Seminars in Arthritis and Rheumatism 44 (2015) 411–416
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Seminars in Arthritis and Rheumatism journal homepage: www.elsevier.com/locate/semarthrit
HIV-associated juvenile systemic sclerosis: A case report Lawrence O. Okong'o, MMed (Paed)n, Kate Webb, MMed, FCPaed (SA), Christian Scott, FCPaed (SA), Grad Cert Paed Rheum (UWA) Red Cross War Memorial Children's Hospital, University of Cape Town, Cape Town, South Africa
a r t i c l e in fo
Keywords: HIV Scleroderma Juvenile Systemic sclerosis Cyclophosphamide Antiretroviral
a b s t r a c t Introduction: Autoimmune connective tissue diseases occur in HIV-infected persons though with a lower frequency than in the general population. However, since the advent of highly active antiretroviral therapy (HAART), the spectrum of autoimmune diseases reported in HIV-infected patients has increased. Objective: To describe the occurrence and management of systemic sclerosis in a HIV-infected child. Methods: A case report of HIV-associated systemic sclerosis and a review of the literature on previously published cases. Results: A nine-year-old girl presented with HIV-associated systemic sclerosis complicated with interstitial lung disease and oesophageal dysmotility. She was treated with intravenous cyclophosphamide with good response on her skin scores and modest improvement in lung function parameters. She manifested no deterioration in her clinical status. However, she developed mild lymphopaenia following the treatment with cyclophosphamide. Conclusion: We have described the rare occurrence of HIV infection and systemic sclerosis in a nine-yearold girl. She received cyclophosphamide for management of the systemic manifestations of SSc and did not manifest any major adverse events except mild lymphopaenia. Thus, though cyclophosphamide appeared safe in the management of HIV-associated systemic sclerosis, close monitoring of lymphocyte and CD4 counts should be done in such patients. & 2014 Elsevier Inc. All rights reserved.
Introduction Autoimmune conditions are thought to occur following breakdown of immune tolerance triggered by environmental factors in genetically predisposed individuals. HIV infection is often associated with immune dysfunction, which may persist despite viral suppression following highly active antiretroviral therapy (HAART) [1]. The immune dysregulation may increase the risk for development of autoimmune diseases [2]. Though rheumatologic manifestations such as arthralgia, arthritis, myalgia and myositis appear to be more common in
The views expressed herein are those of the authors and do not reflect the official policy or position of the University of Cape Town or Red Cross War Memorial Children's Hospital. Lawrence Okong'o is sponsored by the African Paediatric Fellowship Program of the Red Cross War Memorial Children's Hospital and the Children's Hospital Trust. Dr. Kate Webb is on a Discovery Foundation scholarship. n Correspondence to: Lawrence O. Okong'o, MMed (Paed), Room 512, ICH Building, Red Cross War Memorial Children's Hospital, Klipfontein Rd, Rondebosch 7700, Cape Town, South Africa. E-mail addresses: [email protected], [email protected] (L.O. Okong'o). http://dx.doi.org/10.1016/j.semarthrit.2014.08.005 0049-0172/& 2014 Elsevier Inc. All rights reserved.
HIV-infected persons [3], autoimmune connective tissue diseases seem to occur with less frequency than in the general population. The reasons for this are not well understood but could be due to interplay of many factors, including HIVassociated immunosuppression. It has been proposed that autoimmune diseases in HIV-infected persons mainly occur early before severe immunosuppression ensues and later in the disease following HAART-induced immune reconstitution [4]. Since the advent of HAART, an increasing number of autoimmune connective tissue diseases such as SLE, dermatomyositis, Sjögren's syndrome and scleroderma have been reported [5–10]. Scleroderma is an autoimmune disorder that manifests with inflammation and fibrosis of various organs. It may predominantly affect the skin with no or minimal involvement of other organs (localised scleroderma) or may manifest both cutaneous and internal organ involvement [systemic sclerosis (SSc)]. Only a few case reports of HIV-associated scleroderma have been reported in the literature [5,6]. We report a case of a nine-year-old girl with perinatally acquired HIV who presented with features of SSc and highlight some of the challenges in the management of the patient.
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Methods A case report of a nine-year-old girl with perinatally acquired HIV presenting with features of SSc. We also reviewed the published literature in MEDLINEs database for previous articles reporting HIV-infected patients diagnosed with scleroderma between 1980 and June 2014. We used the search terms (scleroderma OR systemic sclerosis) AND (HIV/human immunodeficiency virus).
Results Case report A nine-year-old girl was referred to our rheumatology service with two years history of Raynaud's phenomenon and fingertip ulcers. She was known to be HIV infected and had been on antiretroviral (ARV) therapy since birth. She was on efavirenz, lamivudine, abacavir and cotrimoxazole at the time of presentation. She had previously been on stavudine, which was changed to abacavir a few months before referral due to lipodystrophy. She had no muscle weakness, heliotrope or malar rash, abdominal pain, dysphagia, dysphonia, recurrent oral ulcers or easy fatiguability. Her parents were both HIV infected and a she had a two-yearold sibling who was HIV uninfected. She was treated for TB at the age of 6 months but had no recent history of cough, weight loss, excess sweating, fever or contact with a patient with pulmonary TB. There was no known family history of Raynaud's phenomenon or autoimmune disease. Her immunisations were up to date (for BCG, polio, DPT-Hib, Hepatitis B and Measles) as per the local immunization schedule. She had not received the pneumococcal vaccine. She had no history of contact with any unusual chemicals or use of traditional medicine. On examination, she was afebrile and had a normal blood pressure. Her weight for age and height for age were below the 5th centile. She had digital scarring and pitting, as well as ischaemia of the distal phalanx of the left middle, and right 2nd and 5th fingers (Fig. 1). She had no calcinosis or limitation in mouth opening. The skin over her torso and upper and lower limbs was thickened, and her modified Rodnan skin score (MRSS) was 23/51. She had no arthritis though she had sclerodactyly with limited extension and flexion of the fingers (MCPs and IPJs) bilaterally. Capillaroscopy demonstrated abnormal nail-fold capillary changes with dilated capillary loops interspersed with areas of
A
paucity of capillaries. The chest x-ray was normal, and tuberculin skin test was negative. She had a positive antinuclear antibody (ANA) titer of 1280 (speckled pattern) but tested negative for antiScl70, anticentromere and anti-RNP antibodies. The PM-Scl-70 antibodies were not tested as the test was not available at our centre. She had lower than detectable viral load and the CD4 count was 834 106 per l. A review of her medical records confirmed that she had a normal CD4 count (879, 41%) and undetectable viral load at the time of onset of symptoms. The other laboratory investigation results are summarised in Table 1. Based on the presence of sclerosis proximal to the metacarpophalangeal joints (MCPs), Raynaud's phenomenon, nail-fold capillary changes, sclerodactyly and digital ischaemia, a diagnosis of diffuse cutaneous juvenile SSc was made. She fulfilled the PReS/ EULAR/ACR criteria for classification of juvenile SSc [11]. Despite the absence of respiratory symptoms, pulmonary function tests revealed abnormal diffusion lung capacity for carbon monoxide (DLCO) of 65%, forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV1) of 74% of the predicted with no variation after bronchodilator administration. The high-resolution chest CT (HRCT) scan showed bilateral basal ground-glass changes, honey combing and sub-pleural air cysts (Fig. 2). The electrocardiogram and echocardiogram were normal with no features of cardiac dysfunction or pulmonary hypertension. Barium swallow showed dilatation of distal oesophagus with delayed emptying despite absence of symptoms (Fig. 3). No reflux was demonstrated. She had a reduced tear film dispersal time of 4 s (reference 410 s) consistent with conjunctivitis sicca. She was treated with methyl prednisone 10-mg/kg body weight for 3 days followed by oral prednisone 10 mg daily. She also received amlodipine 5 mg daily to manage the Raynaud's phenomenon and continued to receive her ARVs. She did not demonstrate evidence of immunity against Hepatitis A and B and received Hepatitis A and Hepatitis B (1 dose) vaccines as well as pneumococcal and Mumps, Measles, Rubella (MMR) vaccines prior to initiation of cyclophosphamide. She received monthly cyclophosphamide (500 mg/m2) infusions with a similar dose of 2-mercaptoethane sulphonate Na (MESNA) to reduce the risk of bladder toxicity. After the 3rd infusion, it was deemed too risky to administer further doses of cyclophosphamide in view of her HIV serostatus. She is currently maintained on prednisone (10 mg daily) and azathioprine. Overall, good improvement in vasculitic lesions (Fig. 1) and skin sclerosis was achieved with the MRSS improving from 23/51 to 12/51 over 9 months. Modest improvement was also observed in lung function parameters with the FVC and FEV1 improving from 1.06 to
B
Fig. 1. Fingertip vasculitic lesions with pulp tissue loss: (A) at diagnosis and (B) after 7 months.
L.O. Okong'o et al. / Seminars in Arthritis and Rheumatism 44 (2015) 411–416
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Table 1 Laboratory investigation results Investigation
Diagnosis (2/09/2013)
1st Cyclophosphamide (15/10/2013)
2nd Cyclophosphamide (25/11/2013)
3rd Cyclophosphamide (5/2/2014)
Post-cyclophosphamide review (14/07/2014)
Hb (mg/dl) Plt ( 109 per l) WBC ( 109 per l) Lymphocytes ( 109 per l) CD4 ( 106 per l) CD4% Viral load (copies/ml) ALT AST CRP (0.1–7.5 mg/l) ESR (0–15 mm/h) Creatine (30–48 mmol/l)
12.5 320 12.8 2.44 834 26.7 Lower than detectable 18 27 2.2 8 34
12.8 398 11.9 4.07 Not done Not done Not done 18 22 Not done 2 38
13.4 413 13.6 4.5 1560 36.4 Lower than detectable 31 27 Not done
12.4 513 17.2 1.03 406 39.4 Not done 17
12.5 449 14.3 1.29 398 30.7 Lower than detectable 21 24 Not done 18 31
34
2.2 12 44
Immunology test ANA Anti-RNP Anticentromere antibodies Myeloperoxidase (MPO) antibodies Anti-proteinase 3 antibodies Anti-topoisomerase 1 (Scl-70) Anti-ds DNA Anti-RNP70 antibodies Anti-SM antibodies
Result 1:1280 (speckled) 3.03 U/ml 0.7 EliA U/ml 0.2 EliA U/ml 0.3 EliA U/ml 0.5 EliA U/ml 1.7 IU/ml 1.0 EliA U/ml 1.0 EliA U/ml
Reference – r25.0 o7 o3.5 o2.0 o7 o10 o7 o7
Virology tests Epstein–Barr virus (EBV) IgG Cytomegalovirus (CMV) IgG Varicella antibodies (IgG)
Result Positive Positive Positive
Reference – – –
Other tests Triglycerides (mmol/l) Lactate dehydrogenase (U/l) Creatine kinase (U/l)
Result 0.8 226 125
Reference 0.4–1.2 142–261 26–145
1.27 l (74–90%) and 0.98–1.13 l/s (74–81%), respectively. The DLCO increased from 7.8 to 8.3 mm/min/mmHg (65–69%) 7 months after starting treatment. However, the DLCO reduced to 6.86 (54%) at the last follow-up. Comparison with earlier values was however difficult as it was done in a different (adults) unit due to logistical constraints at our centre. The results of these investigations and evaluations are summarised in Table 2. The radiologic features of oesophageal dysmotility persisted at the 7th month follow-up.
The viral load remained undetectable throughout the 10 months of follow-up. However, she developed lymphopaenia (1.03 109 per l) after two doses of cyclophosphamide. The lymphopaenia was associated with a drop in the absolute CD4 count from 834 (26.76%) at diagnosis to 406 (39.42%) after 7 months and 398 (30.72%) at the last review (after 10 months) (Table 1). Further, at the last review, she was found to have a swollen painful right ankle, and x-ray radiographs confirmed an unrecognised distal
Fig. 2. Chest HRCT scan showing bilateral posterior basal ground-glass appearance and honey combing (arrow).
Fig. 3. Barium swallow showing distal oesophageal dilatation (arrow).
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Table 2 Diagnostic investigation results Assessment
Time after diagnosis
MRSS (out of 51) DLCO mm/min/mmHg (% of predicted) FVC (% of predicted) FEV1 (% of predicted) CMAS (out of 52)
At diagnosis
1 Month (1st cyclophosphamide)
5 Months (3rd cyclophosphamide)
7 Months
10 Months
23 7.8 (65) 1.06 (74) 0.98 (74) 47
21 8.9 (74) (1.06) 74 1.00 (75) 48
28 7.1 (59) 1.07 (79) 0.97 (78) 46
29 8.3 (69) 1.11 (82) 0.99 (80) 49
12 6.86 (54) 1.14 (74) 1.06 (76) Not done
MRSS, modified Rodnan skin score; DLCO, diffusion capacity of carbon dioxide; FVC, forced vital capacity (litres); FEV1, forced expiratory volume (litres) in 1 s; CMAS, childhood myositis assessment scale.
tibial fracture sustained 2 days prior to the visit after minor trauma at home.
Discussion A review of the literature identified only two studies that reported cases of scleroderma in three HIV-infected persons. One other article retrospectively reviewed data on the rheumatic manifestations of HIV among 888 patients and identified one case of scleroderma [12]. This study was only accessed as an abstract however, and there was not enough information on the clinical features of the patient. One of the two included studies reported two middle-aged HIV-infected men who developed localised scleroderma after several years of HAART [6]. In the only published case report of HIV-associated systemic sclerosis, Sikdar et al. described a patient in whom HIV and systemic sclerosis were simultaneously diagnosed and proposed that HIV may have been responsible for the manifestations of systemic sclerosis. The patient developed symptoms of SSc in the background of immune suppression and responded well to therapy with steroids and HAART. Unlike that case, our patient developed symptoms of SSc seven years after HIV infection and HAART. She had good virologic suppression and normal CD4 counts. However, she showed disease (SSc) progression while on HAART and her condition was complicated by vasculitis and interstitial lung disease (ILD) for which she received cyclophosphamide as per international recommendations [13,14]. Many clinicians may be reluctant to use immunosuppressive agents in patients who are already immunocompromised.
Cyclophosphamide has been associated with progression of HIV symptoms in a SLE patient [15] and concerns about deterioration of the clinical symptoms of HIV remain when considering immunosuppressive agents in such patients. Efavirenz and cyclophosphamide are metabolised by the liver (cytochrome P450) and increased levels of active and toxic metabolites of cyclophosphamide may result [16]. Further, cyclophosphamide-induced bone marrow suppression may manifest with leucopenia and greater susceptibility to infections, which may portend a challenge in the management of HIV-infected patients. Despite these concerns, cyclophosphamide has been used for many years for HIV-associated malignancies in children with relatively good safety profile [17,18]. The risk of cyclophosphamide-induced cystitis may be reduced by the use of MESNA. Our patient experienced no HIV clinical disease progression. The viral load remained undetectable though there was reduction in the lymphocyte and CD4 counts (with normal CD4%) after two courses of intravenous cyclophosphamide, which has persisted 5 months after the last dose of cyclophosphamide. The persistent lymphopaenia may also be due to the current therapy with azathioprine, which is known to cause leucopenia [19]. Our patient did not however suffer any infections requiring specific outpatient or inpatient care as a result of the lymphopaenia. The pathogenesis of HIV-associated autoimmunity is not well understood. Direct cytopathic effect of the virus and HIVassociated immune dysregulation may be some of the contributing factors. Prokop and Jagodzinski [20] reported a high prevalence of antibodies to conserved complete retroviral pol sequences in the serum of mixed connective tissue disease (MCTD) and SSc patients suggesting that retroviruses may have a role in the pathogenesis of these diseases. Other investigators have demonstrated production
Table 3 Autoimmune conditions reported in HIV-infected patients (A): Summary of cases of autoimmune connective tissue diseases reported in HIV-infected children Diagnosis (reference)
SLE [30-32] JDM [29]
Total
Cases after HAART initiation
No.
No.
Age
Sex
Years on HAART before AID
CD4 at diagnosis
14 1
3 0
3.5, 14, and 18 8
2F and 1M M
1; 10; NR –
464; 1524; 243 770
(B): Summary of autoimmune connective tissue disease in HIV-infected persons Condition
Scleroderma DM SLE MCTD SS
Total number of cases
Cases occurring after HAART initiation
Ref.
No.
Sex (M:F)
Median age (range) years
No.
Time to AID (months)
CD4 (per mm3) at diagnosis
Viral load (copies/ml)
[5,6] [8,29] [7,9] [33], [10],
3 7 71 1 4
2M:1F 4M:3F 18M:53F F 3M:1F
44 (42–45) 27 (8–50) 28 (0.6–55) 26 47 (38–60)
2 1 19 0 4
4 60 12 33.5 (2–160) 5 NR NA 6, 48, 36, and 48
934; NR; 332 160 390 (267.5, 449) and 3 NR NA 62; 529; 506; and 810
NR NR 29,200 (391; 87,685) and 13 NR NA 1110; o 50; o50; 3170
AID, autoimmune disease; DM, dermatomyositis; MCTD, mixed connective tissue disease; SS, Sjögren's syndrome; NA, not applicable; NR, not reported.
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of SSc-like extracellular matrix proteins by normal human skin fibroblasts following induced expression of retroviral protein [21]. Molecular mimicry is one of the theories that may explain the association between retroviruses and systemic autoimmune diseases [22]. Cross-reactivity between antibodies to components of the HIV envelope glycoprotein (gp120/41) and anti-U1RNP antibodies has been reported [20]. Maul et al. [23] also demonstrated homology between DNA topoisomerase I and the retroviral p30gag protein. The anti-U1RNP antibodies are found in several connective tissue diseases including MCTD and systemic sclerosis (SSc) while DNA topoisomerase 1 is a diffuse systemic-sclerosis-marker antigen that occurs in about 30% of cases of SSc in adults. Environmental factors are thought to be the ultimate triggers of autoimmune diseases. Exposure to chemicals and drugs has been postulated as possible triggers for development of SSc [24]. Among the antiretroviral drugs, some case reports have associated the injectable fusion inhibitor, enfuvirtide with the development of sclerodermatous skin changes near injection sites [25]. Further, a possible increased risk of autoimmune disease exacerbation with the use of antiretroviral integrase inhibitors such as raltegravir has been suggested [26,27]. Our patient, however, had not been on these drugs or any of the other therapeutic agents currently thought or known to be associated with scleroderma. With increasing availability and use of HAART, the spectrum of autoimmune diseases reported in HIV-infected individuals has gradually widened. Some authors have described autoimmune conditions in the context of the immune reconstitution inflammatory syndrome (IRIS). Calabrese et al. [28] reviewed the literature and reported 26 cases of autoimmune diseases following initiation of HAART. Since then many other reports of autoimmune diseases including localised scleroderma [6], SLE [7,9], dermatomyositis [8,29] and Sjögren's syndrome [10] following initiation of HAART have been published (Table 3). However systemic sclerosis following initiation of HAART has not been reported. In the case reported here, features of SSc appeared seven years after initiation of HAART making IRIS an unlikely pathogenic mechanism in the case. In summary, our patient presented with classical features of systemic sclerosis that did not seem to have been influenced by the HIV infection. Since there was no obvious temporal link with any of the ARVs or changes in HIV clinical, immunological or viral load, the occurrence of the two conditions simultaneously could have been coincidental. She was treated with cyclophosphamide with modest improvement though her treatment was complicated by the development of mild lymphopaenia. Conclusion The pathogenesis of HIV-associated autoimmune diseases is still incompletely understood. HIV immune dysregulation may lead to development of autoimmune disease manifestations which may be classical or unique to HIV. The clinical manifestations of SSc in this patient was classical and did not seem to have been influenced by or unique to HIV. The occurrence of the two conditions together may have been coincidental with HIV immune dysregulation providing a conducive environment for the manifestations of SSc in a patient who was probably already genetically predisposed. Where appropriate and as dictated by the clinical manifestations, immunosuppressive agents such as cyclophosphamide may be safely used in the management of such patients. In such instances though, a careful monitoring of the lymphocyte and CD4 counts may be warranted. Acknowledgements We thank L.S. and her parents for allowing us to share her clinical information and photographs for this article.
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Contents lists available at ScienceDirect
Seminars in Arthritis and Rheumatism journal homepage: www.elsevier.com/locate/semarthrit
HIV-associated juvenile systemic sclerosis: A case report Lawrence O. Okong'o, MMed (Paed)n, Kate Webb, MMed, FCPaed (SA), Christian Scott, FCPaed (SA), Grad Cert Paed Rheum (UWA) Red Cross War Memorial Children's Hospital, University of Cape Town, Cape Town, South Africa
a r t i c l e in fo
Keywords: HIV Scleroderma Juvenile Systemic sclerosis Cyclophosphamide Antiretroviral
a b s t r a c t Introduction: Autoimmune connective tissue diseases occur in HIV-infected persons though with a lower frequency than in the general population. However, since the advent of highly active antiretroviral therapy (HAART), the spectrum of autoimmune diseases reported in HIV-infected patients has increased. Objective: To describe the occurrence and management of systemic sclerosis in a HIV-infected child. Methods: A case report of HIV-associated systemic sclerosis and a review of the literature on previously published cases. Results: A nine-year-old girl presented with HIV-associated systemic sclerosis complicated with interstitial lung disease and oesophageal dysmotility. She was treated with intravenous cyclophosphamide with good response on her skin scores and modest improvement in lung function parameters. She manifested no deterioration in her clinical status. However, she developed mild lymphopaenia following the treatment with cyclophosphamide. Conclusion: We have described the rare occurrence of HIV infection and systemic sclerosis in a nine-yearold girl. She received cyclophosphamide for management of the systemic manifestations of SSc and did not manifest any major adverse events except mild lymphopaenia. Thus, though cyclophosphamide appeared safe in the management of HIV-associated systemic sclerosis, close monitoring of lymphocyte and CD4 counts should be done in such patients. & 2014 Elsevier Inc. All rights reserved.
Introduction Autoimmune conditions are thought to occur following breakdown of immune tolerance triggered by environmental factors in genetically predisposed individuals. HIV infection is often associated with immune dysfunction, which may persist despite viral suppression following highly active antiretroviral therapy (HAART) [1]. The immune dysregulation may increase the risk for development of autoimmune diseases [2]. Though rheumatologic manifestations such as arthralgia, arthritis, myalgia and myositis appear to be more common in
The views expressed herein are those of the authors and do not reflect the official policy or position of the University of Cape Town or Red Cross War Memorial Children's Hospital. Lawrence Okong'o is sponsored by the African Paediatric Fellowship Program of the Red Cross War Memorial Children's Hospital and the Children's Hospital Trust. Dr. Kate Webb is on a Discovery Foundation scholarship. n Correspondence to: Lawrence O. Okong'o, MMed (Paed), Room 512, ICH Building, Red Cross War Memorial Children's Hospital, Klipfontein Rd, Rondebosch 7700, Cape Town, South Africa. E-mail addresses: [email protected], [email protected] (L.O. Okong'o). http://dx.doi.org/10.1016/j.semarthrit.2014.08.005 0049-0172/& 2014 Elsevier Inc. All rights reserved.
HIV-infected persons [3], autoimmune connective tissue diseases seem to occur with less frequency than in the general population. The reasons for this are not well understood but could be due to interplay of many factors, including HIVassociated immunosuppression. It has been proposed that autoimmune diseases in HIV-infected persons mainly occur early before severe immunosuppression ensues and later in the disease following HAART-induced immune reconstitution [4]. Since the advent of HAART, an increasing number of autoimmune connective tissue diseases such as SLE, dermatomyositis, Sjögren's syndrome and scleroderma have been reported [5–10]. Scleroderma is an autoimmune disorder that manifests with inflammation and fibrosis of various organs. It may predominantly affect the skin with no or minimal involvement of other organs (localised scleroderma) or may manifest both cutaneous and internal organ involvement [systemic sclerosis (SSc)]. Only a few case reports of HIV-associated scleroderma have been reported in the literature [5,6]. We report a case of a nine-year-old girl with perinatally acquired HIV who presented with features of SSc and highlight some of the challenges in the management of the patient.
412
L.O. Okong'o et al. / Seminars in Arthritis and Rheumatism 44 (2015) 411–416
Methods A case report of a nine-year-old girl with perinatally acquired HIV presenting with features of SSc. We also reviewed the published literature in MEDLINEs database for previous articles reporting HIV-infected patients diagnosed with scleroderma between 1980 and June 2014. We used the search terms (scleroderma OR systemic sclerosis) AND (HIV/human immunodeficiency virus).
Results Case report A nine-year-old girl was referred to our rheumatology service with two years history of Raynaud's phenomenon and fingertip ulcers. She was known to be HIV infected and had been on antiretroviral (ARV) therapy since birth. She was on efavirenz, lamivudine, abacavir and cotrimoxazole at the time of presentation. She had previously been on stavudine, which was changed to abacavir a few months before referral due to lipodystrophy. She had no muscle weakness, heliotrope or malar rash, abdominal pain, dysphagia, dysphonia, recurrent oral ulcers or easy fatiguability. Her parents were both HIV infected and a she had a two-yearold sibling who was HIV uninfected. She was treated for TB at the age of 6 months but had no recent history of cough, weight loss, excess sweating, fever or contact with a patient with pulmonary TB. There was no known family history of Raynaud's phenomenon or autoimmune disease. Her immunisations were up to date (for BCG, polio, DPT-Hib, Hepatitis B and Measles) as per the local immunization schedule. She had not received the pneumococcal vaccine. She had no history of contact with any unusual chemicals or use of traditional medicine. On examination, she was afebrile and had a normal blood pressure. Her weight for age and height for age were below the 5th centile. She had digital scarring and pitting, as well as ischaemia of the distal phalanx of the left middle, and right 2nd and 5th fingers (Fig. 1). She had no calcinosis or limitation in mouth opening. The skin over her torso and upper and lower limbs was thickened, and her modified Rodnan skin score (MRSS) was 23/51. She had no arthritis though she had sclerodactyly with limited extension and flexion of the fingers (MCPs and IPJs) bilaterally. Capillaroscopy demonstrated abnormal nail-fold capillary changes with dilated capillary loops interspersed with areas of
A
paucity of capillaries. The chest x-ray was normal, and tuberculin skin test was negative. She had a positive antinuclear antibody (ANA) titer of 1280 (speckled pattern) but tested negative for antiScl70, anticentromere and anti-RNP antibodies. The PM-Scl-70 antibodies were not tested as the test was not available at our centre. She had lower than detectable viral load and the CD4 count was 834 106 per l. A review of her medical records confirmed that she had a normal CD4 count (879, 41%) and undetectable viral load at the time of onset of symptoms. The other laboratory investigation results are summarised in Table 1. Based on the presence of sclerosis proximal to the metacarpophalangeal joints (MCPs), Raynaud's phenomenon, nail-fold capillary changes, sclerodactyly and digital ischaemia, a diagnosis of diffuse cutaneous juvenile SSc was made. She fulfilled the PReS/ EULAR/ACR criteria for classification of juvenile SSc [11]. Despite the absence of respiratory symptoms, pulmonary function tests revealed abnormal diffusion lung capacity for carbon monoxide (DLCO) of 65%, forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV1) of 74% of the predicted with no variation after bronchodilator administration. The high-resolution chest CT (HRCT) scan showed bilateral basal ground-glass changes, honey combing and sub-pleural air cysts (Fig. 2). The electrocardiogram and echocardiogram were normal with no features of cardiac dysfunction or pulmonary hypertension. Barium swallow showed dilatation of distal oesophagus with delayed emptying despite absence of symptoms (Fig. 3). No reflux was demonstrated. She had a reduced tear film dispersal time of 4 s (reference 410 s) consistent with conjunctivitis sicca. She was treated with methyl prednisone 10-mg/kg body weight for 3 days followed by oral prednisone 10 mg daily. She also received amlodipine 5 mg daily to manage the Raynaud's phenomenon and continued to receive her ARVs. She did not demonstrate evidence of immunity against Hepatitis A and B and received Hepatitis A and Hepatitis B (1 dose) vaccines as well as pneumococcal and Mumps, Measles, Rubella (MMR) vaccines prior to initiation of cyclophosphamide. She received monthly cyclophosphamide (500 mg/m2) infusions with a similar dose of 2-mercaptoethane sulphonate Na (MESNA) to reduce the risk of bladder toxicity. After the 3rd infusion, it was deemed too risky to administer further doses of cyclophosphamide in view of her HIV serostatus. She is currently maintained on prednisone (10 mg daily) and azathioprine. Overall, good improvement in vasculitic lesions (Fig. 1) and skin sclerosis was achieved with the MRSS improving from 23/51 to 12/51 over 9 months. Modest improvement was also observed in lung function parameters with the FVC and FEV1 improving from 1.06 to
B
Fig. 1. Fingertip vasculitic lesions with pulp tissue loss: (A) at diagnosis and (B) after 7 months.
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Table 1 Laboratory investigation results Investigation
Diagnosis (2/09/2013)
1st Cyclophosphamide (15/10/2013)
2nd Cyclophosphamide (25/11/2013)
3rd Cyclophosphamide (5/2/2014)
Post-cyclophosphamide review (14/07/2014)
Hb (mg/dl) Plt ( 109 per l) WBC ( 109 per l) Lymphocytes ( 109 per l) CD4 ( 106 per l) CD4% Viral load (copies/ml) ALT AST CRP (0.1–7.5 mg/l) ESR (0–15 mm/h) Creatine (30–48 mmol/l)
12.5 320 12.8 2.44 834 26.7 Lower than detectable 18 27 2.2 8 34
12.8 398 11.9 4.07 Not done Not done Not done 18 22 Not done 2 38
13.4 413 13.6 4.5 1560 36.4 Lower than detectable 31 27 Not done
12.4 513 17.2 1.03 406 39.4 Not done 17
12.5 449 14.3 1.29 398 30.7 Lower than detectable 21 24 Not done 18 31
34
2.2 12 44
Immunology test ANA Anti-RNP Anticentromere antibodies Myeloperoxidase (MPO) antibodies Anti-proteinase 3 antibodies Anti-topoisomerase 1 (Scl-70) Anti-ds DNA Anti-RNP70 antibodies Anti-SM antibodies
Result 1:1280 (speckled) 3.03 U/ml 0.7 EliA U/ml 0.2 EliA U/ml 0.3 EliA U/ml 0.5 EliA U/ml 1.7 IU/ml 1.0 EliA U/ml 1.0 EliA U/ml
Reference – r25.0 o7 o3.5 o2.0 o7 o10 o7 o7
Virology tests Epstein–Barr virus (EBV) IgG Cytomegalovirus (CMV) IgG Varicella antibodies (IgG)
Result Positive Positive Positive
Reference – – –
Other tests Triglycerides (mmol/l) Lactate dehydrogenase (U/l) Creatine kinase (U/l)
Result 0.8 226 125
Reference 0.4–1.2 142–261 26–145
1.27 l (74–90%) and 0.98–1.13 l/s (74–81%), respectively. The DLCO increased from 7.8 to 8.3 mm/min/mmHg (65–69%) 7 months after starting treatment. However, the DLCO reduced to 6.86 (54%) at the last follow-up. Comparison with earlier values was however difficult as it was done in a different (adults) unit due to logistical constraints at our centre. The results of these investigations and evaluations are summarised in Table 2. The radiologic features of oesophageal dysmotility persisted at the 7th month follow-up.
The viral load remained undetectable throughout the 10 months of follow-up. However, she developed lymphopaenia (1.03 109 per l) after two doses of cyclophosphamide. The lymphopaenia was associated with a drop in the absolute CD4 count from 834 (26.76%) at diagnosis to 406 (39.42%) after 7 months and 398 (30.72%) at the last review (after 10 months) (Table 1). Further, at the last review, she was found to have a swollen painful right ankle, and x-ray radiographs confirmed an unrecognised distal
Fig. 2. Chest HRCT scan showing bilateral posterior basal ground-glass appearance and honey combing (arrow).
Fig. 3. Barium swallow showing distal oesophageal dilatation (arrow).
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Table 2 Diagnostic investigation results Assessment
Time after diagnosis
MRSS (out of 51) DLCO mm/min/mmHg (% of predicted) FVC (% of predicted) FEV1 (% of predicted) CMAS (out of 52)
At diagnosis
1 Month (1st cyclophosphamide)
5 Months (3rd cyclophosphamide)
7 Months
10 Months
23 7.8 (65) 1.06 (74) 0.98 (74) 47
21 8.9 (74) (1.06) 74 1.00 (75) 48
28 7.1 (59) 1.07 (79) 0.97 (78) 46
29 8.3 (69) 1.11 (82) 0.99 (80) 49
12 6.86 (54) 1.14 (74) 1.06 (76) Not done
MRSS, modified Rodnan skin score; DLCO, diffusion capacity of carbon dioxide; FVC, forced vital capacity (litres); FEV1, forced expiratory volume (litres) in 1 s; CMAS, childhood myositis assessment scale.
tibial fracture sustained 2 days prior to the visit after minor trauma at home.
Discussion A review of the literature identified only two studies that reported cases of scleroderma in three HIV-infected persons. One other article retrospectively reviewed data on the rheumatic manifestations of HIV among 888 patients and identified one case of scleroderma [12]. This study was only accessed as an abstract however, and there was not enough information on the clinical features of the patient. One of the two included studies reported two middle-aged HIV-infected men who developed localised scleroderma after several years of HAART [6]. In the only published case report of HIV-associated systemic sclerosis, Sikdar et al. described a patient in whom HIV and systemic sclerosis were simultaneously diagnosed and proposed that HIV may have been responsible for the manifestations of systemic sclerosis. The patient developed symptoms of SSc in the background of immune suppression and responded well to therapy with steroids and HAART. Unlike that case, our patient developed symptoms of SSc seven years after HIV infection and HAART. She had good virologic suppression and normal CD4 counts. However, she showed disease (SSc) progression while on HAART and her condition was complicated by vasculitis and interstitial lung disease (ILD) for which she received cyclophosphamide as per international recommendations [13,14]. Many clinicians may be reluctant to use immunosuppressive agents in patients who are already immunocompromised.
Cyclophosphamide has been associated with progression of HIV symptoms in a SLE patient [15] and concerns about deterioration of the clinical symptoms of HIV remain when considering immunosuppressive agents in such patients. Efavirenz and cyclophosphamide are metabolised by the liver (cytochrome P450) and increased levels of active and toxic metabolites of cyclophosphamide may result [16]. Further, cyclophosphamide-induced bone marrow suppression may manifest with leucopenia and greater susceptibility to infections, which may portend a challenge in the management of HIV-infected patients. Despite these concerns, cyclophosphamide has been used for many years for HIV-associated malignancies in children with relatively good safety profile [17,18]. The risk of cyclophosphamide-induced cystitis may be reduced by the use of MESNA. Our patient experienced no HIV clinical disease progression. The viral load remained undetectable though there was reduction in the lymphocyte and CD4 counts (with normal CD4%) after two courses of intravenous cyclophosphamide, which has persisted 5 months after the last dose of cyclophosphamide. The persistent lymphopaenia may also be due to the current therapy with azathioprine, which is known to cause leucopenia [19]. Our patient did not however suffer any infections requiring specific outpatient or inpatient care as a result of the lymphopaenia. The pathogenesis of HIV-associated autoimmunity is not well understood. Direct cytopathic effect of the virus and HIVassociated immune dysregulation may be some of the contributing factors. Prokop and Jagodzinski [20] reported a high prevalence of antibodies to conserved complete retroviral pol sequences in the serum of mixed connective tissue disease (MCTD) and SSc patients suggesting that retroviruses may have a role in the pathogenesis of these diseases. Other investigators have demonstrated production
Table 3 Autoimmune conditions reported in HIV-infected patients (A): Summary of cases of autoimmune connective tissue diseases reported in HIV-infected children Diagnosis (reference)
SLE [30-32] JDM [29]
Total
Cases after HAART initiation
No.
No.
Age
Sex
Years on HAART before AID
CD4 at diagnosis
14 1
3 0
3.5, 14, and 18 8
2F and 1M M
1; 10; NR –
464; 1524; 243 770
(B): Summary of autoimmune connective tissue disease in HIV-infected persons Condition
Scleroderma DM SLE MCTD SS
Total number of cases
Cases occurring after HAART initiation
Ref.
No.
Sex (M:F)
Median age (range) years
No.
Time to AID (months)
CD4 (per mm3) at diagnosis
Viral load (copies/ml)
[5,6] [8,29] [7,9] [33], [10],
3 7 71 1 4
2M:1F 4M:3F 18M:53F F 3M:1F
44 (42–45) 27 (8–50) 28 (0.6–55) 26 47 (38–60)
2 1 19 0 4
4 60 12 33.5 (2–160) 5 NR NA 6, 48, 36, and 48
934; NR; 332 160 390 (267.5, 449) and 3 NR NA 62; 529; 506; and 810
NR NR 29,200 (391; 87,685) and 13 NR NA 1110; o 50; o50; 3170
AID, autoimmune disease; DM, dermatomyositis; MCTD, mixed connective tissue disease; SS, Sjögren's syndrome; NA, not applicable; NR, not reported.
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of SSc-like extracellular matrix proteins by normal human skin fibroblasts following induced expression of retroviral protein [21]. Molecular mimicry is one of the theories that may explain the association between retroviruses and systemic autoimmune diseases [22]. Cross-reactivity between antibodies to components of the HIV envelope glycoprotein (gp120/41) and anti-U1RNP antibodies has been reported [20]. Maul et al. [23] also demonstrated homology between DNA topoisomerase I and the retroviral p30gag protein. The anti-U1RNP antibodies are found in several connective tissue diseases including MCTD and systemic sclerosis (SSc) while DNA topoisomerase 1 is a diffuse systemic-sclerosis-marker antigen that occurs in about 30% of cases of SSc in adults. Environmental factors are thought to be the ultimate triggers of autoimmune diseases. Exposure to chemicals and drugs has been postulated as possible triggers for development of SSc [24]. Among the antiretroviral drugs, some case reports have associated the injectable fusion inhibitor, enfuvirtide with the development of sclerodermatous skin changes near injection sites [25]. Further, a possible increased risk of autoimmune disease exacerbation with the use of antiretroviral integrase inhibitors such as raltegravir has been suggested [26,27]. Our patient, however, had not been on these drugs or any of the other therapeutic agents currently thought or known to be associated with scleroderma. With increasing availability and use of HAART, the spectrum of autoimmune diseases reported in HIV-infected individuals has gradually widened. Some authors have described autoimmune conditions in the context of the immune reconstitution inflammatory syndrome (IRIS). Calabrese et al. [28] reviewed the literature and reported 26 cases of autoimmune diseases following initiation of HAART. Since then many other reports of autoimmune diseases including localised scleroderma [6], SLE [7,9], dermatomyositis [8,29] and Sjögren's syndrome [10] following initiation of HAART have been published (Table 3). However systemic sclerosis following initiation of HAART has not been reported. In the case reported here, features of SSc appeared seven years after initiation of HAART making IRIS an unlikely pathogenic mechanism in the case. In summary, our patient presented with classical features of systemic sclerosis that did not seem to have been influenced by the HIV infection. Since there was no obvious temporal link with any of the ARVs or changes in HIV clinical, immunological or viral load, the occurrence of the two conditions simultaneously could have been coincidental. She was treated with cyclophosphamide with modest improvement though her treatment was complicated by the development of mild lymphopaenia. Conclusion The pathogenesis of HIV-associated autoimmune diseases is still incompletely understood. HIV immune dysregulation may lead to development of autoimmune disease manifestations which may be classical or unique to HIV. The clinical manifestations of SSc in this patient was classical and did not seem to have been influenced by or unique to HIV. The occurrence of the two conditions together may have been coincidental with HIV immune dysregulation providing a conducive environment for the manifestations of SSc in a patient who was probably already genetically predisposed. Where appropriate and as dictated by the clinical manifestations, immunosuppressive agents such as cyclophosphamide may be safely used in the management of such patients. In such instances though, a careful monitoring of the lymphocyte and CD4 counts may be warranted. Acknowledgements We thank L.S. and her parents for allowing us to share her clinical information and photographs for this article.
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