Successful therapy of retroperitoneal fibrosis due to IgG4-related disease with rituximab, cyclophosphamide and glucocorticoids followed by maintenance therapy wit ritutixmab.

Idiopathic retroperitoneal fibrosis (IRF) is a rare condition characterized by the development of a peri-aortic and peri-iliac tissue showing chronic inflammatory infiltrates and pronounced fibrosis. Ureteral entrapment with consequent obstructive uropathy is one of the most common complications, which can lead to acute renal failure and, in the long term, to varying degrees of chronic kidney disease. Common symptoms at onset include lower back, abdominal or flank pain, and constitutional symptoms such as malaise, fever, and anorexia and weight loss. Pain is frequently referred to the hip, to the groin and to the lateral regions of the leg, with nocturnal exacerbations, and typically does not modify with position. We report a case of 56 year-old male with recurrent lower back pain and lower abdominal pain. Contrast-enhanced computed tomography and was suggestive of retroperitoneal fibrosis and unilateral ureteral occlusion. Histologic examination with immunohistochemical staining for IgG4 demonstrate IgG4-related retroperitoneal fibrosis. Therapy was started with prednison 1 mg/kg, but the tolerance of this dose was poor. Therefore the therapy was switched to combination of rituximab 375 mg/ m2 on day 1, cyclophosphamide 300 mg/m2 mg infusion and dexamethasone 20 mg total dose infusion on day 1 and 15 in 28 days cycle. FDG-PET/CT control in fourth month showed residual accumulation of FDG in retroperitoneal fibrotic mass, and therefore the therapy was prolonged to 8 month. The subjective symptoms of this diseases disappeared in the 8th month. Then the maintenance therapy, administration of rituximab in 6 month interval, was started. The activity of this disease be further evaluated by FDG-PET/CT imagination. Glucocorticoids are considered the cornerstone of therapy. The use of other immunosuppressive agents, including cyclophosphamide, azathioprine, methotrexate, mycophenolate mofetil and biological agents such as rituximab, tocilizumab and infliximab and sirolimus have been reported as a valuable option mostly in case reports, cases series and small studies. This agents allowed to reduce cumulative dose of glucocorticoids and its adverse effects. Therefore in our patients we preferred combination of rituximab cyclophosphamide s dexamethasone with lover dose of prednisonem. This combination is preferable for patients who cannot tolerate glucocorticoids or who are likely to suffer from significant glucocorticoids -related toxicity.

IgG4-related disease. Clinical manifestation differential diagnosis and recent International Diagnostic Criteria for IgG4-related disease.

Immunoglobulin G4- related disease (IgG4-RD) is a rare systemic fibro-inflammatory disorder. Autoimmune pancreatitis is the most frequent manifestation of IgG4-RD. However, IgG4-RD can affect any organ such as salivary glands, orbits, retroperitoneum, prostate and many others. Recent research enabled a clear clinical and histopathological description of IgG4-RD and in 2019 four Clinical phenotypes of IgG4-related disease were described. Diagnosis is based on morphological examination with typical findings of lymphoplasmocellular inflammation, storiform fibrosis and obliterative phlebitis in IgG4-RD biopsies and the tissue invading plasma cells largely produce IgG4. Elevated serum IgG4 levels are found in many but not all patients. New diagnostic criteria for IgG4-RD have been published recently in 2019 and 2021. This review summarizes current knowledge on pathophysiology, clinical manifestations, diagnosis and differential diagnosis of IgG4-RD from the point of view 2022 and in next article brings overview of the IgG4-RD therapy.

Therapy of immunoglonuline IgG4 related disease (IgG4-RD).

Immunoglobulin IgG4 related disease (IgG4-RD) is a heterogeneous disorder with multi-organ involvement recognised as a separate entity at the beginning of this century only. Evolving therapy is reviewed in this paper. Glucocorticoids are first choice drug but long administration of glucocorticoids is connected with many adverse effects. In case of combination glucocorticoids and immunosuppressive agents lower doses of glucocorticoids are needed, the response rate is higher and therapy is better tolerated. Rituximab is drug, that is possible use as monotherapy or in combination with glucocorticoids and immunosuppressive drugs. Only one study compared two immunosuporessive drugs, mycophenolate mofetil and cyclophosphamide. The response rated was similar but remissions were longer after glucocorticoids with cyclophosphamide then glucocorticoids with mycofenolat mofetil. No other comparative study of combination of various imunossupressive drugs with glucocorticoids was published. Rituximab has high number (90 %) of response rate in monotherapy, but can be used in combination with glucocorticoids and immunosuppressives. Rituximab is now preferred and recommended for maintenance therapy administered in 6-month interval. In case of advanced disease, we prefer therefore combination of rituximab, cyclofosphamide and dexamethasone for initial therapy followed by maintenance with rituximab in 6 months interval. There are two new drugs under investigation abatacept and dupilimab with promising results. Although we have very intensive therapies for good results of therapy early diagnosis before irreversible fibrotic changes in IgG4-RD involved organs is still needed.

[Remission of the disease associated/related with immunoglobulin IgG4 accompanied by multiple lymphadenopathy after treatment with rituximab and dexamethasone: a case report]. / Remise "the disease associated/related with immunoglobulin IgG4" provázeného mnohocetnou lymfadenopatií po lécbe rituximabem a dexametazonem: kazuistika.

A disease associated with immunoglobulin IgG4 is a rare unit with very variable symptoms. We describe the course and treatment of the disease in a patient who presented with multiple lymphadenopathy and infiltrates in the area of the retroperitoneum and pelvis and signs of chronic sclerosing pancreatitis. The disease was clinically manifested by a significant loss of weight, but also by a loss of perception of taste and smell. The diagnosis was made based on a high amount of IgG4 expressing plasma cells in the sampled tissue and an increased concentration of immunoglobulins of type IgG and mainly subclass IG4. Rituximab in 475 mg/m2 dose was used in the treatment, the initial four doses of rituximab were administered at 14-day intervals, always with a one-off administration of a 40 mg dose of dexamethasone. According to FDG-PET/CT, only partial remission of the disease was reached after 4 applications of rituximab and dexamethasone. The patient recovered its sense of smell and taste. In another 4 cycles ritu-ximab was administered on day 1 of a 28-day cycle. On days 1 and 15 of the cycle dexamethasone at 40 mg and cyclophosphamide at 600 mg were administered by intravenous infusion. After the completion of 8 cycles of treatment based on rituximab and dexamethasone and with cyclophosphamide added in the second half of the treatment, the control FDG-PET/CT examination proved the complete remission. Before the treatment commencement the concentration of the subclass of immunoglobulin IgG4 was equal to 51.0 g/l, after the completion of the aforementioned treatment it dropped to 3.5 g/l. The patient tolerated the treatment without any adverse effects. Ritu-ximab, dexamethasone and cyclophosphamide induced the complete remission of this disease.Key words: IgG4-associated/releated disease - rituximab.

[Evaluation of five years of treatment of Erdheim-Chester disease with anakinra: case report and overview of literature]. / Hodnocení petileté lécby Erdheimovy-Chesterovy nemoci anakinrou - kazuistika a prehled literatury.

Erdheim-Chester disease is a histiocytic neoplasm of diseases from the group of non-Langerhans-cell histiocytoses, formed by infiltrates of foamy histiocytes. These pathological histiocytes produce pro-inflammatory cytokines. Therefore Erdheim-Chester disease is called inflammatory histiocytary neoplasm. The disease is accompanied by clinical symptoms of systemic inflammatory response, i.e. B symptoms. Imaging examinations detect typical osteosclerotic changes affecting diaphyses and metaphyses of the lower long bones and fibrotic changes which affect the aorta wall and the vessels leading from it. Also characteristic are perirenal fibrotic changes spreading in the retroperitoneum. They can cause serious complications - hydronephrosis with all its consequences. The therapy for this disease was not satisfactory in the previous years. Conventional chemotherapy or glucocorticoids do not bring any substantial and long-term improvement. Considering cytostatic drugs, only 2-chlorodeoxyadenosine (cladribine) is effective, though not in all patients. We have only reached complete remission through 2-chlorodeoxyadenosine in one of our two patients, which now lasts more than 5 years, while cladribine in the same patient did effect the reduction of infiltrates into the CNS, but it did not achieve abatement of the disease activity in other locations as shown by PET/CT with the application of the radio-pharmaceutical fluorodeoxyglucose (FDG). Another effective medicine for patients with Erdheim-Chester disease is interferon α. However its long-term administration is associated with multiple adverse effects and so we did not test it in the described patient. The introduction of anakinra, the interleukin-1 receptor blocker, to therapy brought a new hope for these patients. We are describing the patient who has been treated with anakinra for more than 5 years. The patient applies 1 ampoule of 100 mg subcutaneously per day. This treatment completely removed systemic B symptoms, relieved bone pains and attained normalization of all findings that signalled systemic inflammatory response. The treatment effect is regularly checked by CT imaging of the abdomen and by FDG-PET/CT examinations. The retroperitoneal fibrotic changes gradually regressed during the 5 years of anakinra treatment, as documented by the pictures in the text. Low-dose CT imaging which was part of the PET/CT examination, identified many osteosclerotic lesions in the skeleton, mainly in the legs, with an increased accumulation of 18F-fluorodeoxyglucose (FDG). Osteosclerotic lesions remain well visible at repeated examinations. Still during the course of the 5-year period the FDG accumulation in them decreased, as shown by the pictures in the text. Anakinra treatment has a character of maintenance therapy. The BRAFV600E mutation was not proven in the described patient, therefore we did not test vemurafenib treatment. CONCLUSION: anakinra effected regression of fibrotic changes in the retroperitoneum and disappearance of B symptoms as well as decrease in FDG accumulation at FDG-PET/CT examination.Key words: anakinra - Erdheim-Chester disease - cladribine - retroperitoneal fibrosis - vemurafenib.

[Hypercalcemia, symptoms, differential diagnostics and treatment, or importance of calcium investigation]. / Hyperkalcemie, príznaky, diferenciální diagnostika a lécba aneb dulezitost vysetrování kalcia.

UNLABELLED: The concentration of calcium is carefully maintained under physiological conditions with parathormone, calcitonin and 1,25-dihydroxyvitamin D at appropriate levels. There are multiple causes that may bring about increased concentrations of calcium which exceed physiological values. Increased production of parathormone in parathyroid glands is only one of the possible causes. Malignant diseases are a very frequent cause of hypercalcemia, due to their creating mediators which stimulate osteoclasts and thereby osteolysis. A less frequent cause is represented by granulomatous processes, a typical example of which is sarcoidosis, whose cells increasingly (independently of parathormone) hydroxylate 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D. However there are also hereditary forms of hypercalcemia. One of the causes of the hereditary form of hypercalcemia is mutations of the calcium sensing receptor. In order to locate the adenoma of parathyroid glands, essential apart from sonographic imaging is scintigraphy 99mTc-methoxyisobutylisonitrile (MIBI) and even more exact is PET-CT examination with a radio-pharmaceutical 18F-fluorocholine. PET-CT examinations are beneficial with regard to detecting a malignant cause of hypercalcemia in until then undetected malignancy or an undetected granulomatous process. The essential treatment procedures for malignant hypercalcemia include appropriate hydratation of ionic solutions without calcium, administering of bisphosphonates or denosumab. The text describes in detail the symptoms of hypercalcemia and diagnostics of causes of hypercalcemia. KEY WORDS: bisphosphonates - cinacalcet - denosumab - granulomatous diseases - hereditary hypercalcemia - hypercalcemia - hypercalciuria - hyperparathyreosis - calcimimetics - calcitonin - multiple myeloma - malignant hypercalcemia - parathormone - sarcoidosis - 1,25-dihydroxyvitamin D.

[The patient complains of spinal pain or fatigue and weakness. How do I recognize whether their cause is spondylarthrosis, the patients age or multiple myeloma?]. / Pacient si stezuje na bolesti v páteri nebo na únavu a slabost. Jak rozeznám, zda je prícinou spondylartróza, vek nemocného anebo mnohocetný myelom?

Multiple myeloma has varied manifestations which resemble common patient complaints and that is why this disease is typically not diagnosed until it reaches an advanced stage. Spinal pains can be an expression of deformative and discogenous changes, but also a symptom of multiple myeloma. Pains in the long bones may result from the pain radiating from an arthrotic joint, but also from a large myelomatic osteolytic lesion which makes the bone prone to a spontaneous fracture. Pathological weariness may have many causes, multiple myeloma being one of them. Anemia may have a large number of causes and multiple myeloma is one of them. Raised creatinine levels and renal failure can also be due to many causes and again, multiple myeloma is one of them. Weakened immunity and frequent infections can also have many causes, among them multiple myeloma. Confusion and sleepiness may be due to psychiatric diagnosis, but also may result from hypercalcemia associated with multiple myeloma. The following text which is designed for non-hematology physicians therefore describes in detail the symptoms of multiple myeloma and diagnostic steps leading to establishing the diagnosis and it only briefly outlines the treatment related information. You can also visit www.myeloma.cz for details. This text aims to summarize the symptoms of multiple myeloma for physicians not specializing in hematology in order to facilitate earlier diagnosing of the disease.