[Treatment of rheumatic disease with renal insufficiency]. / Therapie rheumatischer Erkrankungen mit Niereninsuffizienz.

BACKGROUND: Reduced renal function is not rare in patients with inflammatory rheumatic diseases and is associated with an increased risk of treatment-induced and perioperative adverse events. METHOD: A literature search was carried out for the medical treatment and perioperative management of rheumatic disease in the presence of renal insufficiency. RESULTS: Patients with rheumatic disease and renal insufficiency have a higher risk of cardiovascular disease, bone loss and immunodeficiency than those without kidney disease. The perioperative rate of cardiovascular and infectious complications and the risk of acute kidney failure are elevated in these patients. The pharmacokinetics of many drugs used in rheumatology is influenced by the kidney function. Especially methotrexate is contraindicated in patients with an estimated glomerular filtration rate (eGFR) <45 ml/min. Nonsteroidal anti-inflammatory drugs (NSAIDS) and cyclooxygenase (COX)-2 inhibitors should not be used with renal insufficiency or only for a short term with the lowest effective dose. The treatment of osteoporosis with antiresorptive drugs may lead to adynamic bone disease in advanced kidney disease, and, therefore, the use of these drugs is controversial. CONCLUSION: Medication should be modified in patients with rheumatic disease and kidney involvement according the grade of renal insufficiency. There is also a need for special perioperative management in these patients, with interdisciplinary cooperation of rheumatologists, nephrologists and orthopedic doctors.

[Dosage and toxicity of antirheumatic drugs in renal insufficiency]. / Dosierung und Toxizität von Antirheumatika bei Niereninsuffizienz.

BACKGROUND: Patients with inflammatory rheumatic diseases frequently have a reduced renal function. The risk of adverse events is increased in these patients and treatment options in patients with rheumatic disease and renal failure are poorly studied. METHODS: A selective literature search was carried out for pharmocokinetics, dosage and toxicity of antirheumatic drugs in patients with renal insufficiency. RESULTS: The use of nonsteroidal anti-inflammatory drugs (NSAID), cyclooxygenase(COX)-2 inhibitors, gold and cyclosporine is limited in renal insufficiency due to nephrotoxicity. Methotrexate should not be used in patients with a glomerular filtration rate (eGFR) < 45 ml/min, because of the unpredictable pharmacokinetics with a risk for fatal pancytopenia. The dosage of sulfasalazine, azathioprine, mycophenolate mofetil, cyclophosphamide and antimalarial drugs should be reduced in patients with moderate and severe renal insufficiency. In contrast, leflunomide and numerous biologics can be used without dosage modification; however, biologics with a molecular weight < 60 kDa (e.g. anakinra) are an exception and should be reduced in patients with renal insufficiency. Overall, there are only limited data on the use of biologics in this population. Numerous comorbidities and the high risk for infection should be kept in mind when patients with rheumatic disease and renal failure are treated with immunosuppressive drugs. CONCLUSION: Further studies are necessary to obtain more evidence on the use of disease-modifying antirheumatic drugs (DMARD) and biologics in patients with renal insufficiency.

[Diagnostics of glomerulonephritis]. / Diagnostik der Glomerulonephritiden.

Glomerulonephritis occurs frequently in patients with multisystemic rheumatic disease, especially in collagen vascular disorders and vasculitides. From a clinical point of view nephrotic syndrome has to be distinguished from nephritic syndrome. Rapid deterioration of renal function is referred to as rapid progressive glomerulonephritis. The differential diagnosis of glomerulonephritis can be narrowed by the findings on urine sediment, amount of proteinuria, degree of renal insufficiency and serological findings. In particular, the presence of urine acanthocytes and cellular casts are diagnostic for glomerulonephritis or vasculitis. Renal biopsy is necessary to establish the final diagnosis in most cases; however, some histological pattern such as membranous glomerulonephritis may occur in several different etiopathogenetic diseases and one disease process may lead to different histomorphologic pictures. Rapid progressive glomerulonephritis is a nephrological emergency and should be diagnosed and treated early to prevent dialysis-dependent renal insufficiency.

Ultrasonography in the assessment of peripheral joint involvement in psoriatic arthritis : a comparison with radiography, MRI and scintigraphy.

The objective of our study was to investigate the role of musculoskeletal ultrasound (US) in the assessment of hand and foot small joints in psoriatic arthritis (PsA). Thirteen consecutive patients with PsA of hands or feet underwent B-mode US using a 9- to 13-MHz transducer and simultaneous magnetic resonance imaging (MRI), bone scintigraphy and radiography. US findings were compared with radiography, MRI and scintigraphy in 190, 182 and 109 joints, respectively. To assess the sensitivity and specificity of US, radiography was considered as gold standard for the detection of erosions and osteoproliferations and MRI as gold standard for the detection of joint effusion and synovitis. US, MRI and scintigraphy had a higher sensitivity in the detection of overall joint pathology than radiography in painful and/or swollen joints (71%, 72%, 82% vs 32%) and clinically unaffected joints (17%, 21%, 9% vs 2%). US and radiography detected more erosions and osteoproliferations than MRI, with low agreement between the methods in the detection of erosions. Radiography was superior to US in the visualisation of osteoproliferations. Joint effusions and/or synovitis were more frequently detected by MRI than US. Agreement between both imaging methods was better in carpal joints, carpometacarpal joint I, metacarpophalangeal (MCP)/metatarsophalangeal (MTP) joint I, II and V than in MCP/MTP III, IV, PIP and DIP joints. Compared with MRI, radiography and scintigraphy, the specificity of US ranges between 0.84 and 0.94, depending on the joint pathology. In conclusion, the diagnostic sensitivity of US in the detection of PsA-related synovitis of hands and feet is lower than MRI and depends on the joint region. However, the low cost and the acceptable specificity suggest that US is a useful imaging method in addition to radiography in PsA of hands and feet.

Mycophenolate sodium for subacute cutaneous lupus erythematosus resistant to standard therapy.

BACKGROUND: Approximately 75-95% of patients with cutaneous lupus erythematosus respond to antimalarial therapy and/or topical glucocorticosteroids. Immunosuppressive agents are usually considered a second-line approach in patients with resistant disease. OBJECTIVES: This was a prospective, nonrandomized, open pilot study to evaluate the efficacy of mycophenolate sodium monotherapy in patients with recalcitrant subacute cutaneous lupus erythematosus (SCLE). METHODS: Monotherapy with oral enteric-coated mycophenolate sodium 1440 mg daily was given for a total of 3 months. Treatment outcome was evaluated by means of a validated clinical score for cutaneous lupus erythematosus, the Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI), as well as 20-MHz ultrasound measurements and colorimetry. Safety assessment included the monitoring of adverse effects and clinical laboratory parameters. RESULTS: Ten patients with active SCLE resistant to at least one standard therapy were included in the trial. Mycophenolate sodium led to a remarkable improvement of skin lesions, resulting in a significant decrease of the mean +/- SD CLASI from 10.8 +/- 6.0 at the beginning to 2.9 +/- 2.6 at the end of therapy. Clinical improvement was confirmed by ultrasonographic assessments and colorimetry. No serious side-effects were noted. CONCLUSIONS: Mycophenolate sodium is beneficial and safe in the treatment of patients with SCLE that failed standard therapy. However, these preliminary data must be confirmed by randomized controlled trials including a larger sample size.

Analgesic and disease modifying effects of interferential current in psoriatic arthritis.

Interferential current (IFC) was suggested to improve the skin manifestations of psoriasis vulgaris, possibly by enhancing the intracellular concentration of cyclic AMP. We assessed the efficacy of IFC on psoriatic arthritis (PsA). Nine consecutive patients were analyzed at baseline and after 16 weeks of IFC therapy. Bipolar IFC was applied twice daily to hands, feet plus all affected joints. IFC improved SF-36 assessed body pain, but not other SF-36 subscales. Morning stiffness, tender joint counts, and physician assessed disease activity improved. In contrast, visual analogue scale assessed pain, CRP and ESR measurements were unchanged. MRI of the most affected hand or foot documented a tendency towards worsened tendinitis, soft tissue swelling, and new joint space narrowing and erosions. Bone scintigraphy showed a trend towards deterioration. New joints became inflamed within treated sites. Thus IFC has analgesic effects in PsA, but does not have a satisfactory disease modifying effect.

Nephrolithiasis and hematuria--sometimes a stony road to diagnosis.

We report a case of a young man with a history of kidney stones. Occurrence of gross hematuria several months after the extracorporeal shock wave, lithotripsy (ESWL) treatment lead to hospitalization. By ultrasound and abdominal CT scan, the urologist could exclude post-renal causes of the gross hematuria and acute renal failure. After transfer to a department of nephrology hemodialysis was started, an immediate kidney biopsy was performed and prednisolone was administered on the same day. The kidney biopsy revealed an anti-glomerular basement membrane (GBM) disease. The renal function did not recover and the patient remained on hemodialysis. In the literature it has been hypothesized that ESWL-treated patients are prone to develop anti-GBM disease by liberation of glomerular basement antigen through the ESWL high energy shock waves. An additional hypothesis considering the higher susceptibility for anti-GBM disease among certain HLA-tissue types is discussed with regard to our case. Unfortunately, the prolonged track to diagnosis and delayed immunosuppressive treatment could not prevent poor clinical outcome. Although anti-GBM disease is a rather rare disease, it should be included as a differential diagnosis for hematuria--especially months after ESWL treatment. Otherwise early diagnosis may be missed and as in our patient immunosuppressive treatment will remain unsuccessful to recover renal function.

Dihydrotachysterol therapy for hypoparathyroidism: consequences of inadequate monitoring. Five cases and a review.

BACKGROUND: The half synthetic Vitamin D analogue dihydrotachysterol (DHT) is widely used for hypocalcaemic hypoparathyroidism following surgical removal of parathyroids. Such treatment generally initiated by surgeons right after surgery has to be continued in clinical practice. Unfortunately, the required careful monitoring of calcium metabolism is often lacking and as demonstrated may lead to life-threatening conditions. PATIENTS AND METHODS: Here we report on five patients referred to our nephrology unit because of unknown impairment of renal function during therapy with DHT. All patients had clinical signs of hypercalcaemia. Since most symptoms are nonspecific they were not perceived by primary care physicians. In fact DHT treatment was continued for 4 - 50 years. In all cases calcium levels were determined after inadequate long intervals ranging from 3.08 to 4.97 mmol/l. Creatinine levels ranged from 277 to 365 micromol/l. All patients suffered from symptoms of severe hypercalcaemia, three of them needing intensive care unit treatment. RESULTS: All patients were treated effectively with a regimen consisting of intravenous saline, a loop diuretic, and application of bisphosphonates. As confirmed by renal biopsy persisting alleviation of renal function was due to calcifications. After discontinuation of DHT therapy patients were safely switched to shorter acting vitamin D derivates maintaining a normal calcium level. CONCLUSIONS: In comparison to short acting vitamin-D derivates hypercalcaemic episodes with DHT appear to last longer and may therefore occur with higher incidence. A future option could be the use of synthetic parathyroid hormone (s-PTH) recently shown to be safe and effective. Nevertheless a customized therapy and careful monitoring is indispensable in any case to prevent irreversible organ damage.

Infectious CNS disease as a differential diagnosis in systemic rheumatic diseases: three case reports and a review of the literature.

BACKGROUND: Immunosuppressive treatment of rheumatic diseases may be associated with several opportunistic infections of the brain. The differentiation between primary central nervous system (CNS) involvement and CNS infection may be difficult, leading to delayed diagnosis. OBJECTIVE: To differentiate between CNS involvement and CNS infection in systemic rheumatic diseases. METHODS AND RESULTS: Three patients with either longstanding or suspected systemic rheumatic diseases (systemic lupus erythematodes, Wegener's granulomatosis, and cerebral vasculitis) who presented with various neuropsychiatric symptoms are described. All three patients were pretreated with different immunosuppressive drugs (leflunomide, methotrexate, cyclophosphamide) in combination with corticosteroids. Magnetic resonance imaging of the brain was suggestive of infectious disease, which was confirmed by cerebrospinal fluid analysis or stereotactic brain biopsy (progressive multifocal leucoencephalopathy (PML) in two and nocardiosis in one patient). DISCUSSION: More than 20 cases of PML or cerebral nocardiosis in patients receiving corticosteroids and cytotoxic drugs for rheumatic disease have been reported. The clinical aspects of opportunistic CNS infections and the role of brain imaging, cerebrospinal fluid analysis and stereotactic brain biopsy in the differential diagnosis are reviewed.

Kinetics of hepatitis C (HCV) viraemia and quasispecies during treatment of HCV associated cryoglobulinaemia with pulse cyclophosphamide.

OBJECTIVE: To investigate the effect of pulse cyclophosphamide treatment on hepatitis C virus (HCV) kinetics and quasispecies in interferon alpha (IFNalpha) resistant HCV related cryoglobulinaemic vasculitis. METHODS: Reports on two patients with severe manifestations of HCV related cryoglobulinaemia who failed to respond to interferon alpha are given. Both patients were treated with pulse cyclophosphamide (750-1000 mg/month for six and 11 months, respectively). HCV RNA was quantified and HCV quasispecies determined in cryoprecipitates and supernatants before and during treatment. RESULTS: Cryocrit and complement activation decreased in both patients with rebound of cryocrit in one case during continuing pulse cyclophosphamide treatment. Vasculitic symptoms improved. Alanine aminotransferase (ALT) levels and HCV viral load (0.2-0.4 log) increased slightly and reached pretreatment levels after cyclophosphamide was stopped. A highly heterogeneous quasispecies was found in the cryoprecipitate and supernatant of one patient, whereas the viral population was homogeneous in the other patient. After six cycles of cyclophosphamide, viral distances decreased non-significantly. However, phylogenetic analysis showed the evolution of distinct viral strains in one patient and replacement of the main viral population by another population in the second patient. CONCLUSIONS: Immunosuppressive treatment with pulse cyclophosphamide has a temporary limited effect on HCV associated cryoglobulinaemia and leads to a reversible increase of ALT levels and HCV viral load. Short term immunosuppression does not affect the viral heterogeneity as measured by amino acid and nucleotide distances in the hypervariable region 1 of HCV. A change of quasispecies was observed, but further studies are needed to evaluate if this does affect the outcome of IFNalpha treatment in such patients.

End-stage renal disease after treatment with 90Y-DOTATOC.

DOTA-D-Phe1-Tyr3-octreotide (DOTATOC), a newly developed somatostatin analogue which can be stably labelled with the beta-emitter yttrium-90, can be used for receptor-mediated internal radiotherapy. A 78-year-old woman suffering from a carcinoid of the small intestine with multiple metastases in the liver as well as mesenteric and supraclavicular lymph node metastases was treated with this therapy after the disease had progressed under other chemotherapy options employed years previously. The patient received four single doses of 90Y-DOTATOC at 6-week intervals, yielding a cumulative dose of 9,620 MBq (5,659 MBq/m2). Restaging revealed stable metastatic disease. Serum creatinine and urea nitrogen levels were within the normal range prior to starting and during DOTATOC therapy. However, 15 months after cessation of DOTATOC therapy, a progressive deterioration of renal function occurred, leading to end-stage renal disease. Urinalysis revealed a slight proteinuria of 700 mg/day without haematuria, leucocyturia or casts. There was no obvious risk factor for chronic renal insufficiency except DOTATOC therapy. However, it was not feasible to use kidney biopsy to prove the presence of radiation-induced nephritis. Intermittent haemodialysis was started as the creatinine clearance declined to below 10 ml/min. Diuresis was not affected. The presented case shows delayed renal insufficiency after a relatively low cumulative dose of 90Y-DOTATOC (5,659 MBq/m2). This serious adverse event indicates that further studies are needed to evaluate which dose of 90Y-DOTATOC, under which renal protection regimen, will provide optimal management, balancing risks and benefits.

Occurrence of C-reactive protein in cryoglobulins.

A previous case report described the formation of a complex between a monoclonal IgA with cryolabile properties and C-reactive protein (CRP). Our study provides the first evidence for the frequent occurrence of CRP in cryoglobulins (Cg) of all three types according to Brouet's classification. We performed a systematic immunochemical analysis of cryoglobulins from 18 patients by Western blotting and in 15 of 18 cryoprecipitates a single band (23 KD), immunoreactive with anti-CRP antibody, was demonstrable irrespective of the clonal composition of the cryoglobulins. This band was detectable in 4/5 of type I, in 6/8 of type II, and in 5/5 of type III cryoprecipitates, classified according to Brouet et al. In addition, the complement proteins C1q and C3 were present in nearly all CRP-containing cryoglobulins, presumably reflecting previous activation of the classical complement pathway at least. All three CRP-negative cryoprecipitates were derived from sera with low cryoglobulin content (1-2 g/l). Longitudinal investigation of 23 cryoprecipitates from seven patients confirmed that successful detection of CRP by Western blotting depends on the protein concentration of the cryoglobulins. Since complexed CRP was previously shown to be an effective activator of complement, via C1q binding, CRP may modulate pathophysiologic effects mediated by cryoglobulins in vivo.

Alterations of cerebral glucose metabolism indicate progress to severe morphological brain lesions in neuropsychiatric systemic lupus erythematosus.

Neuropsychiatric systemic lupus erythematosus (SLE) is frequently associated with deficits in brain glucose metabolism, even if morphological imaging by magnetic resonance imaging (MRI) shows no abnormalities. In these patients it is unclear whether or not the changes of brain metabolism measured by F-18-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) may progress to lesions of cerebral structure. We describe a 20-year-old woman with SLE who presented with depression, headache and impairment of memory. Initially, a cranial MRI was negative, but FDG-PET revealed significant hypometabolism in the frontal and parieto-temporo-occipital regions on both sides as well as hypermetabolism in the nuclei caudati. Within two months the patient developed an acute confusional state, seizures, visual disturbances and cranial MRI became positive showing hyperintensities at the basal ganglia and the temporo-occipital regions. Focal cerebral symptoms responded to treatment with high dose corticosteroids and brain lesions in MRI disappeared. However, a second FDG-PET showed persistent hypometabolism at frontal regions in accordance with the persistence of subclinical depression. To our knowledge, this is the first SLE case report showing that functional brain lesions visualized by FDG-PET may be a risk factor for subsequent structural brain damage seen in MRI. Thus, FDG-PET may help to verify cerebral involvement of SLE earlier than MRI.