatment of immunological diseases. This study reports two male patients who underwent solid organ transplantation (liver and kidney). After transplant, the patients received continuous immunosuppressive therapy with oral tacrolimus and later presented clinical manifestations and laboratory signs of myopathy. Muscle biopsies of both patients clearly documented an inflammatory myopathy with the histological features of polymyositis including CD8+ T cells which invaded healthy muscle fibers and expressed granzyme B and perforin, many CD68+ macrophages and MHC class I antigen upregulation on the surface of most fibers. Because of the temporal association while receiving tacrolimus and since other possible causes for myopathy were excluded, the most likely cause of polymyositis in our patients was tacrolimus toxicity. We suggest that patients on tacrolimus should be carefully monitored for serum CK levels and clinical signs of muscle disease.

Dramatic remission of nephrotic syndrome after unusual complication of mucormycosis in idiopathic membranous nephropathy

Mucormycosis is a rare and fatal opportunistic infection occurring in severely immunocompromised patients. Here, we report, for the first time, on a 65-year-old man with idiopathic membranous nephropathy and moderate renal dysfunction who suffered from life-threatening pulmonary mucormycosis during immunosuppressive therapy. After amphotericin B (AmB) administration with a total accumulating dose of 1.5 g, not only has he recovered from this fatal infection, but also his nephrotic syndrome has entered complete and long-term remission without any continued corticosteroid and immunosuppressive therapy during the 6-year follow-up. Serum creatinine levels remained stable by adjusting the tolerable daily dose of AmB during the period of treatment.

Gingival Tissue and Apoptosis

Background: Several factors can influence gingival tissues. Among them: disrupting tissue homeostasis and occurrence of pathological conditions. The aim of our study was to investigate and compare the presence of apoptosis in patients treated with immunosuppressive therapy, patients with periodontitis and on the other hand, healthy patients, as well as to better understand the role of apoptosis in the these processes. Methods: The first objective group consisted of 21 patients (10 males and 11 females; mean age 37.4 ± 10.2 years old) with neither kidney diseases nor treated with cyclosporine A (CsA) therapy, who had a verified periodontal disease. The second group consisted of 21 kidney-transplant patients (9 males and 12 females; mean age 36.2 ± 9.5 years old), with diagnosed gingival overgrowth (GO) subjected to continuous immunosuppressive therapy. The control group consisted of the same number of patients, clinically healthy subjects (15 males and 6 females; mean age 29 ± 14.0 years old) with plaque-induced gingivitis. The following indexes were analyzed: plaque index (PI) Sillnes-Loe, index of gingival inflammation (GI) according to Loe-Sillnes, and gingival overgrowth index (GOI) according to MacGaw et al. The determination of CsA in blood was performed by a fluorescence polarised immunoassay (FPIA).The tissue samples were estimated by semiquantitative analysis in order to determine the presence of apoptotic cells and immunohistochemical expression of the bcl-2 and p53 proteins. Results: We found statistical differences in bcl-2 and apoptotic index, among the groups: greatest expression of bcl-2 and apoptotic index was registered in the group treated with CsA, and the lowest expression was noted in the gingivitis group(p 0,05 ; r = 0.187). Conclusion: Our findings suggest that increased apoptosis may have a role in the pathogenesis of CsA-induced gingival overgrowth in the cases of patients on high dose of CsA.

Efficacy of Remission-Induction Regimens for ANCA-Associated Vasculitis

BackgroundThe 18-month efficacy of a single course of rituximab as compared with conventional immunosuppression with cyclophosphamide followed by azathioprine in patients with severe (organ-threatening) antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis is unknown.MethodsIn a multicenter, randomized, double-blind, double-dummy, noninferiority trial, we compared rituximab (375 mg per square meter of body-surface area administered once a week for 4 weeks) followed by placebo with cyclophosphamide administered for 3 to 6 months followed by azathioprine for 12 to 15 months. The primary outcome measure was complete remission of disease by 6 months, with the remission maintained through 18 months.ResultsA total of 197 patients were enrolled. As reported previously, 64% of the patients in the rituximab group, as compared with 53% of the patients in the cyclophosphamide–azathioprine group, had a complete remission by 6 months. At 12 and 18 months, 48% and 39%, respectively, of the patients in the rituximab group had maintained the complete remissions, as compared with 39% and 33%, respectively, in the comparison group. Rituximab met the prespecified criteria for noninferiority (P<0.001, with a noninferiority margin of 20%). There was no significant difference between the groups in any efficacy measure, including the duration of complete remission and the frequency or severity of relapses. Among the 101 patients who had relapsing disease at baseline, rituximab was superior to conventional immunosuppression at 6 months (P=0.01) and at 12 months (P=0.009) but not at 18 months (P=0.06), at which time most patients in the rituximab group had reconstituted B cells. There was no significant between-group difference in adverse events.ConclusionsIn patients with severe ANCA-associated vasculitis, a single course of rituximab was as effective as continuous conventional immunosuppressive therapy for the induction and maintenance of remissions over the course of 18 months. (Funded by the National Institute of Allergy and Infectious Diseases and others; RAVE ClinicalTrials.gov number, NCT00104299.)

75-jähriger Patient mit rezidivierenden Hypoglykämien bei Insulinexzess

Hirata syndrome is a rare differential diagnosis for recurrent hypoglycemia. This immune-mediated disease is associated with the formation of autoantibodies targeting insulin. Although the syndrome resolves spontaneously in the majority of patients, our case illustrates that individual patients require continuous immunosuppressive therapy.

Severe hypercalcemia after a single high dose of vitamin D in a patient with sarcoidosis

Vitamin D supplementation in patients who suffer from sarcoidosis and are simultaneously at high risk of developing glucocorticoid-induced osteoporosis can represent a dilemma in clinical decision making. To illustrate this critical situation, we report the case of a 53-year-old woman with renal sarcoidosis, chronic hepatitis C, and an HIV infection effectively controlled with highly active anti-retroviral therapy. She was admitted to the emergency room due to progressive excessive fatigue, generalized weakness, lethargy, and headache. Physical examination revealed a reduced general condition, signs of hypovolemia, and generalized muscular weakness without focal signs. Regarding her medical history, sarcoidosis was diagnosed 2 years earlier. This disease predominantly affected the kidneys, manifesting itself as an interstitial granulomatous nephritis (Fig. 1). Liver and retinae were affected to a lesser extent, and lungs were free from the disease. Since the diagnosis, she had been treated with glucocorticoids and was taking 25 mg of prednisone per day at the time of admission. Although the patient was additionally taking 75 mg of azathioprine per day, it was impossible to reduce the prednisone dose. Despite the continuous immunosuppressive therapy, sarcoidosis had already led to a significant renal impairment including a moderate proteinuria (1.5 g/day) and a reduced glomerular filtration rate (40 mL/min). During the previous 2 years, the patient occasionally received vitamin D supplementation based on 25(OH)D3 serum levels. Two weeks before the admission to the hospital, 25(OH)D3 serum concentration was measured at 18 ng/mL (47 nmol/L), for which the patient received a single oral dose of 300.000 IU cholecalciferol. At this time, serum calcium was 2.41 mmol/L (normal, 2.15–2.55 mmol/L). Laboratory analysis at the time of admission revealed serum calcium 3.42 mmol/L, serum phosphate 1.88 mmol/L (normal, 0.8–1.4 mmol/L), and serum creatinine 299 lmol/L. Serum levels of 25(OH)D3 and 1,25-dihydroxyvitamin D [1,25(OH)2D3] were 52.4 ng/mL (=130 nmol/L) and 119 pmol/l (normal, 48–160 pmol/L), respectively. In view of these results, we diagnosed severe hypercalcemia, which we traced back to the single high dose of cholecalciferol. Other common causes of hypercalcemia were excluded. The patient was treated with stringent hydration (approx. 3000 mL sodium-chloride 0.9 %/day), which resulted in a slow decrease in serum calcium (2.47 mmol/L) and creatinine (212 lmol/L). The patient recovered from the clinical symptoms within six days and was discharged from hospital. One week later, serum calcium rebounded to 2.76 mmol/L. With a single dose of intravenous pamidronate (30 mg), serum calcium fell in the normal range. 25(OH)D3 and 1,25(OH)2D3 serum levels remained at the normal range (32 ng/mL and 49 pmol/L, respectively) up to four months after the hospitalization. The patient’s clinical condition presented a dilemma in decision making. Indeed, the high risk of glucocorticoidinduced osteoporosis is normally an indication to maintain A. Hassler Johann Wolfgang Goethe University Hospital, University of Frankfurt, 60590 Frankfurt am Main, Germany e-mail: angela_hassler@web.de

Unexpected recovery from longterm renal failure in severe diffuse proliferative lupus nephritis

BackgroundSevere renal manifestation of systemic lupus erythematosus (SLE) is not uncommon and is associated with an indeterminate prognosis. Complete remission can be obtained, however, at least in the young when chronic lesions are absent and adequate anti-inflammatory therapy is immediately initiated.Case presentationWe report the unusual case of a 12-year-old girl who presented with severe oliguric renal failure, macrohematuria and skin rash. Renal biopsy revealed the diagnosis of severe diffuse proliferative glomerulonephritis (GN) with cellular crescents in 15 out of 18 glomeruli and full-house pattern in immunofluorescence indicating lupus nephritis IVB according to WHO, IV-G(A) according to ISN/RPS classification. The serological parameters confirmed the diagnosis of SLE and the patient was immediately treated with methylprednisolone, cyclophosphamide and immunoadsorption. Initially, despite rapid amelioration of her general condition, no substantial improvement of renal function could be achieved and the patient needed hemodialysis treatment for 12 weeks. Unexpectedly, in the further follow-up at first diuresis increased and thereafter also creatinine levels substantially declined so that hemodialysis could be discontinued. Today, 6 years after the initial presentation, the patient has normal renal function and a SLEDAI score of 0 under a continuous immunosuppressive therapy with Mycophenolate mofetil (MMF) and low dose steroid.ConclusionDespite the severity of the initial renal injury and the unfavourable renal prognosis the kidney apparently has a tremendous capacity to recover in young patients when the damage is acute and adequate anti-inflammatory therapy is initiated without delay.

Nanotherapeutic approaches for the treatment of rheumatoid arthritis

Rheumatoid arthritis (RA) is a common inflammatory disease characterized by progressive bone and cartilage destruction, resulting in severe functional limitations, shortened lifespan, and increased mortality rates. Recent advances and new treatment approaches have significantly delayed disease progression and improved the quality of life for many patients. Yet few patients attain or can be maintained in disease remission without continuous immunosuppressive therapy. In addition, a sizable portion of patients also fails to respond or eventually develops tolerance to current therapies. Thus there is a continued need for the development of new therapeutic strategies for the treatment of RA. Unlike conventional drugs, nanosystems are designed to deliver therapeutic agents specifically to the site of inflammation, therefore avoiding potential systemic and off-target unwanted effects. They allow investigators to consider or reconsider therapeutic agents that were previously deemed too toxic to deliver through a systemic route. This article reviews recent nanotechnology-based strategies that are being developed for the treatment of inflammatory arthritis.