An underrecognized association: immune checkpoint inhibitor-related aortitis, a case report with the review of the literature.

Immune-checkpoint inhibitors (ICIs) are considered as the novel treatment modality in certain cancers. They may soon be used widely even as the first-line option for cancer treatment due to their remarkable efficacies and impacts on survival rates, particularly in cases of advanced metastatic cancer. Of note, these agents might unveil new autoimmune diseases as well as causing flare-ups of a pre-existing autoimmune disease. Data in this field have been accumulated during recent years. Early detection and a collaborative approach are, therefore, crucial in the management of a patient who presents with any of these conditions. Herein, we report a patient with a diagnosis of metastatic renal cell cancer presented with vasculitis involvement in the aorta during nivolumab treatment. Our aim with this case is to increase the awareness of ICI-related vasculitis involvement among rheumatologists in the light of literature.

Age-related immunosenescence in Behçet's disease.

Behçet's disease (BD) is a systemic vasculitis of unknown etiology causing recurrent mucocutaneous lesions, ocular involvement, central nervous system involvement, and vascular involvement. The disease is characterized by exacerbations and spontaneous remissions. Prognosis is poor in young men when the vessels are involved. The course is more active and severe in the first years of the disease. One of the most interesting features of BD is that the disease changes to a state of low activity and remission over time. Although the association between aging and lower disease activity is well established, there is limited literature data and research investigating the cause. Similarly, there are not many studies on the late onset of BD and its characteristics. In this regard, understanding the cause of the decline in disease activity over time may open new avenues for pathogenesis and treatment research. In this review, we focus on the immunosenescence caused by chronic inflammation and aging in BD. Based on the effect of testosterone on innate immune cells, we also briefly discussed the potential effects of this hormone on vascular involvement.

Hypercalcemia in IgG4-related disease: coincidental or associated? Case based review.

Immunoglobulin (Ig) G4-related disease (IgG4RD) is a chronic autoimmune disorder characterized by dense lymphoplasmacytic infiltrations and fibrosis of storiform pattern. The most typical manifestations include major salivary or lacrimal gland involvement, autoimmune pancreatitis, and retroperitoneal fibrosis. While the increase in IgG4 is the typical feature of the disease, hypercalcemia has been rarely reported in IgG4RD so far, only one of these cases has been shown parathyroid gland involvement (isolated involvement). In this study, we present a 43-year-old female patient with weight loss, pancreatic mass, lymphadenopathy, nodular lesion in the lung, hypercalcemia, and also increased level of serum IgG4. Histopathological investigation following parathyroidectomy revealed a dense lymphoplasmacytic infiltrate with an IgG4 to IgG ratio of > 50% in the fat tissue surrounding the parathyroid gland, particularly at the perivascular areas. This is the first systemic IgG4RD case in combination with hypercalcemia in the literature who was detected to have parathyroid adenoma. Our aim in this review is to emphasize that, although rarely, IgG4RD may be accompanied by hypercalcemia and parathyroid gland may be one of its target sites.

Familial coexistence of demyelinating diseases and familial Mediterranean fever.

Familial Mediterranean fever (FMF) is a monogenic autoinflammatory disease characterized by fever and serositis attacks caused by mutations in the MEditerranean FeVer (MEFV) gene encoding the pyrin gene. Gain of the function mutations of the pyrin gene lead to stimulation of pro-inflammatory cytokines. Persistent pro-inflammatory situation in the course of FMF may play a role in the development of some other inflammatory diseases such as Behcet's disease, psoriasis, and vasculitis. Multiple sclerosis (MS), as a demyelinating disorder, is also more commonly seen in FMF patients compared to the general population. There are scarcely any research reporting that these two diseases coexist in more than one person in the same family. We have discovered cases of FMF and demyelinating disorders in five members of two different families. Besides the two families we are reporting, there are only four other families reported so far. Having combined the data of all these six families, we present a case-based review in this study. We aimed to draw attention of physicians to familial co-occurence of FMF and demyelinating disorders and also to discuss possible mechanisms of the coexistence of these two diseases in light of the literature.

Evaluation and Differential Diagnosis of Hypereosinophilia in Rheumatology Practice.

BACKGROUND: There has been no investigation so far on the prevalence or causes of hypereosinophilia during rheumatic diseases. OBJECTIVES: The study aimed to identify the prevalence and causes of hypereosinophilia among the patients followed in a rheumatology department. METHODS: The patients aged 18 years or over followed in our rheumatology department between January 2010 and December 2019 who had at least one AEC ≥1,500/µL measurement in their peripheral blood count were identified retrospectively. RESULTS: Over the 10 years, a total of 130,769 peripheral blood counts were performed, of which 3.9% showed eosinophilia and 0.065% showed hypereosinophilia. Hypereosinophilia was identified in 85 patients. The underlying rheumatic disease was determined in 89.4% (n = 76) of patients. Of these, the most frequent one was rheumatoid arthritis at a ratio of 40.8%, followed by eosinophilic granulomatosis with polyangiitis (EGPA) at a ratio of 10.5%. Hypereosinophilia was in primary form in 3.5% of the patients, whereas secondary to another condition in 91.8% (n = 78) of the cases and idiopathic in 4.7% (n = 4) of patients. The most common cause of secondary hypereosinophilia was drug induced, as detected in 61.2%, followed by allergic conditions in 11.5% and EGPA in 9.4%. In 15.2% (n = 13) of the cases, hypereosinophilia was associated with an underlying rheumatic disease. In the cases with drug-induced hypereosinophilia, most often (in 28.8%) methotrexate was the offending agent. CONCLUSIONS: Rheumatologists should be cognizant that hypereosinophilia concurrent to rheumatic diseases is usually not due to the underlying rheumatic disease, except for the conventional eosinophil-related rheumatic diseases.

Evaluation of hyperferritinemia causes in rheumatology practice: a retrospective, single-center experience.

Hyperferritinemia may develop due to various reasons such as inflammation, infection, or malignancy. The purpose of the study to explore the prevalence and to figure out the causes of general hyperferritinemia and extreme hyperferritinemia as detected through the ferritin measurements requested by the rheumatology department. Adult patients at the age of 18 years and older with at least one serum ferritin level measurement at or above 500 ng/mL as requested by the rheumatology department between January 2010 and December 2019 were evaluated retrospectively. Hyperferritinemia was detected in 4.7% of 11,498 serum ferritin tests. The mean age of 242 patients found to have hyperferritinemia was 53.7 ± 17.1 years; of the patients, 63.2% were female, and the mean serum ferritin value was 2820 ± 5080 ng/mL. The most common cause of hyperferritinemia was rheumatological diseases with a ratio of 59.1%, which was followed by infections, iron overload, and solid malignancy. Among the rheumatologic diseases, adult-onset Still's disease (AOSD), rheumatoid arthritis, and vasculitis were the cause accounting for hyperferritinemia. Ferritin levels were significantly higher in the AOSD group compared to the other rheumatologic disease groups (p < 0.0001). While extreme hyperferritinemia (ferritin ≥ 10,000 ng/mL) rate in our cohort was 0.2%, the most common cause was AOSD (15/17). In patients with hyperferritinemia, 3 month mortality was found to be 8.7%. CRP level was identified as the only independent predictor for the 3 month mortality in all patients [OR 1.088 (95% CI 1.004-1.178), p = 0.039]. Although rheumatologic disease activation and infections are the most common causes, the other causes should also be considered for the differential diagnosis.

The coexistence of IgA vasculitis and tuberculosis: a case-based review.

Immunoglobulin (Ig) A vasculitis (IgAV), formerly known as Henoch-Schonlein purpura (HSP), is a relatively uncommon form of vasculitis primarily targeting the skin, gastrointestinal system, and the kidneys. Although the pathogenesis has not yet been well identified, several triggering factors, such as infections, drugs, have been implicated in the development of IgAV. Tuberculosis (TB), albeit rare, may precipitate IgAV. Herein, we have presented a case manifested by purpuric skin rash and proteinuria 6 weeks following diagnosis of pulmonary tuberculosis while receiving anti-TB drugs. The case was diagnosed as having active tuberculosis and TB-related IgA vasculitis with multi-organ involvement. In this case-based review, we recruited cases with TB-related Ig A vasculitis from the literature and discussed the features of tuberculosis that mimic vasculitides and vice versa. We also discussed the difficulties in diagnosis and the therapeutic approach in the light of the literature.

Temporal artery biopsy for suspected giant cell arteritis: a retrospective analysis.

Temporal artery biopsy (TAB) is one of the diagnostic criteria of giant cell arteritis (GCA) according to 1990 ACR criteria and remains a tool for diagnosis. Although clinicians perform TAB with an intent to confirm suspected GCA, some biopsies result in negative and some lead to non-GCA diagnoses. We aim to review the diagnoses after TAB biopsy performed for suspected GCA and also wanted to evaluate the diagnostic changes and concomitant diseases that develop over time. The patients who had undergone TAB for suspected GCA were identified using the record entry code for TAB. Patients meeting the classification criteria for GCA were designated as the GCA group and not meeting criteria were designated as a non-GCA group. Other classification criteria were implemented for the non-GCA group diseases. A total of 51 patients (Female: 62.7%, median age: 72.1 ± 7.4 years) who had undergone TAB for suspected GCA were evaluated. TAB was positive in 23 (69.6%) of the 33 patients who met the GCA classification criteria. No significant difference was found between TAB-positive and TAB-negative GCA patients in terms of clinical and laboratory parameters. In the non-GCA group, 12 patients had isolated polymyalgia rheumatica (PMR), and the diagnoses of the remaining six patients were as follows: four large vessel vasculitis (LVV) not satisfying GCA diagnostic criteria, one chronic myelomonocytic leukemia (CMML), and one amyloidosis. TAB was negative in all patients with isolated PMR. TAB showed primary amyloidosis in one patient. Out of 33 GCA patients, 21 had "isolated" GCA, four had GCA + Rheumatoid arthritis (RA), seven had GCA + PMR, and one had GCA + polymyositis. RA was diagnosed antecedent to GCA in two patients, and after GCA in the other two patients. One of the patients had developed GCA 20 years after polymyositis had been diagnosed. TAB was found to be positive in two-thirds of patients with suspected GCA. Late-onset RA and rarely other inflammatory rheumatic diseases may develop in the course of GCA.

Hyperkalemia in type 4 renal tubular acidosis associated with systemic lupus erythematosus.

Renal tubular acidosis (RTA) is a normal anion gap metabolic acidosis that manifests with insufficiency of hydrogen ion excretion or bicarbonate (HCO3) reuptake as a result of renal tubular dysfunction independent of glomerular filtration rate. Hypokalemic RTA subtypes co-existing with autoimmune diseases particularly appear in Sjogren's syndrome, but rarely in systemic lupus erythematosus (SLE). Type 4 RTA associated with hyperkalemia is very rare during the course of SLE and hence has been scarcely reported in the literature. Here, we report a 42-year-old patient for whom regular follow-up was ongoing due to class IV lupus nephritis when she developed hyperkalemia. The patient had normal anion gap hyperkalemic metabolic acidosis and her urine pH was 5.5. Type 4 RTA was considered and, therefore, tests for renin and aldosterone levels were requested, which revealed that renin was suppressed and aldosterone was decreased. Upon diagnosis of SLE-associated type 4 RTA, short-term oral HCO3 and fludrocortisone were initiated. Potassium (K) and HCO3 levels improved at day 15 of therapy. In this review, we analyzed our case along with five other reports (a total of seven cases) of SLE-associated type 4 RTA we identified through a literature search. We wanted to highlight RTA for differential diagnosis of hyperkalemia emerging during SLE/lupus nephritis and we also discussed possible underlying mechanisms.

Can hyperuricemia predict glycogen storage disease (McArdle's disease) in rheumatology practice? (Myogenic hyperuricemia).

Gout disease is an inflammatory arthritis that arises due to the accumulation of monosodium urate crystals (MSU) around the joints and in tissues. Clinical manifestation of metabolic diseases leading to secondary hyperuricemia most predominantly occurs in the form of gouty arthritis. Hyperuricemia and gout may develop during the course of glycogen storage diseases (GSD), particularly in GSD type I, which involves the liver. On the other hand, during the course of GSD type V (GSDV, McArdle's disease), which merely affects the muscle tissue due to the deficiency of the enzyme myophosphorylase, hyperuricemia and/or gout is rarely an expected symptom. These patients may mistakenly be diagnosed as having idiopathic hyperuricemia and associated gout, leading to the underlying secondary causes be overlooked and thus, diagnostic delays may occur. In this case report, we present a premenopausal female patient who experienced flare-ups of chronic arthritis while on disease-modifying antirheumatic drugs and intraarticular steroids due to a diagnosis of undifferentiated arthritis. The patient was initially suspected of having gouty arthritis because elevated concentrations of uric acid were incidentally detected, but then, a diagnosis of asymptomatic GSDV was made owing to elevated concentrations of muscle enzymes during colchicine use. Our aims were to remind rheumatologists of the phenomenon of "myogenic hyperuricemia" and to discuss the potential causes of hyperuricemia that develop during GSD along with the available literature.

Is it required to routinely check fibrinogen level in patients with rheumatic diseases on tocilizumab? Case-based review.

Tocilizumab (TCZ) may rarely cause hematological side effects including neutropenia and thrombocytopenia. TCZ is essentially expected to lower the fibrinogen levels to stay within the normal range, but TCZ-induced hypofibrinogenemia has been rarely reported in literature. Although it may remain asymptomatic, hypofibrinogenemia has clinical significance owing to the tendency of the condition to result in bleeding. A 65-year-old female patient with known polymyositis was, approximately 20 years after the diagnosis was made, examined due to elevated acute phase reactants leading to the diagnosis of giant cell arteritis (GCA) and TCZ treatment was initiated as she had former steroid-induced osteoporotic fractures. 1 month after the initial dose of intravenous (IV) TCZ, she presented with ecchymosis and was detected to have hypofibrinogenemia. Following the administration of the second dose, hypofibrinogenemia was detected again. In this review, we have analyzed this patient in addition to the cases in six other articles of TCZ induced hypofibrinogenemia which we found out based on our search strategy. Our aim is to point out a rare side effect of TCZ, hypofibrinogenemia, thus to emphasize a possible bleeding disorder and discuss probable underlying mechanisms.

Do Anti-TNF Agents Increase the Risk of Inflammatory Bowel Disease Evolution in Patients with Ankylosing Spondylitis? Real Life Data.

OBJECTIVE: The aim of this study was to determine whether there is any association with anti-tumor necrosis factor (TNF) agent administration and development of new-onset inflammatory bowel disease (IBD) in ankylosing spondylitis (AS) patients. METHODS: Records of the patients who met 1984 modified New York criteria for AS between 1998 and 2016 at Rheumatology Department were evaluated retrospectively and data about the patients, IBD properties and medication were obtained. RESULTS: Among 420 patients, 310 were male, the average age was 42.9 ± 1.3 years, average disease duration was 16.7 ± 10.4 years. Anti-TNF agents were in use by 154 patients, 52 patients were receiving etanercept (ETN), infliximab (INF), adalimumab (ADA), and golimumab (GO) treatments were ongoing in 50, 41, and 11 patients, respectively. New-onset IBD developed in 10 patients; 3 from the group treated with non-anti-TNF drugs (1.1%) and 7 from the group treated with anti-TNF agents (4.5%) (p = 0.042). No significant difference was detected between three anti-TNF agent forms in relation with the risk of IBD onset. In AS patients, existence of familial AS (OR 4.69 (95%CI 1.28-17.19, p = 0.020) and anti-TNF agent treatment (OR 4.17 (95%CI 1.06-16.38, p = 0.041) were independent risk factors for new-onset IBD development. CONCLUSION: Despite the increased risk of new-onset IBD development during the course of AS, paradoxical response to anti-TNF drugs must also be considered as a source that triggers onset of IBD.

Cyclophosphamide-induced severe acute hepatitis in a rheumatic disease: case-based review.

In rheumatology practice, the risk of hepatotoxicity from medications, including non-steroidal anti-inflammatory drugs, notably, and methotrexate, sulfasalazine, leflunomide, and azathioprine is highly recognized by the rheumatologists. On the other hand, hepatotoxicity is neither a commonly expected nor a well-known side effect of cyclophosphamide (CYC) which is particularly used for vital organ involvements in systemic lupus erythematosus (SLE) and systemic vasculitis. Here we reported a 19-year-old case of SLE who, while on oral CYC treatment of 100 mg/day, was detected to have asymptomatic liver enzyme elevation and then developed acute hepatitis due to intravenously administered high-dose (1 g) CYC for neuro-lupus. Results of liver biopsy indicated drug-related toxicity. We discussed here with the other, although rare, cases available in the literature with an attempt to highlight the risk of hepatotoxicity and acute hepatitis due to CYC.

Dose-dependent bradycardia as a rare side effect of corticosteroids: a case report and review of the literature.

Corticosteroids rank at the first place among the most commonly used immunosuppressive agents in the rheumatology practice. Although their conventional adverse effects including hyperglycemia, hypertension, hyperlipidemia, and osteoporosis are well-recognized and managed, steroid-induced cardiac arrhythmias are known to a lesser extent. In this regard, steroid-associated bradycardia is rarely expected and not very well known. Reported cases of steroid-associated bradycardias in the literature predominantly have emerged during the course of intravenous high-dose (pulse) methylprednisolone (MP) administrations. In this paper, we report a patient who developed sinus bradycardia following 52 mg of oral MP administration, improved once the drug was discontinued but repeated with the re-administration. Hence, the patient was shifted to prednisolone (PRED), and again suffered bradycardia which recovered upon dose reduction. Presenting this case along with other similar rare cases in the literature, our aim is to draw attention of fellow rheumatologists, who widely use steroids, to bradycardia-a rare and dose-dependent side effect of steroids.

Bone marrow as a target organ of systemic lupus erythematosus: analysis of cases with myelofibrosis.

AIM: Cytopenia in the course of systemic lupus erythematosus (SLE) may be due to multiple factors. In this study, we aimed primarily to evaluate the detailed results of bone marrow (BM) biopsies of SLE patients, secondly to determine the myelofibrosis (MF) frequency and thirdly to compare BM morphologic findings as well as the clinical and laboratory parameters between groups (with MF and without MF) in cytopenic SLE patients. METHODS: We retrospectively analyzed 224 SLE patients' files. Patients were divided into two groups according to whether they had MF or not. Concurrent SLE organ involvements, medical therapy and detailed BM findings were recorded. RESULTS: Forty-five (20%) of 224 SLE patients were found to have undergone BM biopsy due to cytopenia. Four patients were excluded (two drug-induced cytopenia, one lymphoma, one insufficient BM biopsy samples). While MF was detected in 29 (70.7%) of the 41 patients, 12 patients did not have MF. Between the two groups, no differences were identified in terms Systemic Lupus Erythematosus Disease Activity Index, BM cellularity, or BM dysplastic changes (P = 0.788, P = 0.672 and P = 0.494, respectively). In the SLE-associated MF group, 27 patients responded to immunosuppressive therapy and corticosteroids, but two patients were unresponsive. The response time was longer for the SLE-associated MF group compared to the without MF group (3.3 ± 3.1 months vs. 1.7 ± 1.2 months, P = 0.091). Correlation analysis revealed that increased degree of BM fibrosis delayed the response time (r = 0.471, P = 0.002). CONCLUSIONS: MF is common in SLE patients. SLE-associated MF as an additional factor for cytopenia in SLE patients may lead to delayed response to appropriate therapy, which may be dependent on the increased grade of BM fibrosis.

Can neck pain be an initial symptom of rheumatoid arthritis? A case report and literature review.

Although rheumatoid arthritis (RA) is most commonly associated with peripheral joints, cervical spine involvement can be seen in almost 80% of patients in the presence of long-term disease, joint erosion, and risk factors such as male sex and rheumatoid factor positivity. It is very rare to have cervical involvement in the initial period of RA. If a patient has isolated cervical spine involvement without peripheral arthritis, it is highly likely that inappropriate investigations and delayed treatment may occur. Any damage that occurs in cervical spine may cause symptoms varying from slight instability to atlantoaxial subluxation, spinal cord and brain stem compression and even death. Therefore, physician should be aware that there may be isolated cervical involvement, albeit rare, in patients with RA. In this report, we presented a case of RA presenting with cervical spine involvement without peripheral arthritis to underline the importance of this kind of involvement in clinical practice. We also briefly reviewed other cases similar to ours in light of literature.