Association of polymorphisms in promoter region of TNF-α -238 and -308 with clinical outcomes in patients with immune-mediated inflammatory diseases on anti-TNF therapy.

The hypothesis of the study was that polymorphisms in promoter regions -238 and -308 of TNF-α could be associated with different clinical outcomes in inflammatory bowel diseases (IBD) and immune-mediated rheumatic diseases (IMRD). The aim was to examine the possible association of both polymorphisms with concentration of C-reactive protein (CRP) and fecal calprotectin (fCAL), onset of the remission and development of the ADA in patients on therapy with anti-TNF inhibitors. The prospective study was done in patients with IBD and IMRD on infliximab (IFX) or adalimumab (ADM). Patients were genotyped for TNF-α -238 and -308 polymorphisms. The concentration of CRP, fCAL, IFX or ADM and antibodies to drugs were measured according to manufacturer's instructions and followed-up for 6 or 12 months. Out of all patients (N = 112), number of patients in remission did not differ according to genotypes (for IBD patients P = 0.509 vs 0.223; for IMRD patients P = 0.541 vs 0.132 for TNF-α -238 and -308, respectively). Initial CRP concentration was higher in IBD patients with TNF-α -308 GG than GA/AA genotypes in patients who failed to achieve remission [11.8 (4.4-39.6) vs 3.1 (1.5-6.5), P = 0.033]. In IBD patients with remission, fCAL concentration after at least 6 months of therapy was higher in TNF-α-308 GG than in GA genotype [52 (25-552) vs 20 (20-20) µg/g, P = 0.041]. Our results showed the association of TNF-α -308 GG genotype with a higher concentration of CRP and fecal calprotectin in patients with inflammatory bowel diseases on IFX or ADM therapy. Clinical remission and development of antibodies to anti-TNF drugs were not associated with TNF-α -238 and -308 polymorphisms.

Treatment Satisfaction, Patient Preferences, and the Impact of Suboptimal Disease Control in a Large International Rheumatoid Arthritis Cohort: SENSE Study.

BACKGROUND: Patients' needs and perspectives are important determinants of treatment success in rheumatoid arthritis (RA). Assessing patients' perspectives can help identify unmet needs and enhance the understanding of treatment benefits. OBJECTIVE: The SENSE study assessed the impact of inadequate response to disease-modifying antirheumatic drugs (DMARDs) on treatment satisfaction, disease outcomes, and patient perspectives related to RA disease management. METHODS: SENSE was a noninterventional, cross-sectional study conducted in 18 countries across Europe, Asia, and South America. Adult patients with poorly controlled RA of moderate/high disease activity were eligible. Patient satisfaction was assessed by the Treatment Satisfaction Questionnaire for Medication (TSQM v1.4). Treatment adherence, healthcare resource utilization (HRU), quality of life (QoL), work ability, digital health literacy (DHL), patient preference information, and treatment strategy were also assessed. RESULTS: A total of 1624 patients were included in the study: most were female (84.2%) and middle-aged, and mean disease duration was 10.5 years. Mean TSQM global satisfaction subscore was 60.9, with only 13.5% of patients reporting good treatment satisfaction (TSQM global ≥80). The strongest predictor of good treatment satisfaction was treatment with advanced therapies. Most patients (87.4%) reported good treatment adherence. In general, patients had impaired QoL and work ability, high HRU, and 67.4% had poor DHL. Leading treatment expectations were "general improvement of arthritis" and "less joint pain". Most patients preferred oral RA medications (60.7%) and rapid (≤1 week) onset of action (71.1%). "Increased risk for malignancies" and "increased risk for cardiovascular disease" were the least acceptable side effects. Despite suboptimal control, advanced therapies were only used in a minority of patients, and DMARD switches were planned for only half of the patients. CONCLUSION: Suboptimal disease control negatively impacts treatment satisfaction, work ability, QoL, and HRU. Data collected on patient perspectives may inform shared decision-making and optimize treat-to-target strategies for improving patient outcomes in RA.

The effect of smoking on disease activity in rheumatoid arthritis - our experience.

The aim of this study was to investigate the association of smoking with disease activity, seropositivity, age and gender in patients with rheumatoid arthritis. We included 89 rheumatoid arthritis patients. All patients fulfilled the 2010 American College of Rheumatology/European League Against Rheumatism rheumatoid arthritis classification criteria. Activity of the disease was measured by Disease Activity Score 28-joint count C-reactive protein (DAS28CRP). The subjects were stratified into smoking and non-smoking groups and cross-sectionally analyzed. There were 24 (27%) smokers and 65 (73%) nonsmokers. The mean age of patients was 57.1±8.8 years. The mean DAS28CRP was 5.81 in the smoking group and 5.57 in the non-smoking group, without statistically significant difference between the two groups (p=0.148). Similarly, smokers did not differ significantly from non-smokers according to age (p=0.443), gender (p=0.274), rheumatoid factor positivity (p=0.231), anti-citrullinated protein antibody positivity (p=0.754) or seropositivity (p=0.163). In this study, we found no association between smoking status and disease activity, seropositivity, age or gender in rheumatoid arthritis patients. Furthermore, disease activity was not related to age, gender or seropositivity. Additional studies on the effects of smoking on rheumatoid arthritis activity are needed.

QuantiFERON-TB Gold In-Tube Test in the Diagnosis of Latent Tuberculosis Infection in Arthritis Patients Treated with Tumor Necrosis Factor Antagonists.

The aim of this study was to investigate the role of the QuantiFERON-TB Gold In-Tube test (QFT-GIT) in detecting latent tuberculosis in immunocompromised patients before introducing tumor necrosis factor (TNF-α) antagonists. The study included 300 subjects of similar age. The study group comprised of 150 QuantiFERON (QFT) positive subjects with rheumatoid arthritis, Crohn's disease, ulcerative colitis, ankylosing spondylitis and psoriatic arthritis, while control group comprised of 150 QFT negative respondents with the same diseases. Exhaustive medical history was documented for all patients. Screening tests were performed including QFT-GIT, tuberculin skin test (TST), chest radiography and detection of Mycobacterium tuberculosisin sputum culture 2 times. A positive QFT-GIT test result, regardless of TST result, was considered as an indication for latent tuberculosis infection (LTBI) treatment. Results of this study showed good correlation between the conclusive results of QFT-GIT and TST. All study group patients had normal clinical findings, normal radiologic findings and negative results of sputum microbiological analysis during the course of prophylaxis and after its completion and during the course of biological therapy. Conversion of positive QFT-GIT test to negative was observed in 4% of study group patients, while QFT negative respondents remained negative. There was a statistically significant positive correlation between QFTGIT, TST results and patient age, smoking habit and contact with tuberculosis. Study results showed that along with good clinical evaluation and detailed medical history, it is important to conduct testing in order to avoid disease progression or unnecessary isoniazid prophylaxis.

[GRANULOMATOSIS WITH POLYANGIITIS (GPA) LIMITED TO UPPER RESPIRATORY TRACT--A CASE REPORT]. / GRANULOMATOZA S POLIANGIITISOM (GPA) I LOKALIZIRANIM ZAHVACANJEM GORNJEGA DISNOG SUSTAVA PRIKAZ BOLESNICE.

Granulomatosis with polyangiitis (Wegener's granulomatosis) is one of the anti-neutrophil cytoplasmic anti-body-associated small vessel vasculitides. Upper and lower respiratory system and kidneys are most commonly affected. The disease is characterized by granulomatous inflammation of the respiratory tract and necrotizing vasculitis of small to medium-sized blood vessels. Most patients show involvement of more than one organ systems at the time of diagnosis, and constitutional symptoms may be present. In around a quarter of patients the disease is initially localised, with involvement of upper respiratory tract or lungs. We report a 21-year-old female patient with chronic rhinitis, saddle nose deformity and subglottic stenosis who presented with inspiratory stridor and impending respiratory failure. Initially, urgent tracheotomy was performed. The patient was diagnosed with granulomatosis with polyangiitis limited to upper respiratory tract. Treatment with glucocorticoids and methotrexate was followed by clinical improvement.

[ETIOLOGY AND PATHOGENESIS OF PAIN IN RHEUMATIC DISEASES].

Rheumatic diseases are chronic inflammatory disorders with ongoing inflammation that causes tissue damage. Inflammatory and damaged cells synthetize and release many diff erent intracellular substances which can activate highly specialized subsets of primary sensory neurons called nociceptors. Some of these proinflammatory mediators directly activate the nociceptor terminal and produce pain (such as hydrogen ion, adenosine triphosphate, and bradykinin), and others sensitize the terminal so that it becomes hypersensitive to subsequent and non-noxious stimuli (such as prostaglandin E2 and bradykinin). Acute pain has a protective role since it induces behavior that promotes healing and recovery, such as immobilization which limits tissue damage. Chronic pain is unhelpful pain that tends to be out of proportion to the actual tissue damage and persists long after the tissues have healed, so that the pain becomes the problem rather than the tissues of origin. Chronic pain affects the physical and mental status and causes impairment of quality of life as well as work disability. For rheumatologists the assessment and treatment of pain is a very important integral part of patient care, and understanding the etiology and pathogenesis of pain is necessary to fi nd adequate modalities of treatment to prevent suffering.

Scabies in a Patient with Rheumatoid Arthritis Treated with Adalimumab - A Case Report.

Rheumatoid arthritis is a chronic systemic inflammatory disease characterized by synovitis, erosions, and destruction of affected joints. If untreated, it leads to severe disability and premature mortality. Tumor necrosis factor alpha (TNF-α) inhibitors are biological drugs used in treatment of rheumatoid arthritis. Possible side effects include skin allergic reactions, which, if generalized, are the reason for discontinuation of the drug. We report the case of a 46-year-old female patient with rheumatoid arthritis who presented with pruritus and erythematous papular exanthema after administration of the second dose of adalimumab. At first, we suspected a drug hypersensitivity reaction. As the signs and symptoms persisted for 2 months after discontinuation of adalimumab and despite continuous administration of antihistamines and glucocorticoids, further work-up was performed, and scabies was diagnosed. The patient was treated with topical 10% crotamiton. The symptoms were persistent and additional applications of the preparation were needed. After clinical remission of scabies, treatment of active rheumatoid arthritis with adalimumab was restarted without any complications.

[RETROSPECTIVE DATA ANALYSIS OF THE PATIENTS WITH INFLAMMATORY JOINT DISEASES TREATED WITH GOLIMUMAB IN CROATIA]. / RETROSPEKTIVNA ANALIZA PODATAKA BOLESNIKA OBOLJELIH OD UPALNIH REUMATSKIH BOLESTI U HRVATSKOJ LIJECENIH GOLIMUMABOM.

Golimumab is a human monoclonal antibody which inhibits tumor necrosis factor-alpha (TNF-α) and is approved for the treatment of inflammatory arthritides (rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis) when the conventional non-pharmacological and pharmacological therapies fail to cause remission or low disease activity. In this retrospective study there were included patients with rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis who were treated in Croatia with golimumab, from June 2011 to June 2013. included and these retrospective data are compared with similar data from clinical trials and other available databases. Standard variables of disease activity and functional ability were observed. Results demonstrated significant efficacy of golimumab regarding lowring the disease activity and imrpving functional ability in pateints with these inflammatory rherumatic disease. In conclusion, in this retrospective study during two years treatment golimumab showed efficacy in decreasing disease activity and imrpove functional ability in patiemts with rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis.

Magnetic resonance imaging in the diagnosis and follow-up of giant cell arteritis: case report and review of literature.

A female patient with giant cell vasculitis of the abdominal aorta and its branches and strongly suspected of having extrapulmonary tuberculosis is presented. The diagnoses were based on the clinical picture, laboratory findings, and magnetic resonance imaging (MRI) findings. MRI is highly useful in cases where echosonography and/or vascular biopsy for histopathological analyses are not possible. A combination of giant cell vasculitis and extrapulmonary tuberculosis is extremely rare, and therefore, choosing the right treatment presents a considerable challenge. MRI performed after 6-month antituberculous therapy and 1-year glucocorticoid plus methotrexate therapy showed normal wall of the aorta and its branches, which was consistent with clinical and laboratory remission. Patients with large vessel vasculitis require regular follow-up by MRI.

[Henoch-Schönlein purpura with late-onset necrotising glomerulonephritis--a case report]. / Prikaz bolesnice s Henoch-Schönleinovom purpurom i kasnom pojavom nekrotizirajuceg glomerulonefritisa.

Henoch-Schönlein purpura (HSP) is the most common systemic vasculitis in children, while it is rare in adults. Typical clinical manifestations include palpable purpura without thrombocytopenia and/or coagulopathy, arthritis/arthralgia, abdominal pain, and/or renal involvement. In adulthood the disease tends to be more serious than in children, with renal manifestations developing over a period of several days to one month after initial symptoms. In this article we present a 22-year-old female patient with cutaneous vasculitis and arthralgia, in whom renal disease developed 8 weeks after disease onset with microscopic hematuria and proteinuria in urinalysis. Renal biopsy subsequently performed revealed focal necrotising glomerulonephritis with IgA deposits. The patient was treated with high dose methylprednisolone followed by gradual tapering, which induced complete remission of the disease. In conclusion, patients with HSP should be carefully monitored for systemic involvement, since serious renal disease can develop even as late as two months after disease onset.

[Comorbidities in patients with rheumatoid arthritis]. / Komorbiditet u bolesnika s reumatoidnim artritisom.

Comorbidity in rheumatoid arthritis (RA) patients significantly impairs and limits management of primary disease, decreases general quality of life, and worsens outcomes. Cardiovascular comorbidity is the leading cause of excess mortality in RA patients, which is up to two times higher compared to the general population. Infections, pulmonary disease and malignant diseases also contribute to excess mortality, while fatigue, depression and osteoporosis are related to decreased quality of life. Adequate management of RA patients should therefore, besides tight control of disease activity, also include comorbidity screening and management. This approach should improve both RA and comorbidity related outcomes.

[Clinical manifestations of antineutrophil cytoplasmic antibodies associated vasculitis]. / Klinicka obiljezja vaskulitisa povezanih s antineutrofilnim citoplazmatskim protutijelima.

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides are rare diseases, with the average of 30 new cases per million inhabitants per year. Their main characteristic is systemic involvement with necrosis of the vessel walls (histological changes showing necrosis of the media and inflammation of adventitia and intima). In some forms granulomas may be found surrounding the vessels. ANCA-associated vasculitides include granulomatosis with polyangiitis (GPA, previously called Wegener's), microscopic polyangiitis (MPA) and eosinophilic granulomatosis with polyangiitis (EGPA, previously called Churg-Straus). Honorific eponyms are now changing to a disease-descriptive or etiology-based nomenclature. ANCA-associated vasculitides are a distinctive group of vasculitides because they dominantly involve small sized vessels, sometimes even medium sized vessels, are associated with antineutrophil cytoplasmic antibodies with high risk of developing glomerulonephritis and respond well to immunosuppresion with cyclophosphamide.

[From unexplained fever to visceral leishmaniasis--a case report]. / Od nejasne vrucice do visceralne lismenijaze--prikaz bolesnika.

Visceral leishmaniasis or kala-azar is a systemic infectious vector-borne disease caused by protozoa Leishmania donovani and Leishmania infantum that are transmitted to mammalian hosts by sand flies. It occurrs sporadically in endemic areas, including Mediterranean basin. Southern coastal territories of Croatia have been recognized as the foci of the disease. Dogs are the main reservoir of human infection. Clinical features include prolonged fever, malaise, hepatosplenomegaly, pancytopenia and inversion of albumin-globulin ratio. If left untreated, the disease causes death in majority of cases. We report a 47-year-old Croatian patient who was admitted to hospital with 2-month history of fever of unknown origin. Based on bone marrow aspirate findings and positive serological tests, the diagnosis of visceral leishmaniasis was established. We also considered secondary hemophagocytic lymphohystiocytosis in the differential diagnosis. After a 4-week treatment with sodium-stibogluconate clinical remission was achieved as well as complete recovery of hematopoesis. The aim of our case-report is to stress the importance of considering visceral leishmaniasis in patients with longstanding fever in endemic areas.

Focal myositis of lower extremity responsive to botulinum A toxin.

Focal myositis is a rare, mostly benign disease (pseudotumor) of skeletal muscle, histopathologically characterized by interstitial myositis and tumorous enlargement of a single muscle. The etiology of focal myositis remains unknown; however, localized myopathy has been postulated to be caused by denervation lesions. This case report describes a patient that presented with clinical, laboratory, electromyoneurography, and magnetic resonance imaging features of focal myositis complicated with intervertebral disk protrusion in the lumbosacral spine affected with radicular distress. In most cases, focal myositic lesions show spontaneous regression, relapses are rare, and long-term prognosis is good. There is a wide spectrum of therapeutic options, from no therapy at all through nonsteroidal antirheumatics and glucocorticoids to radiotherapy, surgical excision, and immunosuppressants. In the patient presented, treatment with glucocorticoids, methotrexate, and surgical excision failed to produce satisfactory results. Clinical improvement, pain relief, and reduction in lower leg volume were only achieved by local infiltration of botulinum A toxin.

[Raynaud's phenomenon - first sign of malignancy: case report]. / Raynaudov fenomen kao prvi znak maligne bolesti: prikaz bolesnice.

Raynaud's phenomenon is a common phenomenon in the general population. It most commonly occurs in healthy individuals, in whom there is no associated illness or any other cause of Raynaud's phenomenon (primary or idiopathic Raynaud's phenomenon). Secondary Raynaud's phenomenon is common with rheumatic diseases (systemic sclerosis, systemic lupus erythematosus, primary Sjögren's syndrome, mixed connective tissue disease, etc.), occlusive vascular diseases, hematologic disorders, use of vibrating tools and use of some medications, and rarely with malignancy. We report on a patient who presented with a three-week history of painful Raynaud's attacks, which was the reason for seeking assistance of internists in emergency clinic. Upon admission to the hospital and diagnostic work-up, adenocarcinoma of the lung was found. Antinuclear antibodies (ANA), anti-dsDNA antibodies, anticardiolipin IgM and IgG antibodies were present in a lower titer. It is known that rheumatoid factor or ANA characteristic of rheumatic disease are often present in patients with paraneoplastic rheumatic syndromes, which can lead to wrong conclusions about the possible systemic connective tissue diseases and ultimately delay the correct diagnosis. The first appearance of Raynaud's phenomenon as an isolated symptom in people older than 50, with painful signs of ischemia, as in our patient, or the occurrence of asymmetric grasping fingers, especially in men, regardless of the presence of RF, ANA, anti-dsDNA or other autoantibodies, requires broader diagnostic evaluation for malignancy.

[The proposal of Croatian Society for Rheumatology for anti-TNF-alpha therapy in adult patients with spondyloarthritides, 2013]. / Prijedlog hrvatskog reumatoloskog drustva HLZ-a za primjenu inhibitora TNF-alpha u odraslih bolesnika sa spondiloartritisima, 2013.

Croatian Society for Rheumatology of Croatian Medical Association updated the proposal for the application of TNF-alpha inhibitors in adult patients with spondyloartritides (SpA) in accordance with the new classification of SpA and european recommendations for the treatment of SpA with biologic agents. In this way a standardized method of diagnosis, targeted treatment, monitoring and evaluating outcomes are proposed.

Decrease in circulating DNA, IL-10 and BAFF levels in newly-diagnosed SLE patients after corticosteroid and chloroquine treatment.

Arsenal of pattern-recognition receptors alongside antibody production machinery make B cells vulnerable to autoimmune response if an autoantigen elicits both pathways in a self-sustained fashion. Systemic lupus erythematosus is an autoimmune disease characterized by autoantibodies to DNA, RNA and related structures. Murine studies demonstrated autoreactive B cell activation upon TLR9 stimulation with DNA-containing immune complexes. This activation could be abolished with chloroquine, a drug used in SLE treatment that also blocks TLR9 signaling. We investigated whether chloroquine modulates TLR9 expression, circulating DNA levels and B cell-related cytokines in newly discovered, untreated SLE patients. TLR9 was measured in peripheral blood B cells by flow cytometry, serum DNA by real-time PCR, and IL-10 and BAFF by ELISA before treatment, after 3weeks on corticosteroids, and 3months after introduction of chloroquine. We found that circulating DNA is higher in SLE patients than in controls in every time-point and decreases significantly after chloroquine treatment. Untreated patients had higher serum IL-10 than controls or patients on corticosteroids. Also, corticosteroids decreased and chloroquine completely abolished CpG-mediated CD86 upregulation on B cells and IL-10 secretion in PBMC culture. Providing the TLR9 pathway activation demonstrates its importance in pathogenesis of human SLE, this data supports continuation of chloroquine in SLE treatment protocol. In addition, observed modulation of cytokine and DNA levels after immunomodulatory treatment prompts for inclusion of untreated patients in studies of human immune disorders.

[Relapsing polychondritis--case report]. / Ponavljani polihondritis--prikaz bolesnika.

Relapsing polychondritis (RP) is a rare systemic inflammatory disease in which recurrent episodes of cartilage inflammation result in destruction of ears, nose and tracheobronchal tract. The joints, eyes, audiovestibular system and cardiovascular system can also be involved. About 30% of patients with RP have coexisting autoimmune disease, or malignant disease like colon, breast, and lung carcinoma, or malignant lymphoma. Pathogenesis is still unknown, and there is no consistent laboratory parameter specific for RP, which makes the diagnosis mainly clinical. Glucocorticoids are a mainstay of medical treatment of RP, whereas newer studies show positive effects of biological therapy. The course of RP is characterized by recurrent episodes of cartilage inflammation, and the prognosis has been recently improved because of improved medical and surgical treatment. We present a case of a patient with RP who was diagnosed 1 month after the development of first symptoms and responded well to glucocorticoid therapy.

[Proposal for biologic drugs therapy in rheumatoid arthritis]. / Prijedlog primjene bioloskih lijekova u reumatoidnom artritisu.

Rheumatoid arthritis is a chronic, inflammatory disease with the prevalence about 1%. Rheumatoid arthritis is characterized with synovitis, often evolve erosions of the joints, pain and functional deficit. Etiology is unknown, but the development of such autoimmune disease is due to genetic and environmental factors. Most of the patients with diagnosis of rheumatoid arthritis use nonbiologic disease modifying antirheumatic drugs. Advances in the undersstanding of the disease process have led to the development of biological agents to treat rheumatoid arthritis. With the use of biologic agents we wish to evolve the goal of therapy from that of symptomatiic relief to clinical remission. Biologic drugs have documented, fast and continuous efficacy with generaly well accepted safety profile. On behalf of Croatian Society for Rheumatology we propose recommendations for the biologic therapy in rheumatoid arthritis.