Doron Markovits

Vitamin D, Parathyroid Hormone, and Acroosteolysis in Systemic Sclerosis

Objective Sclerodactyly with acroosteolysis (AO) and calcinosis are prominent features of systemic sclerosis (SSc), but the pathogenesis of these findings is poorly understood. Vitamin D and parathyroid hormone (PTH) have a crucial role in bone metabolism and resorption and may affect AO and calcinosis. We assessed vitamin D and PTH in patients with SSc. Methods Medical records of 134 consecutive patients with SSc (American College of Rheumatology criteria) followed at the rheumatology department during the years 2003–2006 were reviewed for clinical assessment, laboratory evaluation [including 25(OH) vitamin D, calcium, phosphorus, alkaline phosphatase, PTH, creatinine, and albumin]; imaging data confirming AO and/or calcinosis. Patients followed routinely at least once a year were included (81 patients). Of these, 60 patients’ medical records were found to have complete, relevant clinical, laboratory, and radiographic imaging. Results Thirteen patients had diffuse disease and 47 limited disease — 51 women and 9 men, 44 Jews and 16 Arabs; mean age 55 ± 14 years; disease duration 8 ± 6 years. AO with or without calcinosis was observed in 42 patients (70%). Vitamin D deficiency was found in 46% of patients (16 out of 44 Jewish patients, 10 out of 16 Arab patients). PTH was elevated in 21.7% of patients. Significant correlations were observed between acroosteolysis and PTH (p = 0.015), calcinosis (p = 0.009), and disease duration (p = 0.008), and between PTH and vitamin D levels (p = 0.01). All patients had normal serum concentrations of calcium, phosphorus, magnesium, and albumin, and liver and kidney functions. Conclusion In this group of Mediterranean patients with SSc, the incidence of vitamin D deficiency and secondary hyperparathyroidism was surprisingly high. This finding correlated with the occurrence of AO and calcinosis. Low levels of vitamin D may reflect silent malabsorption and might be a risk factor for secondary hyperparathyroidism and bone resorption. Traditional dress habits and low exposure to sun may contribute to vitamin D deficiency in an Arab population but do not explain all the findings. The pathogenesis of these findings needs to be corroborated in other SSc populations.

Relapse of rheumatoid arthritis after substitution of oral for parenteral administration of methotrexate

We read with interest the letters: “Is parenteral methotrexate worth trying?” by Osman and Mulherin1 and “Intramuscular methotrexate in inflammatory rheumatic disease” by Burbage, Gupta, and Lim.2 We would like to present our findings, which indicate that parenteral methotrexate (MTX) may be more efficient than oral MTX at the same dose and in the same patients with inflammatory joint disease. During the second half of 2000 we were faced with an unexpected shortage of parenteral MTX (ABIC, Israel) which lasted for more than five months, and patients were switched to oral MTX (Lederle, Germany). This gave us the opportunity to evaluate the difference in efficacy of parenteral versus oral administration of low dose MTX. Eight patients (seven female) with a mean age of 55 (38–70) years, who fulfilled the following criteria, were analysed retrospectively: ( a ) all had inflammatory joint diseases (four seropositive rheumatoid arthritis (RA), two seronegative RA (revised American Rheumatism Association criteria for RA), and two RA-like psoriatic arthropathy); ( b ) all were receiving parenteral MTX and were in complete clinical remission (fulfilling at least five of six …

Pulmonary Arteries Involvement in Takayasu's Arteritis: Two Cases and Literature Review

OBJECTIVES To review pulmonary arteritis (PA) complicated by pulmonary arterial hypertension (PAH) in Takayasus arteritis (TA). METHODS Two cases of PA and PAH in TA patients and similar cases published in the Medline database from 1975 to 2009 were reviewed. RESULTS Forty-six cases (females 89.1%, Asians 65%, mean age 34.6 years) were analyzed, 42.2% of which had PAH. Isolated PA was reported in 31.8%. Respiratory symptoms were presented as dyspnea (75.5%), chest pain (48.9%), hemoptysis (42.2%), and cough (17.7%). Hypertension, vascular bruits, and diminished/absent pulses were reported in 48.9% of patients. A diagnosis of PA was based on abnormal uptake on pulmonary perfusion scan and a finding of stenosis, narrowing, occlusion, and irregularity on computed tomography or magnetic resonance imaging, and/or pulmonary angiography. Patients were treated with glucocorticoids (77.5%), disease-modified antirheumatic drugs (35%), and warfarin (20%); only a few were treated with biological agents. Vascular procedures were performed in 52.5% of cases, on pulmonary arteries in 37.5% with good results. The outcome was death in 20.5% of PA patient and 33.3% in PAH patients. CONCLUSIONS TA may be complicated by life-threatening PA and PAH. Clinical signs are not specific and may be masked by involvement of the aorta and its branches. Treatment with glucocorticoids and disease-modified antirheumatic drugs has only partial effect, which may be intensified by biological agents. Invasive procedures on pulmonary arteries may be a complementary option. PA and PAH in TA patients should be recognized early and treated promptly for prevention of irreversible vascular damage.

Depletion of B lymphocytes in rheumatoid arthritis patients modifies IL-8-anti-IL-8 autoantibody network

Cytokines and chemokines are key regulatory molecules involved in rheumatoid arthritis (RA). B-cell depletion therapy improves RA clinically but its mechanism is not completely understood. One possible mechanism for this therapy is the modification of the proinflammatory cytokine homeostasis of RA. We show here that the levels of the proinflammatory chemokine IL-8 in serum samples from RA patients unexpectedly increased by up to 100-fold 8 weeks after the administration of rituximab, despite clinical improvement. We also show that RA patients produced anti-IL-8 autoantibodies and that their levels dropped after RTX treatment. Moreover, we identified antibody-IL-8 immune complexes in the synovial fluid and serum of RA patients, and found that the amount of these complexes decreased after the administration of RTX. Our results indicate that B-cell depletion therapy modifies the cytokine-autoantibody network by reducing the levels of anti-cytokine autoantibodies and, consequentially, the formation of antibody-cytokine immune complexes.

Toe necrosis and acute myocardial infarction precipitated by a pheochromocytoma in a patient with systemic sclerosis.

Systemic sclerosis (SSc) patients typically experience Raynaud phenomena that is often complicated by digital ischemic lesions, gangrene, and digital loss. Other causes of peripheral ischemia, such as atherosclerosis, cryoglobulinemia, antiphospholipid syndrome, myeloproliferative disorders, paraneoplastic syndromes, and hyperadrenergic endocrine conditions, may be masked in SSc patients. We present a woman with limited SSc who developed toe necrosis and acute coronary events as a complication of a previously undiagnosed pheochromocytoma.

Large leg ulcers due to autoimmune diseases

Summary Background Large leg ulcers (LLU) may complicate autoimmune diseases. They pose a therapeutic challenge and are often resistant to treatment. To report three cases of autoimmune diseases complicated with LLU. Case Report Case 1. A 55-year old woman presented with long-standing painful LLU due to mixed connective tissue disease (MCTD). Biopsy from the ulcer edge showed small vessel vasculitis. IV methylprednisolone (MethP) 1 G/day, prednisolone (PR) 1mg/kg, monthly IV cyclophosphamide (CYC), cyclosporine (CyA) 100mg/day, IVIG 125G, ciprofloxacin+IV Iloprost+enoxaparin+aspirin (AAVAA), hyperbaric oxygen therapy (HO), maggot debridement and autologous skin transplantation were performed and the LLU healed. Case 2. A 45-year old women with MCTD developed multiple LLU’s with non-specific inflammation by biopsy. MethP, PR, hydroxychloroquine (HCQ), azathioprine (AZA), CYC, IVIG, AAVAA failed. Treatment for underlying the LLU tibial osteomyelitis and addition of CyA was followed by the LLU healing. Case 3. A 20-year-old man with history of polyarteritis nodosa (PAN) developed painful LLU’s due to small vessel vasculitis (biopsy). MethP, PR 1 mg/kg, CYC, CyA 100 mg/d, AAVAA failed. MRSA sepsis and relapse of systemic PAN developed. IV vancomycin, followed by ciprofloxacin, monthly IVIG (150 g/for 5 days) and infliximab (5 mg/kg) were instituted and the LLU’s healed. Conclusions LLU are extremely resistant to therapy. Combined use of multiple medications and services are needed for healing of LLU due to autoimmune diseases.

Silica-related rheumatoid arthritis without lung involvement

Abstract We report a young male with recent onset of rheumatoid arthritis (RA) in whom the remarkable severity of the disease led to additional investigations. The only significant finding was mediastinal lymphadenopathy, without lung involvement. Biopsy of the mediastinal lymph node revealed pathological findings typical of silicosis. To our knowledge, this is the first report of silicosis apparent solely in the mediastinal lymph node of an RA patient. This suggests that lung involvement is not crucial for the development of silica-related arthritis.

Safety of Corticosteroid Treatment in Rheumatologic Patients With Markers of Hepatitis B Viral Infection: Pilot Evaluation Study.

BackgroundImmunosuppressive agents may induce hepatitis B flares. The minimal corticosteroid dose and duration of therapy leading to HBV reactivation is unknown. ObjectiveTo assess whether short-term corticosteroid therapy for rheumatologic diseases induces HBV reactivation. MethodsThe records of all HBsAg or HBcore antibodies positive, anti-HBs negative patients who were hospitalized in the rheumatology department during 2001–2014 and treated with corticosteroids were reviewed. Alanine aminotransferase (ALT), HBV serology, and serum HBV DNA at baseline and 1–3 months after discharge were recorded. ResultsComplete data were found for 23 patients who were hospitalized 73 times for 7 days of treatment with IV corticosteroids. Eighteen patients were HBsAg positive. The mean methylprednisolone dose was 33.9 ± 24 mg/d. The concomitant therapy included DMARDs (15), low-dose corticosteroids (8), and biologicals (10). Serum HBV DNA was detected at baseline in seven patients. Three HBsAg-positive patients treated with cyclophosphamide had HBV hepatitis flare-up with elevated ALT. Two HBsAg-positive patients had reappearance of HBV DNA in serum after treatment with azathioprine and infliximab, respectively, but the ALT levels remained normal. Lamivudine therapy reduced the serum HBV DNA and improved ALT levels in all patients. Corticosteroid therapy by itself did not trigger exacerbation of HBV hepatitis. No HBV reactivation occurred in lamivudine-treated patients after recurrent exposure to biologicals or cyclophosphamide. ConclusionsShort episodes of corticosteroids seem to be safe in HBV carriers, even in the presence of DMARDs, but lamivudine prophylaxis should be considered for patients exposed to biologicals or cyclophosphamide. Larger prospective trials are needed to establish guidelines.

Ultrasound Imaging of Fasciitis Due to Body-Building Supplement

Background:Fascia and soft tissues, rich in collagen, receptors of pain and capable of significant distention, may be targets of autoimmune inflammatory diseases. We observed fasciitis due to the protein supplement Pure Whey, which has not been reported previously. Methods:Sonography (Sonosite-Titan, 5 to 10 MHz, L-38) was performed on a patient (age, 26 years; body mass index, 38 kg/m2) with protein fasciitis. He had developed compact swelling of his forearms, hands, and legs, with skin irregularity and severe disability (without peripheral eosinophilia, normal Ig and ESR 18/hr) after taking Pure Whey, containing L-tryptophan (1.4 g per 100 g of protein). A deep skin biopsy was performed. The thickness of the brachioradial fascia (BRF) was measured and compared with 10 healthy control subjects (men ages 36.7 ± 8.3 years; body mass index, 26.4 ± 6.5 kg/m2). Results:The deep skin biopsy showed severe fat interlobular and fascial thickening with mononuclear (noneosinophilic) infiltrate and fibrosis associated with fasciitis. BRF of the 10 healthy men had a thickness of 0.75 ± 0.19 mm, compared with the patient’s 2.4 mm thickened and cleaved BRF. After 2.5 months of corticosteroid therapy (30 mg/d with tapering) and discontinuation of the protein supplement, the patient’s BRF returned to a monolayer appearance. Its thickness reduced to normal (0.8 mm), with significant clinical improvement. Conclusions:This case of noneosinophilic fasciitis associated with ingestion of L-tryptophan–containing protein supplement responded favorably to corticosteroid therapy. Sonography proved to be an effective method to visualize and confirm the fasciitis and to follow the course and therapy.

THU0343 The effect of adalimumab on clinical manifestations and pro-inflammatory cytokines milieu in patients with behcet's disease

Background Behcets disease is a multisystemic chronic relapsing inflammatory disease, classified among the vasculitides. The aetiology of Behcets disease is unknown. Several cytokines, among them TNF-α, are involved in the pathogenesis of the disease. Objectives We aimed to assess efficacy and safety of Adalimumab (ADA) in patients with active Behcets arthritis not responding to one or more DMARDS and to assess the impact of treatment on the cytokine milieu. Methods Eligible patients (pts) with active arthritis were enrolled in a 24 weeks single center prospective open-label study. Pts who relapsed within 12 weeks following ADA discontinuation could enter a 3 year extension study. The efficacy was assessed by 68 tender and 66 swollen joint count, patient visual analogue scale (VAS) for pain, physician overall disease activity VAS, health assessment questionnaire (HAQ), Behçets Disease Current Activity Form (BDCAF), C reactive protein (CRP) and erythrocyte sedimentation rate (ESR). TNF-α,IL-1β, IL-6, INF-γ, IL-10 and IL-17a were evaluated at baseline, after 24 and 48 weeks of treatment, by ProcartaPlex Human High Sensitivity – Immunoassay kit. Trough ADA serum levels and anti-drug antibodies were measured at baseline, week 24 and 48. Results Ten pts (6 females),age (mean, standard deviation –SD) 45 (8.4) years, with a disease duration of 11.6 (10) years, were enrolled and treated with subcutaneous ADA 40mg every 2 weeks for 24 weeks. The results are described in Table1. A statistically significant improvement was observed in swollen joint count, physician VAS and BDCAF and in IL-6 levels, but not in tender joint count or HAQ. Resolution of oral and urogenital ulcers was achieved in all pts. Significant reduction of pain was reported by 40% of pts. No relapse of uveitis or other disease manifestations occurred during the study. The reduction in IL-6 levels correlated with the physician VAS and BDCAF but not with HAQ. No correlation was found between change in IL-10 level and VAS pain. The levels of INF-γ, IL-17A, TNF-α were undetectable in all pts. IL-1β was elevated in 1 patient only. ADA serum trough levels were in the therapeutic range in 7/10 pts. One patient developed high antidrug antibodies titer and ADA serum trough level of 0 with a concomitant increase in VAS pain and IL-6 concentration. Another patient with low ADA trough levels and no antibodies improved after providing ADA weekly. The disease relapsed in 9/10 pts, within 4–6 weeks following ADA interruption, 7 pts enrolled into the extension study. Baseline mean (SD) 24 weeks mean (SD) P Swollen joints 4.6 (4.2) 0.6 (0.4) 0.006 Tender joints 19 (18.7) 12.6 (10.9) Non significant (NS) Physician VAS 51.5 (18.5) 24.5 (16) 0.002 Patient pain VAS 72 (19) 56 (33) NS BDCAF 5.4 (1.6) 2.1 (1.4) 0.001 HAQ 1.76 (0.8) 1.6 (0.9) NS IL-6 pg/ml 10.06 (13.4) 2.02 (0.8) 0.042 Conclusions ADA treatment was well tolerated and achieved a significant improvement in arthritis and mucocutaneous manifestations and lowered IL-6 serum concentration in all study pts but only 40% reported significant pain reduction. A subset of pts with insufficient improvement in joint tenderness and generalized pain may require comprehensive pain management besides anti-inflammatory therapy. Acknowledgements ABBVIE donated the study medication and supported the lab work Disclosure of Interest None declared