Mycophenolate mofetil in the treatment of childhood systemic polyarteritis nodosa
- 1 Pediatrics, Om Hospital and Research Centre, Kathmandu, Bagmati, Nepal
- 2 Pediatrics, Post Graduate Institute of Medical Education and Research, Chandigarh, India
- Correspondence to Dr Dharmagat Bhattarai; dharmagat@yahoo.co.uk
Abstract
Polyarteritis nodosa (PAN) is a medium vessel vasculitis with necrotising vascular changes along with multisystemic involvement. Due to variable initial presentations, diagnosis of systemic PAN in children requires a comprehensive work up. In addition, systemic PAN needs an aggressive therapy. Mycophenolate mofetil is an emerging newer alternative for the treatment of PAN. We report a case of childhood systemic PAN who initially presented with subtle signs like reduced sensation over lateral foot, non-deforming arthritis and multiform rashes. After comprehensive aetiological work up, nerve biopsy and supporting evidence clinched the diagnosis. Vasculitis in children presenting with benign subtle signs is sometimes a diagnostic challenge to clinicians. Our case highlights the importance of lateral thinking while dealing with non-specific multisystemic signs. Evidence of successful treatment of PAN with mycophenolate mofetil is gradually being built up. It is also described to result lower relapse and increased treatment free survival rate.
Background
Polyarteritis nodosa (PAN), a necrotising medium vessel vasculitis, may have a varied presentation ranging from limited cutaneous involvement to widespread systemic manifestations. ‘Systemic’ PAN in children (c-sPAN) usually presents with cutaneous, musculoskeletal, renal and neurological manifestations which are embodied in the recent classification criteria for c-PAN.1 These children require aggressive therapy with pulse doses of intravenous methylprednisolone and cyclophosphamide (CYC).2 Mycophenolate mofetil (MMF) is an emerging alternative to CYC which may have a more favourable adverse effect profile in treatment of c-PAN. However, evidence for efficacy of MMF in c-sPAN is limited to a handful of reports only and utility of MMF therapy in severe/life-threatening forms of c-sPAN remains unevaluated.3 Herein, we report a case of c-sPAN who was managed successfully with steroids and MMF. The illness in the index child began with multiform skin rashes (including livedoid rash) only which evolved to c-sPAN over the next 7 months. Our case also highlights the prudence of careful follow-up of children with a livedoid rash.
Case presentation
An 11-year-old boy presented with hyperpigmented multiform itchy scabietic rashes which later changed into livedoid rashes over bilateral upper and lower limbs, back and cheek (figure 1A,B). After few weeks he started to have tingling, numbness, change in colour of finger-tips and symmetrical non-migratory non-deforming swelling and pain in bilateral large joints of upper and lower limbs. He also had progressively reduced sensation over the lateral aspect of the upper surface of the right foot after 7 months of disease onset. With steroid treatment, there was mild improvement in symptoms.
Skin lesions of the patient. (A) Itchy hyperpigmented scabietic lesions in dorsum of foot. (B) Hyperpigmented rashes in lateral side of neck. (C) Livedoid rashes evolved from scabietic rashes in legs. (D) Raynaud phenomena noticed in the toes. (E) Livedo racemosa lesions developed over the leg and lateral foot.
On examination, he had hypopigmented scaly coalescent macules over upper chest, lacy generalised hyperpigmented livedo racemosa over bilateral upper and lower limbs, lower back and left cheek sparing palm and soles (figure 1C–E). Though he had no motor deficit, reduced sensation was noted over the lateral margin of the dorsum of right foot. Symmetrical non-deforming arthritis was found over the bilateral ankle, wrist, metatarsophalangeal and metacarpophalangeal joints.
Investigations
Initial investigation showed normal hemogram, biochemical and metabolic profile with elevated erythrocyte sedimentation rate (18 mm in first hour) and C reactive protein (CRP) (8 mg/L). Infectious work up including tubercular tests were unremarkable. Venous and arterial dopplers were normal. Immunoglobulin IgG, IgA, IgM along with IgG subclass levels were normal. Antinuclear antibodies, anti-double stranded DNA antibodies, extractable nuclear antibodies panel and antineutrophilic cytoplasmic antibodies were negative. CT scan of chest and abdomen were normal. Skin biopsy showed orthokeratosis, basal cell hyperpigmentation with dermis consisting fibro-collagenous tissue and dilated capillary vessels with intravascular aggregates of red blood cells (RBC) along with perivascular lymphocytic cells without immune deposits. Interferonopathy and cryoglobulinemia were ruled out due to the age of presentation and lack of clinical pattern. There was no deficiency of activity of adenosine deaminase (ADA) type 2 level in blood (table 1).
Laboratory and radiological investigations
| 1A. Laboratory investigations | |
| Haemoglobin (g/L) | 126 |
| Platelets (cells/mm3) | 359 000 |
| Total leucocyte count (cells/mm3) | 7230 |
| Differential leucocytes count (%) | N57L32M07E04 |
| Erythrocyte sedimentation rate (mm in first hour) | 18 |
| C reactive protein (mg/L) | 8 |
| Mantoux test/VDRL/nitroblue tetrazolium dye reduction test | Negative |
| Serum ferritin (µg/L)/lactate dehydrogenase (U/L)/creatine phosphokinase | 100/219 |
| HIV, HCV and HBsAg serologies | Non-reactive |
| Antineutrophilic cytoplasmic antibodies (myeloperoxidase and anti-PR3) | Negative on immunofluorescence; enzyme linked assays: anti-MPO=0.035 RU/mL and anti-PR3=0.41 RU/mL |
| Antinuclear antibodies (immunofluorescence) | Negative |
| Extractable nuclear antibodies (immunoblot) | Negative |
| Cryoglobulins; complements C3 and C4 | Normal |
| Level of adenosine deaminase type 2 (ADA-2) | Normal |
| Immunoglobulin (Ig) profile | IgG=928 mg/dL (754–1553); IgA=69 mg/dL (47.7–212.8); IgM=137 mg/dL (73.6–221), IgG4=32 mg/dL |
| Antiphospholipid antibodies (lupus anticoagulant, anticardiolipin antibodies and anti-β2 GPI antibodies IgG and IgM) | Negative |
| 1B. Radiological investigations | |
| Ultrasonogram of abdomen and pelvis | Normal study |
| Contrast enhanced CT of head and abdomen | Normal study |
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CT, Computed Tomography; E, eosinophils; GPI, Glycoprotein 1; HBsAg, hepatitis B surface antigen; HCV, hepatitis C virus; HIV, Human Immunodeficiency virus; L, lymphocytes; M, monocytes; N, neutrophils; VDRL, venereal disease research laboratory test.
Sural nerve biopsy showed the presence of demyelination with replacement fibrosis and marked loss of both small and large axons sparing only a few large myelinated fibres. Larger-sized artery was seen with dense neutrophilic infiltration along with fibrinoid necrosis and RBC extravasation. Smaller-sized arteries showed recanalising thrombus and thickened media suggesting healing. These findings were suggestive of polyarteritis nodosa.
Differential diagnosis
With multiform rashes, non-deforming arthritis, Raynaud’s-like phenomenon, peripheral neuropathy, non-specific constitutional symptoms, possibilities like postinfectious or immune vasculitis were considered. Work up for various infections including tuberculosis, syphilis and various bacterial and viral diseases were unremarkable. Among immune vasculitis, we kept possibilities of PAN, deficiency of ADA-2 (a monogenic variant of PAN), cryoglobulinemia, IgG4-related disease and interferonopathy.
Interferonopathy was disregarded in view of late age of presentation and involvement limited to cutaneous and skeletal system only. Though symptoms began in colder temperatures and worsened in cold exposures, negative hepatitis viral serologies, rheumatoid factor along with normal complements, monoclonal immunoglobulins and biopsy findings were against the consideration of cryoglobulinemia. IgG subclass levels were withing normal limits.
In view of temporal heterogeneity and typical nerve biopsy findings, a diagnostic possibility of PAN was offered. Diagnosis was strengthened by clinical evidence of livedoid rash, neuropathy, arthritis, Raynaud phenomenon, some improvement in rash on steroids, age of presentation and skin biopsy findings.
Treatment
MMF is described to have promising result in systemic PAN, we commenced child on MMF (600 mg/m2/dose “two times per day). In addition, nifedipine and tapering dose of steroids were also added on the treatment regimen.
Outcome and follow-up
A follow-up after 6 months, his arthritis, skin lesions, Raynaud phenomenon were improved while neuropathy was gradually becoming better.
Discussion
Systemic PAN is among the rare paediatric vasculitides with an incidence of about 1 case per 106 children per year.4 Hence, there is a paucity of clinical trials comparing various treatment modalities in c-sPAN. The only trial (MYPAN) published to date had an open-label design and compared MMF with CYC which were employed in 6 and 5 children, respectively.3 Besides, deficiency of ADA-2, an important confounding factor determining treatment efficacy in patients presenting with PAN, was not ruled out in all patients in this study. Furthermore, individual case reports/series describing the effectiveness of MMF as induction therapy in c-sPAN in the real-world (out of trial) clinical setting are also sparse. We, herein, report successful induction of c-sPAN with MMF.
In the MYPAN trial, remission at 6 months of treatment was noted in 4 of 6 patients on MMF as compared with 4 of 5 patients on CYC therapy. In a recently published study from Turkey, 3 patients received MMF as induction therapy (included in MYPAN trial); however, the authors noted these patients to have a lower disease activity as compared with the rest of their c-sPAN cohort.5 The same study group has previously noted lower CRP levels and lower frequency of weight loss in c-sPAN as compared with adult systemic PAN (a-sPAN).6 Besides, neurological and possibly gastrointestinal and cardiovascular involvement may be less frequent in c-sPAN as compared with a-sPAN.6 7 These features may suggest lower severity of inflammation in c-sPAN at diagnosis as compared with a-sPAN. We also noted a milder course of PAN in our case which was managed successfully with steroids and MMF. Taken together, MMF may, hence, be a more suitable option for remission induction in c-sPAN, especially, the non-severe/non-life-threatening forms of the disease.
It is prudent to mention that the French Vasculitis Study Group has noted a lower relapse and treatment free survival in c-sPAN as compared with a-sPAN.7 In the MYPAN trial, no relapses occurred in either arm at 1.5 years of follow-up. Therefore, patients with c-sPAN treated with MMF may require a cautious follow-up. Careful assessment of disease severity at diagnosis of c-sPAN and subsequent treatment with CYC in severe cases and MMF in less severe cases may provide the best risk-benefit ratio.
Besides, medium vessel vasculitis especially in children who present with subtle benign presentation at the beginning may be a challenge to clinician. Though classification criteria include necrotising vasculitis in histopathology or imaging, cutaneous, muscular and renal involvement, c-sPAN may begin with a benign skin lesion or subtle neurological symptoms which can easily be misleading for clinicians. Our case highlights the importance of lateral thinking when a child is presenting with multiple different kinds of skin rashes over a period of time. It also emphasises the importance of sensory examination and invasive tests to reach a diagnosis.
Patient’s perspective
I am mother of the patient. I and child’s father were puzzled with non-specific findings like various types of rashes which change their appearance. We were consulting in multiple specialties to reach a diagnosis. Finally, we reached this paediatric rheumatology clinic where multidisciplinary approach was adopted and diagnosis of PAN was reached. With steroid and MMF, child has improved a lot. We are happy with the outcome. We agree for clinical detail and publication in journal.
Learning points
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Polyarteritis nodosa in children may present with benign multiform skin and neuropathic signs.
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Multiform rashes and sensory decrement should raise suspicion of medium vessel vasculitis.
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Skin and nerve biopsy can be important aid to diagnose the queer childhood vasculitic diseases.
Ethics statements
Patient consent for publication
Footnotes
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Contributors DB: Writing and editing manuscript, collection, analysis, and interpretation of data drafting the work and revising it critically for intellectual content, final editing. AZB: Writing and editing manuscript, collection, analysis, and interpretation of data drafting the work and revising it critically for intellectual content, final editing. HN: Acquisition, analysis, or interpretation of data for the work. AG: Conception of work, interpretation of data, editing and final approval.
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Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
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Case reports provide a valuable learning resource for the scientific community and can indicate areas of interest for future research. They should not be used in isolation to guide treatment choices or public health policy.
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Competing interests None declared.
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Provenance and peer review Not commissioned; externally peer reviewed.
- © BMJ Publishing Group Limited 2022. No commercial re-use. See rights and permissions. Published by BMJ.
References
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