CASE REPORT
Anti-RNA Polymerase III Antibodies in the Diagnosis of Scleroderma Renal Crisis in the Absence of Skin Disease Sankalp Virendrakumar Bhavsar, MD, FRCPC and Raj Carmona, MBBS, FRCPC ABSTRACT: Scleroderma renal crisis (SRC) occurs in approximately 10% of patients with systemic sclerosis (SSc), particularly in those with diffuse skin disease. Scleroderma renal crisis has rarely been described to occur in patients with SSc without skin involvement. Scleroderma renal crisis without skin disease represents a major diagnostic challenge, particularly in patients without overt SSc involvement of other organ systems. It closely mimics the presentation of thrombotic thrombocytopenic purpura/ hemolytic uremic syndrome, and treatment is therefore often directed at this entity. Anti-RNA polymerase III antibody testing has been previously reported to be used in 4 patients to diagnose SRC in the absence of sclerotic skin disease. We report 2 patients without skin disease or overt visceral involvement at presentation who presented with microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury. Both patients eventually developed diffuse and rapidly progressive skin thickening. Anti-RNA polymerase III antibodies were strongly positive, supporting that their renal presentations were secondary to SRC. Key Words: scleroderma, systemic sclerosis, renal crisis, TTP/HUS, anti-RNA polymerase III (J Clin Rheumatol 2014;20: 379–382)
S
ystemic sclerosis (SSc) is a multisystem connective tissue disease with the clinical hallmark of skin thickening (scleroderma). Scleroderma renal crisis (SRC), one of the most feared complications of SSc, typically affects patients with diffuse skin thickening and may therefore not be recognized in the absence of skin disease.1 The diagnostic dilemma is further compounded in patients in whom other clinical features of SSc are not present or not previously recognized. Anti-RNA polymerase III antibodies have been previously reported to be used to make a diagnosis of SRC in the absence of skin disease.2–4 Testing for anti-RNA polymerase III antibodies can be extremely valuable in making a diagnosis of SRC and to distinguish this entity from thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS). Early diagnosis of SRC is imperative to instituting appropriate therapy, including angiotensin-converting enzyme (ACE) inhibitors.
CASE 1 A 47-year-old previously healthy woman presented with a 3-month history of pain and swelling in the hands and feet. She did not have a history of Raynaud phenomenon. Examination From the Division of Rheumatology, Department of Medicine, McMaster University, Hamilton, Ontario, Canada. All authors were involved in the preparation of this manuscript. The authors did not receive any grants or other financial support for this study. The authors declare no conflict of interest. Correspondence: Sankalp Virendrakumar Bhavsar MD, FRCPC, Division of Rheumatology, Department of Medicine, McMaster University, Suite 708, 25 Charlton Ave E, Hamilton, Ontario, Canada L8N 1Y2. E-mail: sankalp. [email protected]. Copyright © 2014 by Lippincott Williams & Wilkins ISSN: 1076-1608 DOI: 10.1097/RHU.0000000000000167
revealed a blood pressure (BP) of 140/86 mm Hg and evidence of an inflammatory polyarthritis involving the metacarpophalangeal joint, proximal interphalangeal, and knee joints. There was diffuse puffiness of the fingers without skin thickening. Laboratory investigations revealed a normal complete blood count except for mild lymphopenia and a normal creatinine (57 μmol/L [0.6 mg/dL]). Rheumatoid factor and anticyclic citrullinated peptide antibodies were negative. Antinuclear antibody (ANA) was initially positive at a titer of 1:160 with negative ENA, but subsequent ANA testing by multiplex assay was repeatedly negative. She was started on hydroxychloroquine for her polyarthritis, which subsequently abated. Approximately 3 months after her initial presentation, she began feeling generally unwell and had shortness of breath. She had not developed symptoms of Raynaud phenomenon. Blood pressure was elevated at 192/110 mm Hg. Blood work revealed new anemia (82 g/L [8.2 g/dL]), thrombocytopenia (38 109/L), and renal impairment (serum creatinine 120 μmol/L [1.4 mg/dL]). Urinalysis showed 3+ blood and 2+ protein. Peripheral blood smear examination revealed schistocytes consistent with microangiopathic hemolytic anemia (MAHA). Echocardiogram revealed a small pericardial effusion. She was immediately started on plasma exchange (PLEX) for suspected TTP/HUS. She developed progressive renal failure over the ensuing days with a rise in creatinine to 218 μmol/L (or 2.5 μmol/L) at day 7 of admission. Renal biopsy revealed thrombotic microangiopathy and no evidence of immune complex glomerulonephritis. There were multiple thrombi within the glomerular capillary lumens and the arteries showed only mild fibrointimal proliferation. After incomplete response to PLEX, she was treated with rituximab for refractory TTP/HUS and subsequently eculizumab for possible atypical HUS. She also required initiation of dialysis. Approximately 9 months after her renal presentation, she developed Raynaud phenomenon and diffuse skin thickening. Anti-RNA polymerase III were sent at this time, and these antibodies came back positive. She was started on ACE inhibitor therapy. Her renal function is improving such that the frequency of her hemodialysis is now twice per week 12 months after her renal presentation.
CASE 2 A 32-year-old previously healthy woman presented with new onset of severe Raynaud phenomenon for 2 weeks. On review of systems, she had symptoms suggestive of gastroesophageal reflux. Initial examination revealed BP of 150/100 mm Hg. The tips of all the fingers were persistently cyanotic without ulceration or pitting scars. Splinter hemorrhages were present. There was no evidence of skin thickening. Laboratory investigations were notable for a normal complete blood count except for mild lymphopenia and a normal creatinine (58 μmol/L [0.7 mg/dL]). Antinuclear antibody was initially positive at a titer of 1:640 (nucleolar pattern) but repeatedly negative on subsequent multiplex assay. She was started on nifedipine XL for her Raynaud phenomenon, but her digital cyanosis did not improve. Angiogram revealed absent blood flow beyond the proximal interphalangeal joints of the hands and no improvement following vasodilators.
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Angiogram of the renal arteries was unremarkable. She was started on prednisone 50 mg daily for possible vasculitis based on the angiogram findings in the hands, and the dose of nifedipine was increased. After lack of improvement for 2 weeks, she was treated with prostaglandin infusion, which led to improvement in the finger discoloration. Prednisone was subsequently tapered. During routine blood work 3 months after her initial presentation, she was found to have new-onset anemia (hemoglobin 84 g/L [8.4 g/dL]), thrombocytopenia (93 109/L), and renal failure (156 μmol/L [1.8 mg/dL]). Blood pressure was 132/ 86 mm Hg. Urine showed 2+ blood and 2+ protein. Peripheral blood smear examination revealed schistocytes compatible with MAHA. Echocardiogram revealed a small pericardial effusion and suspicion of pulmonary hypertension (right ventricular systolic pressure 41 mm Hg). Renal function progressively deteriorated to 295 μmol/L (or 3.3 mg/dL) at day 7 of admission. Kidney biopsy showed thrombotic microangiopathy. Thrombosis was present in the hilar arterioles as well as in the capillaries. The arterioles outside the glomeruli were also affected with marked narrowing of the lumens but without “onion skin” changes in the small interlobular arteries. She was treated with PLEX for suspicion of TTP/HUS. She also required initiation of dialysis. After incomplete response to PLEX, she was subsequently treated with eculizumab for possible atypical HUS. She was also treated with an ACE inhibitor. Anti-RNA polymerase III antibodies were checked within 3 weeks of her renal presentation and came back strongly positive. About 6 weeks after her renal presentation, she developed rapidly progressive diffuse skin thickening. She currently remains on nightly peritoneal dialysis with no significant renal recovery after 13 months. Repeat echocardiogram did not show any signs of pulmonary hypertension.
DISCUSSION Systemic sclerosis is a multisystem connective tissue disease characterized by the pathophysiologic triad of fibrosis of the skin and internal organs, autoimmunity and inflammation, and vascular hyperreactivity and obliterative phenomena. The clinical hallmark of SSc is fibrotic skin thickening (scleroderma). Based on the Leroy and Medsger5 criteria, SSc can be classified into 2 variants based on the extent of skin involvement: SSc with limited cutaneous involvement and SSc with diffuse cutaneous involvement. The diffuse form consists of more widespread skin disease (involving the trunk and extremities proximal to elbows and knees) and more frequent visceral disease, which can affect the gastrointestinal tract, lungs, heart, and kidneys. Scleroderma renal crisis affects up to 10% of patients with SSc1 and is associated with significant morbidity and mortality. Scleroderma renal crisis classically presents with the abrupt onset of hypertension and rapidly progressive renal failure. In a retrospective review of 91 patients with SRC, the mean BP was 184/107 mm Hg.6 In up to 10% of cases, however, SRC occurs without hypertension. Anemia is also common in SRC and can include signs of MAHA. Thrombocytopenia, hematuria, and proteinuria can occur as well. The renal pathologic findings of both SRC and TTP/HUS are that of a thrombotic microangiopathy.7 The findings in SRC are very similar to TTP/HUS, and it is often impossible to distinguish these entities solely by histologic examination. In contrast to TTP/HUS, however, extraglomerular small vessel lesions usually predominate over glomerular capillary microangiopathic changes (glomerular capillary thrombosis) in SRC. The presence of vascular adventitial fibrosis has also been considered by some investigators to be characteristic of SRC. Importantly, the histologic
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manifestations may vary during the course of SRC. Early changes may include intimal accumulation of myxoid material, thrombosis, and/or fibrinoid necrosis. The classic “onion-skin” lesions of SRC develop only later. Patients with early SSc with diffuse cutaneous involvement are at the highest risk of developing SRC, and approximately 80% of cases occur during the first 4 years of disease.1 Systemic sclerosis is particularly associated with rapidly progressive skin disease.1 Exposure to corticosteroids equivalent to 15 mg or greater daily in the preceding 6 months is also a risk factor for SRC,6,8 and corticosteroids should therefore be used very cautiously in patients with SSc. Anti-RNA polymerase III antibodies have been reported to be present in 3.4% to 28% of patients with SSc.9 Importantly, anti-RNA polymerase III antibodies are detected almost exclusively in diffuse SSc and thus can be especially useful in patients with very early diffuse SSc without skin involvement. Unlike other autoantibody profiles in SSc, anti-RNA polymerase III antibodies are strongly associated with SRC. Anti-RNA polymerase III antibodies are present in 10% to 60% of patients with SRC,1 and 1 cohort study reported that these antibodies carry a 25% risk of developing SRC compared with a 2% risk in their absence.10 Scleroderma renal crisis has rarely been reported to occur in the absence of skin involvement. Scleroderma renal crisis without skin involvement represents a unique diagnostic challenge and closely mimics the presentation of TTP/HUS. In some patients, SRC may be suspected in the setting of typical features of SSc, specifically a combination of Raynaud phenomenon, visceral involvement, and SSc-associated antibodies. The diagnosis is much more challenging in patients in whom other clinical features of SSc are not present or not previously recognized. RNA polymerase III antibodies have previously been reported to be used to diagnose SRC in the absence of sclerotic skin lesions in 4 patients, one of whom had a lupus overlap syndrome.1–3 In the Table, we have summarized the previous and current cases of SRC without skin disease with positive anti-RNA polymerase III antibodies. Because anti-RNA polymerase III antibodies are not measured in standard multiplex assays, an ANA should be measured by immunofluorescence in patients with clinical suspicion for SSc or SRC. If a positive ANA is detected by immunofluorescence, specific testing for anti-RNA polymerase III antibodies should be performed. Other than anti-RNA polymerase III testing, evaluation of ADAMTS13 activity is also helpful in distinguishing SRC from TTP/HUS because low activity is a characteristic feature of TTP.9 Distinguishing between SRC and TTP/HUS at the time of presentation is crucial because the treatment of these conditions varies considerably. The primary treatment for TTP is PLEX. More recently, eculizumab (an anti-C5 monoclonal antibody) has been reported to be used in patients with atypical HUS (defined by the presence of typical features of HUS but without a diarrheal illness). Two prospective phase 2 trials of patients with refractory thrombotic microangiopathy despite PLEX or infusion showed positive results in improving platelet counts (mean increase of 73 109/L in trial 1) and inducing a thrombotic microangiopathy event-free status (80% of patients in trial 2). Eculizumab was also associated with significant and sustained improvements in renal function.11 The mainstay of treatment of SRC is ACE inhibitor therapy and management of hypertension. Captopril is the agent of choice because of its short half-life, which allows for rapid titration. It is imperative to initiate ACE inhibitors very early in the course of SRC, and if there is failure to normalize BP with maximal dose of ACE inhibitors, additional antihypertensive agents should be added. Angiotensin-converting enzyme inhibitor therapy must © 2014 Lippincott Williams & Wilkins
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
JCR: Journal of Clinical Rheumatology • Volume 20, Number 7, October 2014
Anti-RNA Polymerase III in SRC Without Skin Disease
TABLE. Overview of Patients With SRC Without Skin Involvement and Positive Anti-RNA Polymerase III Antibodies
Age, y Gender Blood pressure, mm Hg Clinical features of connective tissue disease Pulmonary manifestations Cardiac manifestations Hemoglobin, g/L MAHA Platelets, 109/L Creatinine, μmol/L
Case 1
Case 2
Case 3
Case 4
Case 5 (Present Case 1)
Case 6 (Present Case 2)
50 Female 190/110
59 Male 190/110
58 Male 200/100
25 Female 220/150
47 Female 192/110
32 Female 132/86
Polyarthritis
Minimal pleural effusions Cardiomegaly, moderate pericardial effusion 96 − 128 283
ANA + Anticentromere − Anti-Scl70 − RNAP III + End-stage Yes renal disease Development Yes, within 4 mo of skin thickening after SRC
Raynaud phenomenon, dysphagia Pleural effusions
Arthralgias, myalgias
Congestive heart failure
Pericardial effusion
91 + 104 120 + − − + Yes None at 9-mo follow-up
None
109 + 101 260 Autoantibodies + − − + Yes Yes, at 15 mo
Alopecia, Transient seizures polyarthritis (lupus overlap) None None
Ventricular hypertrophy
Severe Raynaud phenomenon, GERD Suspected pulmonary hypertensiona Small pericardial Small pericardial effusion effusiona
108 − 93 105
82 + 38 120
84 + 93 156
+ − − + No
+/− − − + Yes
+/−b − − + Yes
None at 2-y follow-up
Yes, at 9 mo
Yes, at 6 wk
a No cardiac or respiratory symptoms. A screening echocardiogram showed a small pericardial effusion and signs of possible pulmonary hypertension (right ventricular systolic pressure 41 mm Hg). b ANA positive initially by immunofluorescence and negative repeatedly by multiplex assay. GERD indicates gastroesophageal reflux disease; RNAP III, anti-RNA polymerase III antibodies.
be prescribed even if there is a continued deterioration in renal function. Prophylactic ACE inhibitors are not associated with a lower risk of developing SRC6 and might potentially lead to poorer outcomes.12 The routine use of ACE inhibitors has dramatically improved outcomes in SRC, reducing mortality from 76% at 1 year to less than 15%.13 This reduction in mortality also likely reflects the increased use of dialysis. About 50% of SRC patients require initiation of dialysis; however, up to 33% of patients may be able to discontinue dialysis within 2 years after SRC onset.9 As a result of improved treatment of SRC, the cause of mortality in SSc has now shifted to more commonly involve lung disease and less frequently renal disease.14 In conclusion, SRC should be considered in the differential diagnosis along with TTP/HUS in patients presenting with a combination of anemia, thrombocytopenia, and acute kidney injury. The possibility of SRC even in the absence of skin disease should be considered especially in patients who have any clinical or serologic features of connective tissue disease. It is important to recognize that diffuse skin thickening is not always present at the onset of disease and that there can be a prodrome of other rheumatic presentations prior to the skin thickening developing. Patients presenting with thrombotic microangiopathy and any features suggestive of connective tissue disease should be © 2014 Lippincott Williams & Wilkins
tested early for anti-RNA polymerase III antibodies, which can be valuable to diagnose SRC in the absence of skin disease.
KEY POINTS • Scleroderma renal crisis should be considered in the differential diagnosis of patients presenting with anemia, thrombocytopenia, and acute kidney injury, especially in patients with any clinical or serologic features of connective tissue disease. • Anti-RNA polymerase III antibody testing is valuable to diagnose SRC in the absence of skin disease. • An ANA should be measured by immunofluorescence in patients with clinical suspicion for SRC. If a positive ANA is detected by immunofluorescence, specific testing for anti-RNA polymerase III antibodies should be performed. • Angiotensin-converting enzyme inhibitor therapy is the mainstay of treatment of SRC and should be instituted as early as possible when the diagnosis is suspected. REFERENCES 1. Shanmugam VK, Steen VD. Renal disease in scleroderma: an update on evaluation, risk stratification, pathogenesis and management. Curr Opin Rheumatol 2012;24:669–676.
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2. Molina JF, Anaya JM, Cabrera GE, et al. Systemic sclerosis sine scleroderma: an unusual presentation in scleroderma renal crisis. J Rheumatol 1995;22:557–560. 3. Phan TG, Cass A, Gillin A, et al. Anti-RNA polymerase III antibodies in the diagnosis of scleroderma renal crisis sine scleroderma. J Rheumatol 1999;26:2489–2492. 4. Horn HC, Ottosen P, Junker P. Renal crisis in asclerodermic scleroderma—lupus overlap syndrome. Lupus 2001;10:886–888. 5. Leroy EC, Medsger TA Jr. Criteria for the classification of early systemic sclerosis. J Rheumatol 2001;28:1573–1576. 6. Guillevin L, Bérezné A, Seror R, et al. Scleroderma renal crisis: a retrospective multicenter study on 91 patients and 427 controls. Rheumatology 2012;51:460–467. 7. Batal I, Domsic RT, Medsger TA, et al. Scleroderma renal crisis: a pathology perspective. Int J Rheumatol 2010;2010:543704. 8. Steen V, Medsger TA Jr. Case–control study of corticosteroids and other drugs that either precipitate or protect from the development of scleroderma renal crisis. Arthritis Rheum 1998;41:1613–1619.
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9. Mouthon L, Bussone G, Berezné A, et al. Scleroderma renal crisis. J Rheumatol 2014;41:1040–1048. 10. Nikpour M, Hissaria P, Byron J, et al. Prevalence, correlates and clinical usefulness of antibodies to RNA polymerase III in systemic sclerosis: a cross-sectional analysis of data from an Australian cohort. Arthritis Res Ther 2011;13:R211. 11. Legendre CM, Licht C, Muus P, et al. Terminal complement inhibitor eculizumab in atypical hemolytic-uremic syndrome. N Engl J Med 2013; 368:2169–2181. 12. Hudson M, Baron M, Tatibouet S, et al. International scleroderma renal crisis study investigators. Semin Arthritis Rheum 2014;43:666–672. 13. Steen V, Costantino J, Shapiro A, et al. Outcome of renal crisis in systemic sclerosis: relation to availability of angiotensin converting enzyme (ACE) inhibitors. Ann Intern Med 1990;113:352–357. 14. Steen VD, Medsger TA Jr. Changes in causes of death in systemic sclerosis, 1972–2002. Ann Rheum Dis 2007;66:940–944.
© 2014 Lippincott Williams & Wilkins
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Anti-RNA Polymerase III Antibodies in the Diagnosis of Scleroderma Renal Crisis in the Absence of Skin Disease Sankalp Virendrakumar Bhavsar, MD, FRCPC and Raj Carmona, MBBS, FRCPC ABSTRACT: Scleroderma renal crisis (SRC) occurs in approximately 10% of patients with systemic sclerosis (SSc), particularly in those with diffuse skin disease. Scleroderma renal crisis has rarely been described to occur in patients with SSc without skin involvement. Scleroderma renal crisis without skin disease represents a major diagnostic challenge, particularly in patients without overt SSc involvement of other organ systems. It closely mimics the presentation of thrombotic thrombocytopenic purpura/ hemolytic uremic syndrome, and treatment is therefore often directed at this entity. Anti-RNA polymerase III antibody testing has been previously reported to be used in 4 patients to diagnose SRC in the absence of sclerotic skin disease. We report 2 patients without skin disease or overt visceral involvement at presentation who presented with microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury. Both patients eventually developed diffuse and rapidly progressive skin thickening. Anti-RNA polymerase III antibodies were strongly positive, supporting that their renal presentations were secondary to SRC. Key Words: scleroderma, systemic sclerosis, renal crisis, TTP/HUS, anti-RNA polymerase III (J Clin Rheumatol 2014;20: 379–382)
S
ystemic sclerosis (SSc) is a multisystem connective tissue disease with the clinical hallmark of skin thickening (scleroderma). Scleroderma renal crisis (SRC), one of the most feared complications of SSc, typically affects patients with diffuse skin thickening and may therefore not be recognized in the absence of skin disease.1 The diagnostic dilemma is further compounded in patients in whom other clinical features of SSc are not present or not previously recognized. Anti-RNA polymerase III antibodies have been previously reported to be used to make a diagnosis of SRC in the absence of skin disease.2–4 Testing for anti-RNA polymerase III antibodies can be extremely valuable in making a diagnosis of SRC and to distinguish this entity from thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS). Early diagnosis of SRC is imperative to instituting appropriate therapy, including angiotensin-converting enzyme (ACE) inhibitors.
CASE 1 A 47-year-old previously healthy woman presented with a 3-month history of pain and swelling in the hands and feet. She did not have a history of Raynaud phenomenon. Examination From the Division of Rheumatology, Department of Medicine, McMaster University, Hamilton, Ontario, Canada. All authors were involved in the preparation of this manuscript. The authors did not receive any grants or other financial support for this study. The authors declare no conflict of interest. Correspondence: Sankalp Virendrakumar Bhavsar MD, FRCPC, Division of Rheumatology, Department of Medicine, McMaster University, Suite 708, 25 Charlton Ave E, Hamilton, Ontario, Canada L8N 1Y2. E-mail: sankalp. [email protected]. Copyright © 2014 by Lippincott Williams & Wilkins ISSN: 1076-1608 DOI: 10.1097/RHU.0000000000000167
revealed a blood pressure (BP) of 140/86 mm Hg and evidence of an inflammatory polyarthritis involving the metacarpophalangeal joint, proximal interphalangeal, and knee joints. There was diffuse puffiness of the fingers without skin thickening. Laboratory investigations revealed a normal complete blood count except for mild lymphopenia and a normal creatinine (57 μmol/L [0.6 mg/dL]). Rheumatoid factor and anticyclic citrullinated peptide antibodies were negative. Antinuclear antibody (ANA) was initially positive at a titer of 1:160 with negative ENA, but subsequent ANA testing by multiplex assay was repeatedly negative. She was started on hydroxychloroquine for her polyarthritis, which subsequently abated. Approximately 3 months after her initial presentation, she began feeling generally unwell and had shortness of breath. She had not developed symptoms of Raynaud phenomenon. Blood pressure was elevated at 192/110 mm Hg. Blood work revealed new anemia (82 g/L [8.2 g/dL]), thrombocytopenia (38 109/L), and renal impairment (serum creatinine 120 μmol/L [1.4 mg/dL]). Urinalysis showed 3+ blood and 2+ protein. Peripheral blood smear examination revealed schistocytes consistent with microangiopathic hemolytic anemia (MAHA). Echocardiogram revealed a small pericardial effusion. She was immediately started on plasma exchange (PLEX) for suspected TTP/HUS. She developed progressive renal failure over the ensuing days with a rise in creatinine to 218 μmol/L (or 2.5 μmol/L) at day 7 of admission. Renal biopsy revealed thrombotic microangiopathy and no evidence of immune complex glomerulonephritis. There were multiple thrombi within the glomerular capillary lumens and the arteries showed only mild fibrointimal proliferation. After incomplete response to PLEX, she was treated with rituximab for refractory TTP/HUS and subsequently eculizumab for possible atypical HUS. She also required initiation of dialysis. Approximately 9 months after her renal presentation, she developed Raynaud phenomenon and diffuse skin thickening. Anti-RNA polymerase III were sent at this time, and these antibodies came back positive. She was started on ACE inhibitor therapy. Her renal function is improving such that the frequency of her hemodialysis is now twice per week 12 months after her renal presentation.
CASE 2 A 32-year-old previously healthy woman presented with new onset of severe Raynaud phenomenon for 2 weeks. On review of systems, she had symptoms suggestive of gastroesophageal reflux. Initial examination revealed BP of 150/100 mm Hg. The tips of all the fingers were persistently cyanotic without ulceration or pitting scars. Splinter hemorrhages were present. There was no evidence of skin thickening. Laboratory investigations were notable for a normal complete blood count except for mild lymphopenia and a normal creatinine (58 μmol/L [0.7 mg/dL]). Antinuclear antibody was initially positive at a titer of 1:640 (nucleolar pattern) but repeatedly negative on subsequent multiplex assay. She was started on nifedipine XL for her Raynaud phenomenon, but her digital cyanosis did not improve. Angiogram revealed absent blood flow beyond the proximal interphalangeal joints of the hands and no improvement following vasodilators.
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Angiogram of the renal arteries was unremarkable. She was started on prednisone 50 mg daily for possible vasculitis based on the angiogram findings in the hands, and the dose of nifedipine was increased. After lack of improvement for 2 weeks, she was treated with prostaglandin infusion, which led to improvement in the finger discoloration. Prednisone was subsequently tapered. During routine blood work 3 months after her initial presentation, she was found to have new-onset anemia (hemoglobin 84 g/L [8.4 g/dL]), thrombocytopenia (93 109/L), and renal failure (156 μmol/L [1.8 mg/dL]). Blood pressure was 132/ 86 mm Hg. Urine showed 2+ blood and 2+ protein. Peripheral blood smear examination revealed schistocytes compatible with MAHA. Echocardiogram revealed a small pericardial effusion and suspicion of pulmonary hypertension (right ventricular systolic pressure 41 mm Hg). Renal function progressively deteriorated to 295 μmol/L (or 3.3 mg/dL) at day 7 of admission. Kidney biopsy showed thrombotic microangiopathy. Thrombosis was present in the hilar arterioles as well as in the capillaries. The arterioles outside the glomeruli were also affected with marked narrowing of the lumens but without “onion skin” changes in the small interlobular arteries. She was treated with PLEX for suspicion of TTP/HUS. She also required initiation of dialysis. After incomplete response to PLEX, she was subsequently treated with eculizumab for possible atypical HUS. She was also treated with an ACE inhibitor. Anti-RNA polymerase III antibodies were checked within 3 weeks of her renal presentation and came back strongly positive. About 6 weeks after her renal presentation, she developed rapidly progressive diffuse skin thickening. She currently remains on nightly peritoneal dialysis with no significant renal recovery after 13 months. Repeat echocardiogram did not show any signs of pulmonary hypertension.
DISCUSSION Systemic sclerosis is a multisystem connective tissue disease characterized by the pathophysiologic triad of fibrosis of the skin and internal organs, autoimmunity and inflammation, and vascular hyperreactivity and obliterative phenomena. The clinical hallmark of SSc is fibrotic skin thickening (scleroderma). Based on the Leroy and Medsger5 criteria, SSc can be classified into 2 variants based on the extent of skin involvement: SSc with limited cutaneous involvement and SSc with diffuse cutaneous involvement. The diffuse form consists of more widespread skin disease (involving the trunk and extremities proximal to elbows and knees) and more frequent visceral disease, which can affect the gastrointestinal tract, lungs, heart, and kidneys. Scleroderma renal crisis affects up to 10% of patients with SSc1 and is associated with significant morbidity and mortality. Scleroderma renal crisis classically presents with the abrupt onset of hypertension and rapidly progressive renal failure. In a retrospective review of 91 patients with SRC, the mean BP was 184/107 mm Hg.6 In up to 10% of cases, however, SRC occurs without hypertension. Anemia is also common in SRC and can include signs of MAHA. Thrombocytopenia, hematuria, and proteinuria can occur as well. The renal pathologic findings of both SRC and TTP/HUS are that of a thrombotic microangiopathy.7 The findings in SRC are very similar to TTP/HUS, and it is often impossible to distinguish these entities solely by histologic examination. In contrast to TTP/HUS, however, extraglomerular small vessel lesions usually predominate over glomerular capillary microangiopathic changes (glomerular capillary thrombosis) in SRC. The presence of vascular adventitial fibrosis has also been considered by some investigators to be characteristic of SRC. Importantly, the histologic
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manifestations may vary during the course of SRC. Early changes may include intimal accumulation of myxoid material, thrombosis, and/or fibrinoid necrosis. The classic “onion-skin” lesions of SRC develop only later. Patients with early SSc with diffuse cutaneous involvement are at the highest risk of developing SRC, and approximately 80% of cases occur during the first 4 years of disease.1 Systemic sclerosis is particularly associated with rapidly progressive skin disease.1 Exposure to corticosteroids equivalent to 15 mg or greater daily in the preceding 6 months is also a risk factor for SRC,6,8 and corticosteroids should therefore be used very cautiously in patients with SSc. Anti-RNA polymerase III antibodies have been reported to be present in 3.4% to 28% of patients with SSc.9 Importantly, anti-RNA polymerase III antibodies are detected almost exclusively in diffuse SSc and thus can be especially useful in patients with very early diffuse SSc without skin involvement. Unlike other autoantibody profiles in SSc, anti-RNA polymerase III antibodies are strongly associated with SRC. Anti-RNA polymerase III antibodies are present in 10% to 60% of patients with SRC,1 and 1 cohort study reported that these antibodies carry a 25% risk of developing SRC compared with a 2% risk in their absence.10 Scleroderma renal crisis has rarely been reported to occur in the absence of skin involvement. Scleroderma renal crisis without skin involvement represents a unique diagnostic challenge and closely mimics the presentation of TTP/HUS. In some patients, SRC may be suspected in the setting of typical features of SSc, specifically a combination of Raynaud phenomenon, visceral involvement, and SSc-associated antibodies. The diagnosis is much more challenging in patients in whom other clinical features of SSc are not present or not previously recognized. RNA polymerase III antibodies have previously been reported to be used to diagnose SRC in the absence of sclerotic skin lesions in 4 patients, one of whom had a lupus overlap syndrome.1–3 In the Table, we have summarized the previous and current cases of SRC without skin disease with positive anti-RNA polymerase III antibodies. Because anti-RNA polymerase III antibodies are not measured in standard multiplex assays, an ANA should be measured by immunofluorescence in patients with clinical suspicion for SSc or SRC. If a positive ANA is detected by immunofluorescence, specific testing for anti-RNA polymerase III antibodies should be performed. Other than anti-RNA polymerase III testing, evaluation of ADAMTS13 activity is also helpful in distinguishing SRC from TTP/HUS because low activity is a characteristic feature of TTP.9 Distinguishing between SRC and TTP/HUS at the time of presentation is crucial because the treatment of these conditions varies considerably. The primary treatment for TTP is PLEX. More recently, eculizumab (an anti-C5 monoclonal antibody) has been reported to be used in patients with atypical HUS (defined by the presence of typical features of HUS but without a diarrheal illness). Two prospective phase 2 trials of patients with refractory thrombotic microangiopathy despite PLEX or infusion showed positive results in improving platelet counts (mean increase of 73 109/L in trial 1) and inducing a thrombotic microangiopathy event-free status (80% of patients in trial 2). Eculizumab was also associated with significant and sustained improvements in renal function.11 The mainstay of treatment of SRC is ACE inhibitor therapy and management of hypertension. Captopril is the agent of choice because of its short half-life, which allows for rapid titration. It is imperative to initiate ACE inhibitors very early in the course of SRC, and if there is failure to normalize BP with maximal dose of ACE inhibitors, additional antihypertensive agents should be added. Angiotensin-converting enzyme inhibitor therapy must © 2014 Lippincott Williams & Wilkins
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
JCR: Journal of Clinical Rheumatology • Volume 20, Number 7, October 2014
Anti-RNA Polymerase III in SRC Without Skin Disease
TABLE. Overview of Patients With SRC Without Skin Involvement and Positive Anti-RNA Polymerase III Antibodies
Age, y Gender Blood pressure, mm Hg Clinical features of connective tissue disease Pulmonary manifestations Cardiac manifestations Hemoglobin, g/L MAHA Platelets, 109/L Creatinine, μmol/L
Case 1
Case 2
Case 3
Case 4
Case 5 (Present Case 1)
Case 6 (Present Case 2)
50 Female 190/110
59 Male 190/110
58 Male 200/100
25 Female 220/150
47 Female 192/110
32 Female 132/86
Polyarthritis
Minimal pleural effusions Cardiomegaly, moderate pericardial effusion 96 − 128 283
ANA + Anticentromere − Anti-Scl70 − RNAP III + End-stage Yes renal disease Development Yes, within 4 mo of skin thickening after SRC
Raynaud phenomenon, dysphagia Pleural effusions
Arthralgias, myalgias
Congestive heart failure
Pericardial effusion
91 + 104 120 + − − + Yes None at 9-mo follow-up
None
109 + 101 260 Autoantibodies + − − + Yes Yes, at 15 mo
Alopecia, Transient seizures polyarthritis (lupus overlap) None None
Ventricular hypertrophy
Severe Raynaud phenomenon, GERD Suspected pulmonary hypertensiona Small pericardial Small pericardial effusion effusiona
108 − 93 105
82 + 38 120
84 + 93 156
+ − − + No
+/− − − + Yes
+/−b − − + Yes
None at 2-y follow-up
Yes, at 9 mo
Yes, at 6 wk
a No cardiac or respiratory symptoms. A screening echocardiogram showed a small pericardial effusion and signs of possible pulmonary hypertension (right ventricular systolic pressure 41 mm Hg). b ANA positive initially by immunofluorescence and negative repeatedly by multiplex assay. GERD indicates gastroesophageal reflux disease; RNAP III, anti-RNA polymerase III antibodies.
be prescribed even if there is a continued deterioration in renal function. Prophylactic ACE inhibitors are not associated with a lower risk of developing SRC6 and might potentially lead to poorer outcomes.12 The routine use of ACE inhibitors has dramatically improved outcomes in SRC, reducing mortality from 76% at 1 year to less than 15%.13 This reduction in mortality also likely reflects the increased use of dialysis. About 50% of SRC patients require initiation of dialysis; however, up to 33% of patients may be able to discontinue dialysis within 2 years after SRC onset.9 As a result of improved treatment of SRC, the cause of mortality in SSc has now shifted to more commonly involve lung disease and less frequently renal disease.14 In conclusion, SRC should be considered in the differential diagnosis along with TTP/HUS in patients presenting with a combination of anemia, thrombocytopenia, and acute kidney injury. The possibility of SRC even in the absence of skin disease should be considered especially in patients who have any clinical or serologic features of connective tissue disease. It is important to recognize that diffuse skin thickening is not always present at the onset of disease and that there can be a prodrome of other rheumatic presentations prior to the skin thickening developing. Patients presenting with thrombotic microangiopathy and any features suggestive of connective tissue disease should be © 2014 Lippincott Williams & Wilkins
tested early for anti-RNA polymerase III antibodies, which can be valuable to diagnose SRC in the absence of skin disease.
KEY POINTS • Scleroderma renal crisis should be considered in the differential diagnosis of patients presenting with anemia, thrombocytopenia, and acute kidney injury, especially in patients with any clinical or serologic features of connective tissue disease. • Anti-RNA polymerase III antibody testing is valuable to diagnose SRC in the absence of skin disease. • An ANA should be measured by immunofluorescence in patients with clinical suspicion for SRC. If a positive ANA is detected by immunofluorescence, specific testing for anti-RNA polymerase III antibodies should be performed. • Angiotensin-converting enzyme inhibitor therapy is the mainstay of treatment of SRC and should be instituted as early as possible when the diagnosis is suspected. REFERENCES 1. Shanmugam VK, Steen VD. Renal disease in scleroderma: an update on evaluation, risk stratification, pathogenesis and management. Curr Opin Rheumatol 2012;24:669–676.
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2. Molina JF, Anaya JM, Cabrera GE, et al. Systemic sclerosis sine scleroderma: an unusual presentation in scleroderma renal crisis. J Rheumatol 1995;22:557–560. 3. Phan TG, Cass A, Gillin A, et al. Anti-RNA polymerase III antibodies in the diagnosis of scleroderma renal crisis sine scleroderma. J Rheumatol 1999;26:2489–2492. 4. Horn HC, Ottosen P, Junker P. Renal crisis in asclerodermic scleroderma—lupus overlap syndrome. Lupus 2001;10:886–888. 5. Leroy EC, Medsger TA Jr. Criteria for the classification of early systemic sclerosis. J Rheumatol 2001;28:1573–1576. 6. Guillevin L, Bérezné A, Seror R, et al. Scleroderma renal crisis: a retrospective multicenter study on 91 patients and 427 controls. Rheumatology 2012;51:460–467. 7. Batal I, Domsic RT, Medsger TA, et al. Scleroderma renal crisis: a pathology perspective. Int J Rheumatol 2010;2010:543704. 8. Steen V, Medsger TA Jr. Case–control study of corticosteroids and other drugs that either precipitate or protect from the development of scleroderma renal crisis. Arthritis Rheum 1998;41:1613–1619.
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9. Mouthon L, Bussone G, Berezné A, et al. Scleroderma renal crisis. J Rheumatol 2014;41:1040–1048. 10. Nikpour M, Hissaria P, Byron J, et al. Prevalence, correlates and clinical usefulness of antibodies to RNA polymerase III in systemic sclerosis: a cross-sectional analysis of data from an Australian cohort. Arthritis Res Ther 2011;13:R211. 11. Legendre CM, Licht C, Muus P, et al. Terminal complement inhibitor eculizumab in atypical hemolytic-uremic syndrome. N Engl J Med 2013; 368:2169–2181. 12. Hudson M, Baron M, Tatibouet S, et al. International scleroderma renal crisis study investigators. Semin Arthritis Rheum 2014;43:666–672. 13. Steen V, Costantino J, Shapiro A, et al. Outcome of renal crisis in systemic sclerosis: relation to availability of angiotensin converting enzyme (ACE) inhibitors. Ann Intern Med 1990;113:352–357. 14. Steen VD, Medsger TA Jr. Changes in causes of death in systemic sclerosis, 1972–2002. Ann Rheum Dis 2007;66:940–944.
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Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
