Polyarteritis nodosa isolated to muscles-A case series with a review of the literature

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Polyarteritis nodosa isolated to muscles- A case series with a review of the literature Luckshman R. Ganeshanandan MBBS, BMedSc , Anna M. Brusch BA, MBChB, FRACP, FRCPA , Jason M. Dyke MBChB, FRCPA , Andrew P.C. McLean-Tooke BSc, MBChB, MD, FRCP, FRCPath, FRCPA, FRACP PII: DOI: Reference:

S0049-0172(19)30723-1 https://doi.org/10.1016/j.semarthrit.2019.12.002 YSARH 51571

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Seminars in Arthritis & Rheumatism

Please cite this article as: Luckshman R. Ganeshanandan MBBS, BMedSc , Anna M. Brusch BA, MBChB, FRACP, FRCPA , Jason M. Dyke MBChB, FRCPA , Andrew P.C. McLean-Tooke BSc, MBChB, MD, FRCP, FRCPath, FRCPA, FRACP , Polyarteritis nodosa isolated to muscles- A case series with a review of the literature, Seminars in Arthritis & Rheumatism (2019), doi: https://doi.org/10.1016/j.semarthrit.2019.12.002

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Polyarteritis nodosa isolated to muscles- A case series with a review of the literature. Luckshman R. Ganeshanandan1,2, MBBS, BMedSc, Anna M. Brusch1,2, BA, MBChB, FRACP, FRCPA, Jason M. Dyke3, MBChB, FRCPA Andrew P.C. McLean-Tooke1,2, BSc, MBChB, MD, FRCP, FRCPath, FRCPA, FRACP Department of Clinical Immunology, PathWest Laboratory Medicine WA, Queen Elizabeth II Medical Centre, Perth, Western Australia, Australia 1 Department of Clinical Immunology, Sir Charles Gairdner Hospital, Perth, Western Australia, Australia 2 Department of Neuropathology, PathWest Laboratory Medicine, Royal Perth Hospital, Perth, Western Australia, Australia 3

Luckshman Ganeshanandan1,2 [email protected] Department of Clinical Immunology Sir Charles Gairdner Hospital Hospital Avenue, Nedlands, Perth, Western Australia 6009

Abstract Muscular polyarteritis nodosa where disease is isolated to skeletal muscle is a rare and often poorly recognised clinical entity. Patients typically present with fever and severe muscle pain limiting ability to ambulate without rise in creatine kinase. Often there is a significant delay between presentation and diagnosis, which requires histological confirmation. Musculoskeletal MRI is a sensitive investigation that can lead to timely biopsy and improve diagnostic yield. Early diagnosis of this condition is essential as patients typically respond favourably to corticosteroid treatment. Here we report 4 cases of muscular polyarteritis nodosa and review the reported literature. Keywords Polyarteritis Nodosa; Vasculitis; Muscular; Myositis

1. Introduction Polyarteritis nodosa (PAN) is a necrotising vasculitis characteristically involving medium and small calibre blood vessels in a multisystem distribution, most commonly

the

visceral,

renal

and

cutaneous

vasculature.

Occasionally,

presentations of PAN may be localised to a single organ system, most commonly the skin or testis [1]. Muscular PAN (M-PAN), where involvement is confined to the skeletal muscle has rarely been reported [2, 3]. We describe four patients diagnosed with M-PAN presenting with marked fevers and severe limb pain without weakness or elevation of creatine kinase (CK). The diagnoses were made following MRI and subsequent biopsy of affected muscle. 2.1 CASE 1 A 53-year-old male presented with a 5-day history of abrupt onset severe generalised myalgia associated with pyrexia and malaise. The myalgia affected most muscle groups but was most severe in the thighs and lumbar region of his back. He was unable to stand or walk due to severe pain. Examination showed preserved power in all muscle groups but severe tenderness on palpation of all compartments of the lower limbs, with exacerbation on extension and flexion of affected muscle groups. He was pyrexial up to 39°C. There was no swelling or cutaneous eruption. Laboratory evaluation revealed a neutrophil predominant leucocytosis of 30 cells/uL (normal range 4.0-11.0), elevated C-reactive protein (CRP) of 440 mg/ml (normal range <5) and elevated erythrocyte sedimentation rate (ESR) of 85 mm/hr (normal range <20). CK was 30 U/L (normal range 30-190). Extensive microbiological studies including viral hepatitis, human immunodeficiency virus (HIV) and bacterial and fungal cultures were negative. Autoantibody screen including antinuclear antibodies

(ANA), anti-neutrophil cytoplasmic antibody (ANCA), myositis specific antibodies and serum complement levels were within normal limits. MRI of the spine showed features suggestive of paraspinal myositis. MRI of the bilateral thighs revealed extensive muscle oedema within the anterior and proximal adductor compartments bilaterally, with inter-muscular and subcutaneous oedema, consistent with myofasciitis. Computed Tomography (CT) angiogram of the abdomen and lower limbs did not identify characteristic findings associated with PAN. Positron emission tomography (PET) scan showed low grade diffuse uptake involving the anterior and proximal adductor compartment muscles of the thighs corresponding to the MRI findings. A diagnosis of M-PAN was reached 18 days following presentation after a muscle biopsy of right vastus lateralis (targeted by MRI findings) confirmed active chronic vasculitis of small and medium sized epimysial arteries with focal fibrinoid necrosis and mixed inflammatory infiltrate. Following commencement of intravenous methylprednisolone 250 mg for 3 days, the patient’s pain dramatically improved with marked reduction in inflammatory markers. He was commenced on prednisolone 60 mg in addition to intravenous cyclophosphamide (15 mg/kg). Following 3 cycles of cyclophosphamide he was unable to wean prednisolone below 50 mg due to myalgia and rising inflammatory markers. Cyclophosphamide was abandoned and 2 doses of Rituximab 1 g were given one fortnight apart. His disease flared again upon attempting to reduce steroid dose approximately 3 months after Rituximab despite persistent B-cell depletion. He was treated with a further pulse of IV methylprednisolone and commenced on high dose intravenous immunoglobulin (IVIG) 2 g/kg over 4 days. Two further cycles of

maintenance dose IVIG 1g/kg were given and methotrexate was commenced. Prednisolone dose has been gradually reduced and he remains clinically well 3 months after commencement of IVIG therapy. 2.2 CASE 2 A 78-year-old male presented with a 3-day history of pyrexia and myalgia that limited walking due to severe pain. Examination revealed fever to 40°C. Muscle power was normal but there was marked tenderness on palpation of calf muscles bilaterally. There was no swelling or cutaneous eruption. Laboratory evaluation revealed a neutrophil predominant leucocytosis of 28 cells/uL (normal range 4.0-11.0). CRP peaked at 260 mg/ml (normal range <5). CK was 22 U/ml (normal range 30-190). Infectious screen including viral hepatitis serology was negative. Autoantibody screen was negative and PET imaging was normal. MRI of the lower legs demonstrated widespread muscle oedema involving all four compartments bilaterally, with inter-muscular, deep investing fascia and subcutaneous oedema also present. Biopsy of the gastrocnemius muscle demonstrated severe, chronic vasculocentric inflammation with a mixed inflammatory infiltrate including neutrophils, T-lymphocytes and macrophages. This transmural inflammation predominantly affected small muscularised epimysial arteries and arterioles with low-grade secondary interstitial myositis, without features of a primary myositis. These findings were in keeping with a clinical diagnosis of M-PAN which was made 1 month following presentation. Oral prednisolone (1 mg/kg) was commenced with dramatic improvement in pain and resolution of pyrexia within 24 hours. The patient

has remained well with steroid monotherapy and has tolerated a reduction in dose to 10 mg, 6 months after initial presentation. 2.3 CASE 3 A 23-year-old female presented with a 3-week history of progressive swelling and pain in the left lower limb such that she was unable to walk due to pain. Her history was significant for co-morbid renal disease, having been diagnosed aged 9 with nephrotic syndrome secondary to focal segmental glomerulosclerosis (FSGS). She had sequentially received high dose steroids, cyclosporine and 3 doses of cyclophosphamide. A flare of renal disease had been treated with rituximab 6 months prior to presentation. She remained on tacrolimus and mycophenolate for FSGS at the time of presentation. Examination revealed tender, non-pitting induration localised to the left lower leg without rash. She was apyrexial and muscle power was normal. Laboratory evaluation showed mild leucocytosis with neutrophilia of 13 cells/uL (normal range 4.0-11.0). CRP was 36 mg/L (normal range <5) and ESR 76 mm/hr (normal range 120). CK was 29 U/L (normal range 30-190). Autoantibody screening was negative. PET imaging was not performed. MRI revealed diffuse muscle oedema within all four compartments of the left leg. In addition, patchy muscle oedema was evident in the anterior and distal posterior compartment of the left thigh and within the plantar muscles of the left foot. Biopsy of the medial gastrocnemius muscle showed multifocal necrotising vasculitis of medium and small epimysial and perimysial arteries, with a mixed inflammatory cell infiltrate. CT angiogram of abdomen and lower limbs did not reveal characteristic findings of

PAN. These findings supported a clinical diagnosis of M-PAN, which was made 2 weeks after initial admission. Following commencement of intravenous methylprednisolone 250 mg for 3 days, there was a rapid clinical response. Oral prednisolone (1 mg/kg) was weaned to 7.5 mg over 18 months without clinical recurrence. Mycophenolate and tacrolimus were continued as part of management of primary FSGS. 2.4 CASE 4 A 42-year-old male presented with a 4-week history of recurrent pyrexia and bilateral calf myalgia. He described abrupt onset pyrexia with initially migratory myalgia, before becoming most prominent in the calves. He was unable to walk due to severe calf pain. Examination revealed pyrexia up to 38.9°C. Muscle power was normal but there was tenderness on palpation of the calves bilaterally. There was no rash or swelling noted. Laboratory evaluation revealed neutrophil predominant leukocytosis of 22 cells/uL (normal range 4.0-11.0). CRP was 130 mg/L (normal range <5.0 mg/L) and ESR was 87 mm/hr (normal range 1-20 mm/hr). CK was 24 U/L (normal range 30-190). Infectious screens were negative. Autoantibody serology revealed negative ANA and ANCA. MRI of the lower legs demonstrated widespread muscle oedema involving all four compartments bilaterally, suggestive of myositis. Biopsy of gastrocnemius muscle showed a necrotising, non-granulomatous vasculitis of small epimysial arteries and arterioles, without associated myositis. A clinical diagnosis of M-PAN was made 3 weeks after initial admission. PET imaging was performed following confirmed

diagnosis to assess for additional foci of activity. Significantly increased uptake was noted only at the site of biopsy. The patient was commenced on oral prednisolone (1 mg/kg) with significant clinical response within hours of administration. Methotrexate was commenced at diagnosis as a steroid sparing agent. The patient weaned and ceased prednisolone over 12 months without return of symptoms. Methotrexate was ceased 12 months later and the patient has remained symptom free since that time. 3. Literature review and analysis 3.1 Methods A review of English language articles published in databases Pubmed, OVID, and Medline from 1990 to current was conducted, using MESH terms including “muscle polyarteritis nodosa”, “limb-restricted polyarteritis nodosa”, “muscular polyarteritis nodosa” and “localised polyarteritis nodosa”. Bibliographies were also reviewed and additional identified references were assessed. Cases with clear evidence of additional organ involvement including cutaneous, genitourinary or nervous system were excluded (Figure 1). This yielded 14 publications and a total of 19 patients (inclusive of our series) presenting with isolated muscular PAN (Table 1). 3.2 Results The mean age of presentation was 47 years with 2:1 distribution of male and female patients, similar to the expected epidemiology of PAN [4]. Of the 17 cases where presence or absence of pyrexia was reported, 12/17 (71%) of patients were pyrexial. Patients presented with predominantly lower limb disease (18/19), with the calves the most frequently involved muscle groups (16/19). Despite muscle pain and MRI

changes, an elevated CK was only reported in 1/19 (5%) of cases. The median time to diagnosis was 3 months and included two patients with over 3 years diagnostic delay [5, 6]. Inclusive of our reported cases, 13 patients underwent MRI. Whilst abnormal in all cases, findings were relatively heterogeneous and non-specific. Radiological features included diffuse or patchy increased short tau inversion recovery (STIR) signal in muscle, fascia and periosteum [7]. In contradistinction, PET imaging was performed in just 4 of the 19 reported cases and only confirmed pathological metabolic uptake in 1 (25%) patient. Histologically, the biopsy features of all reported cases were compatible with PAN. Necrotising small and medium vessel vasculitis was identified in all patients where histological features were described, with fibrinoid necrosis noted in 45% of reported samples. Myonecrosis was absent in all cases, although two reported extension of the inflammatory process into adjacent muscle and fibroadipose tissue [2, 8]. The first line therapy for all patients with M-PAN was corticosteroids. The majority of patients were treated with prednisolone at doses of 1 mg/kg, although one patient [9] in addition to Case 2.1 received methylprednisolone for induction. Only four patients previously reported in the literature were treated with a steroid sparing agent. One received methotrexate [9], two received azathioprine [3, 10] and another was treated with IVIG [11]. Inclusive of our series, 15 of the 19 cases reported follow up data. All patients were initially responsive to prednisolone with often dramatic and rapid response to initiation of treatment. Including our series, only two patients were reported to be unsuccessful in achieving remission [11], although a further three (16%) patients suffered relapse on prednisolone withdrawal [2, 5, 12].

4. Discussion Classical PAN most commonly affects the kidney, peripheral nerves, skin and gastrointestinal tract. Musculoskeletal involvement is not uncommon, but typically occurs as part of a multisystem disease [13]. Localised PAN has been reported but typically involves the skin or testis [3]. M-PAN is a rare but important subtype of PAN [1-3, 7, 14, 15]. When present, it typically involves a single muscle group, most commonly the gastrocnemius muscle. However, we also describe 1 patient with both clinical and radiological evidence of forearm compartment and paraspinal involvement, which, to our knowledge, has not previously been described. Although lower limbs were affected in all identified cases, it is likely that muscular PAN can affect any muscle group. The presentation of M-PAN in our case series, is notable for the severity of muscle pain which was often out of keeping with the clinical signs. In all our cases, despite being unable to ambulate due to severe pain and with significant tenderness on muscle palpation, the muscle power was preserved and the CK levels remained normal. Indeed, inclusive of cases from the reviewed literature, only one patient where this information was reported had elevation of CK. Muscular PAN does not cause a primary myositis but rather involves the investing fascial planes and supplying small to medium blood vessels. A secondary interstitial myositis was seen in one case highlighting that biopsy was critical in securing a diagnosis. The diagnosis of M-PAN is challenging with relatively non-specific presentations and diagnostic delay is frequently a feature of this condition. No serological testing is helpful in excluding PAN but selected autoimmune serological tests should be undertaken to exclude important differential diagnoses. MRI of affected muscles,

whilst not specific [7], is a useful adjunct in directing appropriate site and increasing diagnostic biopsy yield. PET imaging, on the hand, lacks sensitivity and is not an optimal imaging modality for exclusion of PAN. Histological findings of PAN include necrotising vasculitis of arteries, often at branch points with aneurysmal dilatation, fibrinoid necrosis and neutrophil infiltration of vessel wall [16]. In our case series the vasculitic inflammatory cell infiltrate was mixed, with neutrophils present in addition to T-lymphocytes and macrophages. All our patients responded within 24 hours of corticosteroid administration, with substantial reduction in pain, fever and inflammatory markers. Treatment with corticosteroids invariably results in therapeutic response, although the need for and optimal steroid sparing agent is yet to be determined. Nonetheless, the majority of patients described have a relatively monophasic trajectory, enabling weaning and withdrawal of immunosuppression, although long-term data has not been reported in most published cases. Muscular PAN is a rare but important subtype of localised PAN. The non-specific presentation and limited awareness of this condition amongst clinicians often leads to diagnostic delay. A high index of suspicion is required in patients with severe myalgia, normal muscle power and CK levels with elevated inflammatory markers and should raise the need for MRI and targeted muscle biopsy, which are critical for timely diagnosis and treatment.

Conflict of interest The authors do not report a conflict of interest in the publication of this manuscript. Funding

This work did not receive funding from any source in the completion of this manuscript. Acknowledgments Dr Reimar Junckerstorff and Dr Jason Dyke from Department of Neuropathology, PathWest Laboratory Medicine, Royal Perth Hospital, Perth WA for providing diagnostic reports and interpretation of biopsy specimens. References 1. Kamimura T, Hatakeyama M, Torigoe K, Nara H, Kaneko N, Satou H, et al. Muscular polyarteritis nodosa as a cause of fever of undetermined origin: a case report and review of the literature. Rheumatol Int. 2005;25(5):394-7. 2. Nakamura T, Tomoda K, Yamamura Y, Tsukano M, Honda I, Iyama K. Polyarteritis nodosa limited to calf muscles: a case report and review of the literature. Clin Rheumatol. 2003;22(2):149-53. 3. Gallien S, Mahr A, Rety F, Kambouchner M, Lhote F, Cohen P, et al. Magnetic resonance imaging of skeletal muscle involvement in limb restricted vasculitis. Ann Rheum Dis. 2002;61(12):1107-9. 4. Mahr A, Guillevin L, Poissonnet M, Ayme S. Prevalences of polyarteritis nodosa, microscopic polyangiitis, Wegener's granulomatosis, and Churg-Strauss syndrome in a French urban multiethnic population in 2000: a capture-recapture estimate. Arthritis Rheum. 2004;51(1):92-9. 5. Hofman DM, Lems WF, Witkamp TD, Putte VD, Bijlsma JW. Demonstration of calf abnormalities by magnetic resonance imaging in polyarteritis nodosa. Clin Rheumatol. 1992;11(3):402-4. 6. Reading PJ, Hudgson P, Johnson MA, Jenkins A. A sartorial challenge. Lancet. 1999;354(9183):996. 7. Kang Y, Hong SH, Yoo HJ, Choi JY, Park JK, Park J, et al. Muscle Involvement in Polyarteritis Nodosa: Report of Eight Cases With Characteristic Contrast Enhancement Pattern on MRI. AJR Am J Roentgenol. 2016;206(2):378-84.

8. Hall C, Mongey AB. Unusual presentation of polyarteritis nodosa. J Rheumatol. 2001;28(4):871-3. 9. Tripoli A, Barsotti S, Pollina LE, Della Rossa A, Neri R, d'Ascanio A, et al. Muscular vasculitis confined to lower limbs: description of two case reports and a review of the literature. Rheumatol Int. 2017;37(12):2115-21. 10. Haroon M, Bermingham N, Keohane C, Harney S. Polyarteritis nodosa presenting with clinical and radiologic features suggestive of polymyositis. Rheumatol Int. 2012;32(4):1079-81. 11. Taniguchi Y, Ogata K, Yoshimatsu R, Yamagami T, Terada Y. Polyarteritis Nodosa of the Iliopsoas Muscle. Arthritis Rheumatol. 2015;67(9):2426. 12. Yang SN, Cho NS, Choi HS, Choi SJ, Yoon ES, Kim DH. Muscular polyarteritis nodosa. J Clin Rheumatol. 2012;18(5):249-52. 13. Plumley SG, Rubio R, Alasfar S, Jasin HE. Polyarteritis nodosa presenting as polymyositis. Semin Arthritis Rheum. 2002;31(6):377-83. 14. Garcia F, Pedrol E, Casademont J, Mellado B, Cordoba R, Cid M, et al. Polyarteritis nodosa confined to calf muscles. J Rheumatol. 1992;19(2):303-5. 15. Khellaf M, Hamidou M, Pagnoux C, Michel M, Brisseau JM, Chevallier X, et al. Vasculitis restricted to the lower limbs: a clinical and histopathological study. Ann Rheum Dis. 2007;66(4):554-6. 16. Arkin A. A Clinical and Pathological Study of Periarteritis Nodosa: A Report of Five Cases, One Histologically Healed. Am J Pathol. 1930;6(4):401-26 5. 17. Esteva-Lorenzo FJ, Ferreiro JL, Tardaguila F, de la Fuente A, Falasca G, Reginato AJ. Case report 866. Pseudotumor of the muscle associated with necrotizing vasculitis of medium- and small-sized arteries and chronic myositis. Skeletal Radiol. 1994;23(7):572-6. 18. Lupoli S, Gargiulo A, Rossi R, Ames PR. Myositis as a presenting feature of polyarteritis nodosa. Clin Exp Rheumatol. 2004;22(4):507-8. 19. Andres M, Sivera F, Alonso S, Pack C. MRI myositis sine myositis: the importance of the histopathology. Rheumatology (Oxford). 2015;54(1):76.

Figure 1 (appended)

Fig. 2A. Case 1: Small epimysial artery in transverse section showing perivascular cuffing by a mixed inflammatory cell infiltrate with infiltration of the tunica media by neutrophils and early fibrinoid necrosis of the tunica intima and inner tunica media. (H&E, 200x) Fig. 2B. Case 2: Longitudinal section of an epimysial artery showing more florid neutrophil infiltration of the tunica media than that seen in Case 1 (Fig. A). (H&E, 200x) Fig. 2C. Case 3: Longitudinal section of an artery in the fibroadipose connective tissue adjacent to the skeletal muscle, with vasculitic changes as described for Fig.’s A. and B. (above) and patchy partial and full thickness fibrinoid necrosis of the vessel wall. (H&E, 100x). Fig. 2D. Case 4: Epimysial arteriole in transverse section with inflammatory cell infiltrate and partial-thickness fibrinoid necrosis of the vessel wall. (H&E, 200x).

* Colour print required

Figure 3. Initial axial T2 fat saturated MRI of the bilateral thighs: Increased T2 signal (muscle oedema) involving the anterior and proximal adductor compartment muscles bilaterally, with inter-muscular oedema.

* Colour print not required

Figure 4. Axial STIR imaging of the bilateral lower legs: Widespread patchy increased STIR signal (muscle oedema) involving muscles of all four compartments bilaterally consistent with myositis, with inter-muscular and deep investing fascial oedema.

* Colour print not required

Table 1. Muscular Polyarteritis Nodosa cases with clinical involvement limited to muscles only reported. Case (refere nce)

Da te

Age/Ge nder

Onset Fev to er diagno sis

C Affected K muscle ris e

M RI

Initial treatm ent

Recurre nce

1 [14]

19 92

23/F

9 NA months

N A

Left tibialis anterior, peroneus longus and peroneus brevis

N P

PNL

No

2 [14]

19 92

25/M

3 Yes months

N A

Right N anterior P and posterior compartme nt muscles of the leg

PNL

No

3 [5]

19 92

36/F

?

Yes

N A

Gastrocne mius, tibialis anterior, extensor digitorum longus

Ye s

Steroid Yes

4 [17]

19 94

56/M

7 year

Yes

N A

Right quadriceps and biceps femoris

Ye s

PNL

No

5 [6]

19 99

38/M

3 years Yes

No Sartorius muscle

Ye s

PNL

No

6 [8]

20 01

54/M

3 days

No Left tibialis anterior and gastrocne mius

N P

PNL

No

7 [3]

20 02

40/M

3 No months

No Left peroneus longus, peroneus brevis, and tibialis

Ye s

PNL, Aza

Yes

Yes

anterior 8 [2]

20 03

38/F

1 week

9 [18]

20 04

68/M

10 [1]

20 05

11 [10]

No

No Bilateral gastrocne mius

Ye s

PNL

No

2 Yes months

Ye Proximal s muscles of the lower limbs

N P

PNL

?

59/M

3.5 Yes months

N P

N P

PNL

No

20 11

65/F

3 weeks

No All Ye compartme s nts of lower limbs bilaterally

PNL, Aza

No

12 [12]

20 12

26/M

3 No months

No Bilateral soleus left gastrocne mius

PNL

Yes

13 [19]

20 14

67/F

?

No All Ye compartme s nts of lower leg

?

?

14 [9]

20 15

27/F

8 Yes months

No All Ye compartme s nts of thighs and calves bilaterally

MP, MTX

No

15 [11]

20 15

67/M

2 weeks

Yes

N A

PNL, IVIG

?

Case1

20 19

53/M

3 weeks

Yes

No Lumbar Ye paraspinal, s anterior and proximal adductor compartme nt thighs

MP, CYC, RTX, IVIG

Yes

Case2

20 19

78/M

5 weeks

Yes

No Bilateral gastrocne mius muscle

PNL, Aza

No

Yes

NA

Bilateral calves

Left iliopsoas

Ye s

N P

Ye s

Case3

20 19

22/F

5 weeks

No

No Left Ye posterior s lateral and anterior compartme nt of the leg in addition to the plantar and intraosseo us muscles of the left foot.

MP, RTX

No

Case4

20 19

43/M

6 weeks

Yes

No All Ye compartme s nts of lower legs

PNL, MTX

No

Aza,

azathioprine;

CK,

creatine

kinase;

CYC,

cyclophosphamide;

Dex,

dexamethasone; IVIG, intravenous immunoglobulin; MP, methylprednisolone; MRI, magnetic resonance imaging; MTX, methotrexate; NA, not available PNL, prednisolone; RTX, rituximab * Colour print not required