Sinead Harney

Cyclophosphamide-refractory scleroderma-associated interstitial lung disease: remarkable clinical and radiological response to a single course of rituximab combined with high-dose corticosteroids.

We would like to report our experience of using rituximab in cyclophosphamide refractory, rapidly progressive interstitial lung disease (ILD) in a patient with limited scleroderma. A 40-year-old man presented with 10-week history of inflammatory polyarthritis, which responded to a short course of oral corticosteroids. However, 3 weeks later, he developed new onset of exertional dyspnoea. High-resolution CT of the thorax was suggestive of early ILD. Surgical lung biopsy showed features of fibrotic non-specific interstitial pneumonia. He was diagnosed with scleroderma on the basis of: presence of anticentromere antibodies, Raynaud’s phenomenon, pulmonary fibrosis, digital oedema and hypomotility along with a dilated oesophagus. He was treated aggressively with pulse doses of corticosteroids and cyclophosphamide; however, his ILD continued to deteriorate. At this stage, he received rituximab (two pulses of 1 g each), which led to a gradual clinical improvement. Now, 12 months since his rituximab infusion, he walks 2 miles daily without any exertional dyspnoea.

Successful control of scleroderma myocarditis using a combination of cyclophosphamide and methylprednisolone.

Myocarditis is a rare but life-threatening complication of systemic sclerosis (SSc). Here we present the case of a 38-year-old man who presented with rapidly progressive diffuse cutaneous systemic sclerosis (dcSS) with skin, gastrointestinal, lung, and cardiac involvement in the form of myocarditis. His myocarditis has been successfully controlled with pulsed intravenous (IV) cyclophosphamide and methylprednisolone. Serial cardiac magnetic resonance imaging (MRI) scans have demonstrated disease stability in the interim. The 38-year-old male, a landscape gardener, presented with a 6-month history of arthritis affecting the small joints of his hand, Raynaud’s disease, and sclerodactyly. Blood pressure and urinanalysis were normal. Antinuclear antibody (ANA) and anti-Scl-70 antibody tests were positive. Rheumatoid screen was negative. The clinical impression was that of early dcSS and the patient was commenced on a calcium channel blocker and prednisolone 20 mg once daily. The patient’s disease progressed rapidly, with skin tightness developing over the face, chest wall, back, forearms, and hands. Suspected oesophageal dysmotility was confirmed by oesophageal manometry. Renal indices remained normal. In September 2008 the patient developed exertional dyspnoea. Pulmonary function tests, echocardiogram, and right heart catheterization were normal. High-resolution computed tomography (CT) of the thorax showed no evidence of pulmonary fibrosis but did reveal extensive mediastinal lymphadenopathy. Lymph node and lung biopsy were obtained by video-assisted thorascopic surgery (VATS). Histology revealed reactive lymphadenopathy and desquamative interstitial pneumonitis indicating early pulmonary involvement of SSc. Shortly after the VATS procedure the patient developed chest pain at rest, elevated cardiac enzymes (creatine kinase 494 U/L), troponin leakage (troponin T 0.39 μg/L), and intermittent atrio-ventricular re-entrant tachycardia. Coronary angiogram was normal. A cardiac MRI was obtained that demonstrated normal ventricular function and no obvious abnormal subendocardial enhancement (Figure 1). Although symptoms initially settled they recurred over the following 6 weeks with further chest pain at rest, recurrent dysrhythmias, persistently raised cardiac enzymes, and troponin leakage that proved refractory to treatment with oral steroids and anti-arrhythmic agents. A repeat cardiac MRI 6 weeks after the previous MRI showed a deterioration of ventricular function with a right ventricular ejection fraction of 25% and a left ventricular ejection fraction of 39%. In addition, abnormal subendocardial enhancement was noted in the left ventricular papillary muscle and the right ventricular trabeculum septum marginale (Figure 1). The MRI findings confirmed the clinical impression of an acute myocarditis secondary to SSc and the patient was commenced on pulsed IV cyclophosphamide (10 mg/kg monthly). Unfortunately, cardiac enzymes remained persistently elevated 3 days following the start of treatment indicating ongoing myocarditis. Intravenous methylprednisolone was therefore added to the regimen (0.5 mg/kg given for 3 days each month with a maintenance dose of prednisolone 70 mg given once daily between cycles). Immediately following the commencement of IV methylpednisolone, cardiac enzymes began to return to normal. To date, the patient has received a total of nine doses of cyclophosphamide and three courses of methylprednisolone. Treatment has resulted in resolution of the patient’s symptoms. The patient remains in sinus rhythm, is normotensive, and troponin T and creatine kinase have normalized. Repeat echocardiogram 5 months after the start of treatment showed an improvement of left ventricular function with an ejection fraction of 50%. In addition, repeat cardiac MRI after three cycles of cyclophosphamide showed no progression of cardiac muscle enhancement (Figure 1). At 9 months post-initiation of treatment, the patient has had no further admissions to hospital. It should be noted that although we were aware of the potential complication of renal crisis using high doses of steroid, the risk of ventricular fibrillation secondary to myocarditis was deemed to be a greater risk. As prophylaxis, the patient was commenced on a low-dose angiotensin-converting enzyme (ACE) inhibitor prior to the initiation of steroid and the patient has never manifested any signs of renal disease. The steroid dosage was weaned after 3 months to a maintenance dose of prednisolone 20 mg once daily. The plan is for the patient to complete a total of 12 Sc an d J R he um at ol D ow nl oa de d fr om in fo rm ah ea lth ca re .c om b y U ni ve rs ity C ol le ge C or k on 1 2/ 22 /1 4

Cogan’s syndrome: present and future directions

Cogan’s syndrome, typified by the combination of interstitial keratitis and immune-mediated sensorineural hearing loss, is a rare condition, and commonly associated with a diagnostic delay. Using a standard search protocol, we review the literature to date, focusing on a number of key areas pertaining to diagnosis, presentation and treatment. Using a case illustration of atypical disease which led to fulminant aortic regurgitation, we highlight the need for continued and collaborative research in order to identify negative prognostic factors and thus tailor therapeutic regimens. Atypical Cogan’s syndrome is more commonly associated with systemic manifestations than typical disease, and may be refractory to immunosuppressive treatment. We discuss the application of laboratory (e.g antibodies targeting inner ear antigens) and radiological (PET-CT) aids to disease confirmation and detection of sub-clinical vascular inflammation. As illustrated by the included case description, some patients remain refractory to intense immunosuppression and delineation of adverse prognostic factors which may direct treatment, perhaps including the use of PET-CT, will contribute in the future to improving patient outcomes

Generalized subcutaneous edema as a rare manifestation of dermatomyositis: clinical lesson from a rare feature.

Generalized subcutaneous edema is a very rare manifestation of inflammatory myopathies. A 61-year-old woman presented with classic signs and symptoms of dermatomyositis. She was also noted to have generalized edema that was so florid that an alternative diagnosis was considered. Her disease was resistant to corticosteroids, azathioprine, and mycophenolate mofetil. Intravenous administration of immunoglobulins was started because of marked worsening of her disease-muscle weakness, generalized anasarca, and involvement of her bulbar muscles. This led to dramatic resolution of her subcutaneous edema and significant improvement of her skin and muscle disease. As the initial screen for malignancy was negative, a positron emission tomography-computed tomography scan was requested, which interestingly showed a metabolically active cervical tumor. Anasarca is an unusual manifestation of dermatomyositis. In treatment-refractory cases, it seems reasonable to consider positron emission tomography scan in excluding underlying malignant disease.

Molecular genetics of rheumatoid arthritis.

Following the successful determination of the molecular genetics of single-gene disorders, attention has not surprisingly turned to complex genetic disorders. However, preliminary experience suggests that unravelling the genetic component of common inflammatory disorders, such as rheumatoid arthritis, multiple sclerosis and systemic lupus erythematosus, might be a harder nut to crack.

Polyarteritis nodosa presenting with clinical and radiologic features suggestive of polymyositis.

We report a patient who presented with clinical and MRI findings suggestive of polymyositis but, in whom, muscle biopsy disclosed a strikingly different diagnosis. A 65-year-old woman presented with 3-week history of bilateral proximal muscle pain and weakness. Laboratory investigations showed markedly elevated inflammatory markers and mildly elevated muscle enzymes. MRI scans of lower limbs showed features suggestive of polymyositis. However, muscle biopsy showed features of a polyarteritis-type vasculitis affecting an intramuscular blood vessel. Our reports highlight the critical role of muscle biopsy in establishing the correct diagnosis in patients with suspected myositis.

Systemic listeriosis with adalimumab therapy.

Systemic listeriosis is caused by infection with the gram-positive, facultative intracellular rod Listeria Monocytogenes. Although infection is rare, it is a well-known cause for concern in particular subgroups, such as pregnant females and the immunocompromised patient population. In the latter, infection may manifest as meningoencephalitis or sepsis, in contrast with the more nonspecific symptoms of malaise, gastrointestinal disturbance, and lymphadenopathy, which are more typical of the immunocompetent host. Tumor necrosis factor alpha (TNF ) plays a pivotal role in both the pathogenesis of rheumatoid arthritis, and in host defense. The use of the TNF inhibitors, infliximab, etanercept, and adalimumab have indeed, lead to significant improvements in disease control in both early and refractory rheumatoid arthritis. There remains debate, however, surrounding the accompanying potential increase in severe infections. Biologically, TNF plays an important role in innate immunity and is essential for granuloma formation and maintenance. This is of particular importance in the case of infection with intracellular pathogens, such as Mycobacterium Tuberculosis, histoplasmosis, and L. Monocytogenes. Although the increased incidence of reactivation of latent tuberculosis is now well reported with all 3 anti-TNF agents, in particular, infliximab, there also appears to be a small but increased risk of listeriosis in this patient cohort. Here, we describe the case of a 58-year-old lady who developed systemic listeriosis within the first 6 months of adalimumab commencement. A 58-year-old woman was diagnosed with seropositive rheumatoid arthritis in 2000, presenting at that time with a 10-month history of pain and swelling in the small joints of her extremities. Her history of subsequent disease modifying therapy includes an initial trial of hydroxychloroquine owing to patient choice and a lack of erosive disease. With ongoing evidence of disease activity, methotrexate was introduced in conjunction with intermittent lowdose corticosteroids. Despite an initial response to both diseasemodifying antirheumatic drugs, she had recurrent flares of arthritis, leading to the initiation of adalimumab in February of 2006. Although, this led to a significant improvement in both clinical and laboratory markers of disease, she presented to the emergency department 5 months after anti-TNF commencement, with a 3-day history of severe diarrhea and vomiting in conjunction with a pyrexia of 38°C. At this time her immunosuppressive medications included adalimumab 40 mg fortnightly, methotrexate 10 mg weekly, and Deltacortril 12.5 mg once daily. On admission, she was hypovolemic, hypotensive, and tachycardic with ongoing gastrointestinal symptoms. She had no signs or symptoms of meningism throughout the duration of her illness. Although stool cultures did not show growth of significant pathogens, cultures of blood samples taken on admission showed growth of L. Monocytogenes on day 3. She was treated with a combination of high-dose ampicillin (2 g, 3 times a day) and gentamicin which was continued for a duration of 2 weeks. This treatment regimen led to a rapid resolution of both gastrointestinal and systemic symptoms with discharge shortly upon completion of antibiotic therapy. She remains well and her arthritis is currently controlled with a combination of methotrexate and minimal maintenance dose of corticosteroid. This represents the second reported case of listeria infection in a patient receiving adalimumab for the treatment of rheumatoid arthritis. On review of the literature, only one previous case with this, the most recent of the anti-TNF medications to come to the market, was found. That patient was identified through the British Society for Rheumatology Biologics Register and presented with septic arthritis. There have, however, been a number of case series reporting an increased incidence of infection with both etanercept and infliximab. Using data from postmarketing surveillance, through the US Food and Drug Administration, both Slifman et al and Wallis et al have published case series reporting the incidence of listerial infections in patients receiving TNF inhibitors. The former reported on 15 cases, and the latter 38 cases, during a 4-year period. Both series found that the incidence of infection was increased in patients where the treatment indication was rheumatoid arthritis, and when infliximab was the anti-TNF of choice. The reason for the discrepancy with, for example inflammatory bowel disease, is unclear but may reflect differences in concurrent immunosuppression or infection risk relating to the underlying disease. When compared with annual incidence rates of listeria infection in the general population the rates were as follows: 0.5 per 100,000 in the general population; 15.5 per 100,000 in those receiving infliximab, and 1.8 in those receiving etanercept. Although the most common presentation in these patient series was either sepsis or meningitis, there have been a number of cases of listerial infection manifesting as septic arthritis. This is an important point as the standard treatment regimen for septic arthritis is inadequate for listerial joint infection. Hence, this should be borne in mind, in particular, in patients on biologic therapy, who are not responding to standard antimicrobials or who have additional risk factors. The incidence of infection was not characterized in adalimumab under the encompass of these studies as it did not receive licensing until after the study completion dates in 2002. Although, the incidence of listeriosis appears to be lower on this TNF inhibitor, it should be noted that this is the most recently licensed and further study is required to ascertain the comparative risk of nontuberculous granulomatous infections with this agent. This case highlights the need for increased vigilance for intracellular organisms as a cause of infection in all patients receiving anti-TNF therapy. It also raises the question of whether we should advise our patients who are receiving such treatment to avoid foods that are potential sources of this organism such as soft cheeses, unpasteurized milk, etc. Nonetheless, early recognition and consideration of this organism as a cause of infection is necessary to direct treatment and to reduce the morbidity and mortality associated with this disease. Finally, it should be noted that although most cases of listeriosis in patients receiving biologic therapy occur in those receiving infliximab therapy, vigilance is warranted in all patients receiving TNF-targeting therapies. From the *Department of Rheumatology, Cork University Hospital, Wilton, Cork, Ireland; and †St. Vincent’s University Hospital, Dublin, Ireland. Correspondence: Grainne Murphy, MB, MRCPI, Department of Rheumatology, Cork University Hospital, Wilton, Cork, Ireland. E-mail grainne.murphy@ucc.ie. Copyright

Using the maternal-fetal genotype incompatibility test to assess non-inherited maternal HLA-DRB1 antigen coding alleles as rheumatoid arthritis risk factors

Non-inherited maternal antigens encoded by specific HLA-DRB1 alleles (NIMA) have been implicated as a rheumatoid arthritis (RA) risk factor. Using genotype data from North American Rheumatoid Arthritis Consortium study participants and the maternal-fetal genotype incompatibility (MFG) test, we find evidence for offspring allelic effects but no evidence for NIMA as a RA risk factor. We discuss possible reasons why our result conflicts with several previous studies (including one of our own) that used RA patients from northern Europe.

A case of severe pulmonary infiltration with eosinophilia (PIE) syndrome induced by sulphasalazine

Dear Editor, Abnormal pulmonary radiologic features are not uncommon among patients with rheumatoid arthritis, and drug-related pulmonary disease is an important consideration in the differential diagnosis of such patients. However, many of the pulmonary reactions to drugs used for the treatment of rheumatoid arthritis are rare, with only case reports to support the potential association. Radiologic pulmonary infiltration may be associated with eosinophilia of the peripheral blood, and when this association occurs, the descriptive term ‘pulmonary infiltration with eosinophilia’ (PIE syndrome) is used; and sulphasalazine is implicated in this adverse pulmonary reaction. Here, we present a patient with inflammatory arthritis who developed PIE syndrome with sulphasalazine use, and this recovered completely with sulphasalazine withdrawal and the introduction of oral corticosteroids. A 53-year-old man presented in August 2008 with inflammatory arthritis involving his hands, shoulders and knee joints. Laboratory evaluation revealed raised inflammatory markers and negative tests for rheumatoid factor, anti-cyclic citrullinated peptide antibody (anti-CCP) antibodies and anti-nuclear antibodies. He had a significant improvement of his inflammatory arthritis with a short course of oral corticosteroids, and sulphasalazine was added. However, he re-presented in 6 weeks time with a 3-day history of exertional dyspnea. He was found to be tachypnic (respiratory rate of 22/min) along with low blood oxygen levels – arterial oxygen pressure (PaO2) of 9.1 kPa (range 10–13.3) and oxygen saturation of 92% on room air. His sulphasalazine was put on hold. Serum anti-neutrophil cytoplasmic antibodies, brucella antibodies, viral hepatitis serology and HIV serology was negative. Tuberculin skin test, repeated sputum acidfast bacilli and cultures were found negative. Chest X-ray and high-resolution computed tomography (HRCT) of the thorax revealed new reticulonodular changes throughout both lung fields, and there were no pathologically enlarged mediastinal or hilar lymph nodes. A note was made of persistent serum eosinophilia (0.6 · 109/L, range 0.04–0.4 · 109/L). He had bronchoscopic examination and infective aetiologies, especially tuberculosis and Pneumocystis carinii, were out ruled. Subsequently, mediastinoscopy and videoassisted thoracic surgical (VATS) biopsy was carried out to exclude other causes of rapidly progressive interstitial lung disease, and as an additional support for our clinical suspicion of drug-induced lung disease. Examination of tissue specimens demonstrated filling of bronchiolar structures with foamy histiocytes together with focal fibrous plugs, peribronchiolar fibrosis in association with occasional giant cells, and a patchy bronchiolocentric distribution of mononuclear cells. The diagnosis of hypersensitivity pneumonitis was made on the basis of clinicopathological, radiological and relevant microbiological correlation. Oral corticosteroids were introduced and he made significant improvement with gradual normalization of his exercise tolerance and serum eosinophil levels. Moreover, his repeat chest X-ray and HRCT has confirmed almost complete resolution of reticulonodular changes (Fig. 1). In the meantime, his inflammatory arthritis was treated with maintenance oral steroids; however, any attempt to reduce steroids below 10 mg/ day would lead to flare of his synovitis. He could not tolerate leflunomide because of development of hypertension. In November 2009, it was decided to commence him on etanercept, which led to complete resolution of his inflammatory arthritis, and there has been no recurrence of his respiratory symptoms or radiological abnormalities. Sulphasalazine is probably the second most common disease-modifying anti-rheumatic drug (DMARD) used and it is often the drug of choice in milder disease. Pulmonary disease associated with sulphasalazine most commonly presents with new onset dyspnoea and abnormal chest radiography. The pulmonary toxicity related to sulphasalazine is caused by International Journal of Rheumatic Diseases 2012; 15: e150–e152

Spontaneous pneumomediastinum in a patient with anti-centromere antibody-positive limited scleroderma.

T he patient, a 40-year-old man, presented to our rheumatology outpatient department with increasing pain and swelling of the small joints of hands and wrists, and painful and stiff knees and ankles. He also experienced profound early morning stiffness, which lasted for 2 hours. Apart from Raynaud phenomenon and gastroesophageal reflux disease, there were no features to suggest connective tissue disease. Examination revealed synovitis affecting his wrists and multiple metacarpal phalangeal joints. On laboratory tests, he had negative anti/cyclic citrullinated peptide antibodies, positivity for antinuclear antibodies and anti/centromere antibodies, and mildly raised inflammatory markersVC-reactive protein of 42 mg/L (reference range, 1Y10 mg/L) and ESR of 29 mm/hr (reference range G30 mm/hr). He was commenced on oral corticosteroids. However, within a month, he presented with a new development of exertional dyspnea. Further investigations in May 2009 (high-resolution computed tomography [CT] scan of the thorax, pulmonary function tests, mediastinoscopy, and video-assisted thoracic surgery lung biopsy) revealed that he had an underlying interstitial cellular and fibrotic process highly suggestive of nonspecific interstitial pneumonia; this was considered pulmonary involvement (interstitial lung disease) because of scleroderma. He was then diagnosed with scleroderma on the following basis: the presence of disease-specific autoantibodies (anti/centromere antibodies), Raynaud phenomenon, pulmonary fibrosis, and dilated esophagus. Oral corticosteroids (1 mg/kg) and intravenous monthly cyclophosphamide for scleroderma-associated interstitial lung disease were administered. In September 2009, he presented with sudden worsening of his exertional dyspnea. Chest x-ray showed no acute deterioration. High-resolution CT of the thorax was requested, and to our surprise, this showed free air in the anterior and middle mediastinum. He was diagnosed to have spontaneous pneumomediastinum, and this resolved completely on conservative management with bed rest, supplemental oxygen, analgesia, and close observation (Fig.). Spontaneous pneumomediastinum is typically a benign and self-limited disorder. Dyspnea, as in our case, is one of the common symptoms; this may be due to associated chest discomfort, which typically is worsened by inspiratory maneuvers. Spontaneous pneumomediastinum can mimic the worsening of associated disease, such as interstitial lung disease. Chest radiographs and CT scans are important in confirming the diagnosis of spontaneous pneumomediastinum. In such cases, the mainstay of management remains conservative, and once resolved, no restriction in physical activity is required. Although, few cases of spontaneous pneumomediastinum as a complication of systemic scleroderma (antiYscl-70 positive) have been reported, this is the first reported case of spontaneous pneumomediastinum in a patient with limited scleroderma with anti/centromere antibodies. In addition to the development or worsening of interstitial lung disease and/or pulmonary hypertension, new-onset dyspnea in a patient with scleroderma should prompt evaluation for other causes. For example, in our patient, acute worsening of dyspnea was attributed to development of spontaneous pneumomediastinum. Moreover, as our patient had rapidly progressive pulmonary fibrosis, this pneumomediastinum is likely secondary to the rupture of subpleural cysts. The patient developed pneumomediastinum 4 months after undergoing lung biopsy, so it is highly unlikely that the procedure would have caused the pneumomediastinum. Similarly, there was no evidence of esophageal rupture causing this pneumomediastinum. This case highlights the importance of considering spontaneous pneumomediastinum in the differential diagnoses of sudden worsening of dyspnea in a patient with scleroderma. Spontaneous pneumomediastinum should be considered as a possible alternative in a patient with sudden worsening of dyspnea in a patient with scleroderma. From the Departments of *Rheumatology, †Radiology, and ‡Respiratory Medicine, Cork University Hospital, Cork, Ireland. Correspondence: Muhammad Haroon, MB, MMedSc, MRCPI, Department of Rheumatology, Cork University Hospital, Cork, Ireland. E-mail: mharoon301@hotmail.com. Copyright * 2010 by Lippincott Williams & Wilkins ISSN: 1076-1608/11/1701Y0042 DOI: 10.1097/RHU.0b013e3182055d5e FIGURE. Axial high-resolution chest CT images from September 2009 (series A), October 2009 (series B), and May 2010 (series C). Images from series A demonstrate gas in the anterior and middle mediastinum. Subsequent images (series B and C) show a successive decrease in volume of pneumomediastinum with no residual gas in series C. CONCISE REPORT