Predrag Ostojic

Different clinical features in patients with limited and diffuse cutaneous systemic sclerosis

This study aims to analyze differences among established disease damage indicators in patients with limited cutaneous systemic sclerosis (lcSSc) and diffuse cutaneous systemic sclerosis (dcSSc). Fifty patients with lcSSc and 55 patients with dcSSc were included in this study. Difference in mean disease duration between the two subgroups of patients was not statistically significant (z=−0.88, p=0.38). Patients with lcSSc and dcSSc were compared, and differences in vascular, esophageal, lung, heart, renal, and musculoskeletal involvement were statistically assessed using χ2, Mann–Whitney, and Kruskal–Wallis tests. Using the technique of nailfold capillaroscopy, we found normal capillaries or nonspecific capillary change in 10.0% of the patients with lcSSc and only in 3.6% of the patients with dcSSc. Dilated capillaries without loss of capillaries were found in 42% of the patients with lcSSc and in 10.9% of the patients with dcSSc (p=0.05). However, severe capillary damage (loss of capillaries) was noticed more frequently in patients with dcSSc (dcSSc/lcSSc: 85.5%/48.0%, p=0.002). Pitting scars or digital ulcers were found in 46.0% of the patients with lcSSc and in 67.3% of the patients with dcSSc (p=0.04). We did not notice a significant difference in frequency of fingertip osteolysis and telangiectasia. Esophageal hypomotility was found in 64% of the patients with lcSSc and in 85.5% of the patients with dcSSc (p<0.01). We found interstitial lung fibrosis more frequently in patients with dcSSc (lcSSc/dcSSc: 16.0%/72.7%, p<0.001). Reduced forced vital capacity (FVC) was found in 6.0% of the of patients with lcSSc and in 41.8% of the patients with dcSSc (p<0.001). A decreased value of the transfer factor for carbon monoxide (DLCO) was also observed more frequently in patients with dcSSc. Heart involvement was found in 29.1% of the patients with dcSSc and less frequently (p<0.001) in patients with lcSSc (8%). Similarly, we found renal involvement more frequently in patients with dcSSc (lcSSc/dcSSc: 2.0%/16.3%). Tendon friction rubs were noticed in 23.6% of the patients with dcSSc and only in 6% of the patients with lcSSc (p<0.01). Joint contractures were observed in 70.9% of the patients with dcSSc and in 26.0% of the patients with lcSSc (p<0.001). Muscle weakness was noticed more frequently in patients with dcSSc (lcSSc/dcSSc: 22.0%/40.0%, p<0.05). Arthralgia was found more frequently in patients with dcSSc, but arthritis became apparent, without significant difference in frequency, in 16% of the patients with lcSSc and in 16.4% of the patients with dcSSc. Loss of capillaries (detected by nailfold capillaroscopy), digital ulcers, interstitial lung fibrosis, decreased FVC and DLCO, esophageal hypomotility, musculoskeletal impairment, and heart and renal involvement are more common in patients with dcSSc. Fingertip osteolysis, telangiectasia, and arthritis are equally frequent in both forms of the disease.

The prognostic value of nailfold capillary changes for the development of connective tissue disease in children and adolescents with primary raynaud phenomenon: a follow-up study of 250 patients.

Abstract:  To assess the prognostic value of capillaroscopy findings for the development of connective tissue disease in children and adolescents with Raynaud phenomenon, we followed up a group of 250 (mean age 15 years) for 1 to 6 years after the first capillaroscopy was performed. Every 6 months they were screened for signs and symptoms of connective tissue disease. Analysis was performed on capillary changes registered 6 months before the development of connective tissue disease. Capillary changes were classified into three types: normal, nonspecific, and sclerodermatous. At the end of the follow‐up period, 191 (76%) subjects had primary Raynaud phenomenon, 27 (10.8%) were diagnosed as having undifferentiated connective tissue disease, and 32 (12.8%) fulfilled the criteria for a diagnosis of a specific connective tissue disease. Systemic lupus erythematosus was found in nine (3.6%) patients, rheumatoid arthritis in 10 (4%) patients (six of them with juvenile onset rheumatoid arthritis), and scleroderma spectrum disorders in 13 (5.2%). The mean time for the evolution of Raynaud phenomenon into undifferentiated connective tissue disease or a form of the disease was 2 years. Most of the subjects with primary Raynaud phenomenon (173/191, 91%), undifferentiated connective tissue disease (22/27, 81%), juvenile onset rheumatoid arthritis/rheumatoid arthritis (7/10, 70%), and systemic lupus erythematosus (6/9, 67%) had normal capillary findings. Nonspecific capillary changes occurred in 3 of 10 (30%) patients with rheumatoid arthritis, 2 of 9 (22%) with systemic lupus erythematosus, 4 of 27 (15%) with undifferentiated connective tissue disease, and 18 of 191 (9%) with primary Raynaud phenomenon. Of all the subjects, only 10 (4%) showed sclerodermatous disease type capillary changes 6 months before the expression of a particular disease: eight (62%) of these developed scleroderma spectrum disorders, one expressed systemic lupus erythematosus, and one had undifferentiated connective tissue disease. We concluded that there were no specific capillary changes predictive for future development of systemic lupus erythematosus, juvenile onset rheumatoid arthritis/rheumatoid arthritis, and undifferentiated connective tissue disease in children and adolescents with Raynaud phenomenon. Most of our study subjects with Raynaud phenomenon who developed these diseases had normal capillary findings or nonspecific changes. Children and adolescents who developed scleroderma spectrum disorders showed a sclerodermatous type of capillary changes 6 months before the expression of the disease, indicating that this type of capillary changes in children and adolescents with Raynaud phenomenon highly correlated with further development of scleroderma spectrum disorders.

Symptoms of depression and anxiety in Serbian patients with systemic sclerosis: impact of disease severity and socioeconomic factors

This study aimed to assess symptoms of depression and anxiety in Serbian patients with systemic sclerosis (SSc) and to estimate the impact of disease severity and socioeconomic factors on development of depression and anxiety in SSc. Thirty-five patients with SSc and 30 age- and gender-matched healthy individuals participated. Symptoms of depression and anxiety were evaluated using the Beck’s depression inventory and Zung’s anxiety self-assessment scale. We estimated the impact of gender, age, economic status, marital status, disease duration, disease subset (limited or diffuse), and some clinical features on development of depressive symptoms and anxiety in patients with SSc. Symptoms of depression were found in 68.6% of patients (compared with 23.3% in the control group), were more frequent in patients with longer disease duration and in female and older patients, and were more common in unemployed and retired patients than in employed individuals. No differences in anxiety and depressive symptoms was noticed between patients with limited and diffuse SSc or those with or without restrictive lung disease, pulmonary hypertension, finger-tip ulcers, and heart involvement. Symptoms of depression were associated with severe pain. Symptoms of anxiety were found in 80% of patients compared with 13.3% of healthy individuals and were equally as frequent in patients of different gender, age, socioeconomic status, and disease duration and severity. Symptoms of depression and anxiety are common in Serbian patients with SSc. Depressive symptoms depended mostly on socioeconomic factors, disease duration, and pain intensity, whereas disease severity had no significant impact on development of depressive symptoms and anxiety.

Interstitial Lung Disease in Systemic Sclerosis

We reviewed the literature concerning pathogenesis, clinical features, diagnosis and treatment of interstitial lung disease (ILD) in patients with systemic sclerosis (SSc). ILD is detectable in approximately 70% of patients at autopsy. Nonspecific interstitial pneumonia (NSIP) is the most common pathologic finding. The earliest phase of ILD in SSc is characterized by microvascular injury and alveolitis. Endothelial lesions, activation of coagulation proteases, especially thrombin, fibroblast proliferation, and differentiation of normal lung fibroblasts to a myofibroblasts phenotype are hallmarks of ILD in SSc. Diagnostic procedures used to detect ILD are chest X-ray, high-resolution computed tomography, bronchoalveolar lavage, lung function tests, and sometimes thoracoscopic lung biopsy. Novel and potentially useful methods to diagnose ILD in SSc are induced sputum and technetium-labeled diethylenetriamine pentaacetate (99mTC-DTPA) clearance time. Cyclophosphamide seems to be relatively effective to treat ILD in the earliest phase, but the effects of other immunosuppressive drugs on the lungs are less convincing.

Indices of the Scleroderma Assessment Questionnaire (SAQ) can be used to demonstrate change in patients with systemic sclerosis over time

OBJECTIVE This study aims to estimate the value of the Scleroderma Assessment Questionnaire (SAQ) to demonstrate change in patients (pts) with systemic sclerosis (SSc) over time. METHODS Sixty pts with SSc were evaluated at two occasions, 12 months apart. Pts were divided into three subgroups according to criteria of improved, unchanged or deteriorated status of vascular, respiratory, gastrointestinal and musculosceletal system. All pts filled in the SAQ as part of both evaluations, and the Index of Vascular Status (IVS), Index of Respiratory Status (IRS), Index of Gastrointestinal status (IGS) and Index of Musculoskeletal Status (IMSS) were calculated. Average index scores for particular organ system at the beginning and after the follow-up period in all subgroups of pts were compared. RESULTS The mean value of IVS decreased significantly in pts with objectively improved vascular status (1.91 vs. 1.29, p=0.01), but increased in pts with deteriorated status (1.54 vs. 2.13, p=0.003). In the subgroup of pts with unchanged vascular morphology or function, the IVS did not change significantly either (1.84 vs. 1.77, p=0.36). The mean value of IRS decreased significantly in pts with objectively improved lung function (1.08 vs. 0.62, p=0.027), and increased in pts with deteriorated function (0.69 vs. 1.12, p=0.012). In the subgroup of pts with unchanged pulmonary function, the IRS did not change significantly (0.13 vs. 0.14, p=0.18). A statistically significant decrease in mean IGS value was found in pts who were treated with prokinetics (1.20 vs. 0.70, p<0.001). In pts who were not treated with prokinetics, an increase of IGS was observed (0.58 vs. 0.76, p=0.002). Differences between mean values of the IMSS were statistically significant in subgroups of pts with improved (1.28 vs. 0.90, p=0.004) or deteriorated musculoskeletal status (0.98 vs. 1.44, p=0.012), but not in pts with unchanged condition of this organ system (0.72 vs. 0.68, p=0.498). CONCLUSION The SAQ is a sensitive measurement to demonstrate change in patients with SSc over time.

Induced sputum in systemic sclerosis interstitial lung disease: comparison to healthy controls and bronchoalveolar lavage.

Background: Induced sputum (IS) is a noninvasive tool, which can be used to collect cellular and soluble materials from lung airways. Objective: To evaluate if IS may be a useful and safe tool for the detection of airway inflammation in patients with interstitial lung disease (ILD) in systemic sclerosis (SSc). Methods: Sixty-eight patients with SSc and ILD as well as 18 healthy individuals (controls) were selected and submitted to IS examination. In 34 of 68 patients with SSc, bronchoalveolar lavage (BAL) was also performed. Safety of IS was assessed by comparison of forced expiratory volume in the first second (FEV1), FEV1/forced vital capacity ratio and peak expiratory flow before and after the IS procedure. Cell composition in samples collected by BAL and IS was correlated, and IS total and differential cell count in SSc patients and controls were compared. Results: The total number of cells was significantly higher in IS samples of SSc patients compared to those of healthy controls. Mean percentage of neutrophils was also higher in SSc patients (41.79 ± 23.89 vs. 27.37 ± 17.90), as well as lymphocytes (17.42 ± 19.70 vs. 3.13 ± 2.28) and eosinophils (2.35 ± 4.43 vs. 0.41 ± 0.46). On the other hand, mean percentage of macrophages was higher in healthy individuals (69.10 ± 19.15 vs. 36.96 ± 20.68). In fluid recovered by BAL, the most frequent cells were macrophages (67.89% ± 17.26), while neutrophils (14.77 ± 17.18%) and lymphocytes (15.62 ± 13.46%) were less frequent and eosinophils (1.66 ± 2.08%) were rare. A similar pattern of cell composition was found in IS samples (41.15 ± 21.67% of macrophages, 39.72 ± 23.15% of neutrophils, 15.28 ± 19.46% of lymphocytes and 2.56 ± 5.03% of eosinophils). Strength of correlation between BAL and IS was significant for macrophages and neutrophils. After IS procedure was performed, improvement of FEV1 (mean value before IS was 85.09 ± 14.44 and 88.93 ± 16.40 after IS) and FEV1/forced vital capacity (mean value before IS was 98.53 ± 12.11 and 105.22 ± 10.78 after IS) was observed. Conclusion: The IS method may allow a noninvasive assessment of cell composition in airway fluid and may contribute to the better understanding of upper/medium airway inflammation in SSc. Future studies are needed to verify whether IS can replace invasive procedures for the detection and monitoring of lung inflammation in SSc.

Cryoglobulinemic vasculitis in systemic sclerosis successfully treated with mycophenolate mofetil

Cryoglobulinemic vasculitis is extremely rare in patients with systemic sclerosis (SSc). So far, only two cases of cryoglobulinemic vasculitis in SSc were described in the literature. This report is about a patient with SSc and secondary Sjőgren’s syndrome, who developed typical clinical features of small-vessel vasculitis, including arthritis, purpura, microhaematuria, gangrene of fingers, and toes and myocardial ischemia, in the presence of mixed cryoglobulinemia, ANA, rheumatoid factor, and anti-SSA/Ro antibodies. Symptoms and signs of vasculitis worsened despite initial treatment with corticosteroids and cyclophosphamide, but improved significantly when mycophenolate mofetil was used instead cyclophosphamide.

Managing refractory cryoglobulinemic vasculitis: challenges and solutions

Cryoglobulinemia is thought to be a rare condition. It may be an isolated disorder or secondary to a particular disease. According to immunoglobulin composition, cryoglobulinemia is classified into three types. In mixed cryoglobulinemia (types II and III), vascular deposition of cryoglobulin-containing immune complexes and complement may induce a clinical syndrome, characterized by systemic vasculitis and inflammation – cryoglobulinemic vasculitis (CryoVas). Most common clinical manifestations in CryoVas are skin lesions (orthostatic purpura and ulcers), weakness, peripheral neuropathy, Raynaud’s phenomenon, sicca syndrome, membranoproliferative glomerulonephritis, and arthralgia and seldom arthritis. In patients with mixed cryoglobulinemia, prevalence of anti-hepatitis C virus (HCV) antibodies and/or HCV RNA, detected by polymerase chain reaction (PCR), is reported to be up to 90%, indicating a significant role of HCV in the development of this condition. The goals of therapy for mixed cryoglobulinemia include immunoglobulin level reduction and antigen elimination. CryoVas not associated with HCV infection should be treated according to treatment recommendations for small-vessel vasculitides. CryoVas associated with chronic HCV infection should be treated with antivirals along with immunosuppressive drugs, with or without plasmapheresis, depending on disease severity and organ involvement. Patients who do not respond to first-line therapy may achieve remission when treatment with rituximab is started as second-line therapy. In HCV-related CryoVas, antiviral therapy should be given along with rituximab in order to achieve complete or partial remission. Moreover, rituximab has proven to be a glucocorticoid-sparing medication. Other potential therapies for refractory CryoVas include mycophenolate mofetil and belimumab, while tumor necrosis factor (TNF) inhibitors are not effective.

Cerebellar ataxia in a patient with primary Sjögren's syndrome after treatment with chloroquine.

Dear Editor, We report a 65-year-old female patient with primary Sjögren’s syndrome, who developed cerebellar ataxia during treatment with chloroquine. From 1993 to 2006 the patient was observed at the Institute of Rheumatology, Belgrade, Serbia, as having undiVerentiated connective tissue disease. Through this period she had painful joints, intermittent arthritis, recurrent urticaria and positive antinuclear antibodies (1/320). Because the diagnosis was unclear, she was treated for many years only with non-steroidal anti-inXammatory drugs (NSAID). However, in 2004 the patient started to take chloroquine 250 mg daily. Every 6 months she was advised to stop the treatment for 4 weeks and was examined by an ophthalmologist to exclude potential side eVects of the drug. In 2006, symptoms of dry eyes and mouth appeared and she was found to have positive rheumatoid factor, ANA and anti-SS-A antibodies. Schirmer’s and Rose-Bengal tests were positive. Decreased uptake and secretion of 99 m-technetium sodium pertechnetate in submandibular glands was noticed. Typical histological pattern for primary Sjögren’s syndrome (grade IV on Mason–Chisholm scale) was found after minor salivary gland biopsy [1]. The patient continued to take chloroquine and NSAID. In March 2007, she presented with transitory right-side hemiparesis, which appeared 1–2 times a week, lasting for about 2 h. She felt very unstable when walking. No headache or unconsciousness was reported. Apart from Sjögren’s syndrome, she had also a history of arterial hypertension for about 8 years and peripheral paralysis of the left facial nerve in 2005. A cerebrovascular insult due to hypertension or cerebral vasculitis as clinical feature of Sjögren’s syndrome was expected, but endocranial CT scan revealed extensive cortical atrophy in the frontal part of the brain, as well as atrophy of the cerebellum and vermis. The patient was hospitalized and further examined at the Institute of Neurolgy, Belgrade, Serbia. Ataxia, right-side bradyteleokinesis and hypodiadochokinesis were observed. Cranial nerves were found to be normal, except a residual paresis of the left facial nerve. Muscular hypotonus on both the arms was present, with symmetrically increased reXexes. Patient’s right arm sunk and set below the left arm, when Wartenberg pendulum test was performed. Muscular tonus and deep tendon reXexes on legs were normal. Paraneoplastic syndrome and dysfunction of the thyroid gland, as possible causes of brain atrophy, were excluded. Laboratory results (including analysis of the cerebrospinal Xuid), chest X-ray and abdominal ultrasound Wndings were normal. After complete examination, idiopathic cerebellar ataxia with late onset was diagnosed. Treatment with chloroquine was stopped. Despite treatment discontinuation, neurological Wndings were unchanged. In February 2008, the patient underwent endocranial MRI, which revealed cortical atrophy in the frontoparietal part of the brain, in the cerebellum (especially in the left hemisphere) and vermis, with consequently dilatation of the ventricular system and subarachnoid space. The patient is now treated with vitamins and Aspirin 100 mg daily. She continued to take artiWcial tears and NSAID. It is believed that chloroquine is a relatively safe drug, but it is necessary to examine patients for potential side V. Milic Clinical Rheumatology IVb, Institute of Rheumatology, Belgrade, Serbia

FRI0405 Prevalence, clinical correlates and possible causes of neuropathic pain in patients with systemic sclerosis

Objectives To assess prevalence, possible causes and clinical correlates of neuropathic pain (NP) in patients with systemic sclerosis (SSc). Methods In 42 patients with SSc, presence of NP was assessed using the PainDetect questionnaire and subsequently confirmed by neurological evaluation. Patients with previously diagnosed neurological disorders and diabetes were excluded. Relationship between NP and disease status, symptoms of depression and quality of life was estimated. Index of disease status (IDS) was assessed using the Scleroderma Assessment Questionnaire (SAQ), occurrence of depressive symptoms by the Becks Depression Inventory (BDI), whilst quality of life was evaluated using the EQ-5D index. In order to evaluate possible causes of NP in SSc, all patients with NP, except one (who did not agree with further assessments) underwent detailed neurological and electroneurography (ENG) examination, as well as HgbA1C and vitamin B12 level testing. Results 12/42 (28.6%) of patients were found to have NP. Patients with and without NP were similar in age and disease duration. NP was found more frequently in patients with lcSSc (32.3%), than in dcSSc (18.2%), as well as in patients with ACA (46.7%) compared to patients with ATA (17.6%) and both ACA and ATA negative patients (20%), but the differences were not statistically significant. Patients with NP had significantly higher mean values of IDS (1.28 vs 0.66) and BDI (18.3 vs 9.9) than patients without NP (p<0.01). Mean value of the EQ-5D index was significantly lower in patients with NP (0.39 vs 0.79, p<0.01). Patients with NP had significantly higher mean value of Index of vascular status, then patients without NP (2.26 vs 1.36, p=0.02). HgbA1C and vitamin B12 levels were normal in all SSc patients with NP. Clinical signs of polyneuropathy were noticed in 10 patients by neurological evaluation. Typical symmetric glove-and-stocking hyperesthesia was found in 10/11 (90.9%) of SSc patients with NP, along with symmetric hyporeflexia in 6/11 (54.5%) patients on lower, and 7/11 (63.6%) on upper extremities. None of patients had allodynia, but impaired vibratory sensibility was found in all patients with NP. Clinical signs of radiculopathy were present in 6 patients. Hypoesthesia was registered in typical dermatomes in 6/11 (54.5%) of patients, with asymmetric hyporeflexia in 2/11 (18.1%) patients on lower, and none of patients on upper extremities. Despite the fact that almost every patient had symptoms and signs suggesting polyneuropathy, in only four of them demyelinating polyneuropathy was detected by ENG. Conclusions NP is common in patients with SSc. Presence of NP is associated with more severe SSc, symptoms of depression and worse quality of life. Almost all SSc patients (90.9%) with NP have typical symptoms and signs for polyneuropathy. However, in only few of them polyneuropathy could be detected by ENG. This finding suggests that pure small-fiber polyneuropathy, which is not detectable by ENG, may be the cause of NP in most of patients. Disclosure of Interest None declared