Clinical Meetings at RH Year 2005

2005 - QMH - A man with muscle weakness and recurrent pneumonia

Dr Julie KL Wang, Dr. Simon KS Ip, Dr. James CM Ho University Department of Medicine, Queen Mary Hospital

Case History
The patient was a 67- year old retired truck driver with good past health, who lived in China with his family. He was a non-smoker and non-drinker with no known drug allergy history. He presented with fever and cough in the end of September, 2003 while staying in Guangdong. Before he came back to Hong Kong, he had been treated in China with intravenous cefepime and subsequently imipenem for 2 weeks. As he was also found to have low platelet count, intravenous immunoglobulins, dexamethasone and platelet transfusion had been given.

He returned to Hong Kong in mid of October, 2003, still suffering from shortness of breath and low grade fever. Physical examination revealed bilateral basal coarse crepitations with otherwise normal findings.

Chest radiograph showed bibasal and subpleural interstitial infiltrates (Figure 1) , while HRCT thorax demonstrated subpleural and peribronchial consolidation, interlobular septal thickening and ground glass appearance predominantly in the basal and periphery regions of both lung fields (Figure 2). Platelet count was 50, other blood count, renal and liver functions were normal. Arterial blood gas showed hypoxia. Sputum grew xanthomonas maltophilia, AFB smear was negative. Tests for HIV, coronavirus and immune markers were also negative. Bone marrow examination was normal. Spirometry showed restrictive defects with impaired diffusing capacity.


A course of intravenous timentin was started and the patient was referred for open lung biopsy as there was no improvement. Histology of the lung biopsy showed airspaces plugged with pale myxoid granulation tissue forming spherical polyps and short bundles, consistent with bronchiolitis obliterans organizing pneumonia (BOOP) (Figure 3).


Prednisolone 50mg daily was started in mid of November, 2003. There was remarkable resolution of pulmonary shadows from both CXR and HRCT thorax (Figure 4 & 5).


Steroid was tapered down to 20mg daily within 8 weeks’ time . Thereafter, the patient developed low grade fever and shortness of breath. Increased bibasal ground glass shadows was noted in chest radiograph (Figure 6). At the same time, there was mild proximal muscle weakness with creatine phosphokinase (CPK) elevated to ~1200U/L, facial rash was also noted. Vasculitic markers like ANCA, Anti-ENA, anti-Jo 1 antibodies were negative, HRCT thorax showed resolving peribronchial consolidation at the basal zone, and there was more ground glass opacities , interlobular septal thickening and traction bronchiectasis resembling pattern of non-specific interstitial pneumonitis (NSIP) ( Figure 7).


This condition was compatible with relapse of BOOP with elements of NSIP and underlying dermatomyositis. Hence, prednisolone was stepped up to 50mg daily once again, coupled with intavenous tazocin to cover for possible infective elements.

Despite these treatment, there was still intermittent fever, with both radiological and respiratory worsening (Figure 8). Fibreoptic bronchoscopy and bronchioalveolar lavage (BAL) was performed , which found pneumocystis carinii (PCP); cytomegalovirus (CMV) early antigen detection was positive from BAL and CMV pp65 antigenaemia showed 1 pos/ 2x105 WBC. Standard intravenous septrin therapy was given and steroid continued for PCP infection. Followed by septrin prophylaxis and steroid tapering in the subsequent 3 weeks. Apparently, the clinical condition improved . Malignancy screening including nasal biopsy, Epstein bar virus (EBV)-IgA, alpha fetal protein, carcinoembryonic antigen, prostate specific antigen and carbohydrate antigen 19.9, CT abdomen and pelvis were all negative.


In mid of May, 2004, the patient complained of severe exertional dyspnoea with thick whitish sputum , he was taking prednisolone 20mg daily at that juncture and was intubated and admitted into ICU (Figure 9). Sputum culture, AFB smear, CMV pp65 antigenaemia and BAL culture were negative. Echocardiography showed satisfactory LVEF ~ 55%. HRCT thorax revealed increase in coarse reticular shadowings, ground glass attenuations and interlobular septal thickening were seen involving both lungs predominantly in bilateral lung bases. Disease progression was apparent as compared with previous study in March 2004 (Figure 10).


Intravenous methylprednisolone 60mg Q12H and cyclophosphamide was started for second relapse of BOOP/NSIP. Surveillance for CMV pp65 antigenaemia detected 24 pos/ 2x105 WBC upon high dose immunosuppression, although there was no clinical CMV disease. Pre-emptive treatment for CMV reactivation with ganciclovir was given for 3 weeks according to microbiologist recommendation. He improved subsequently and was maintained on cyclophosphamide 50mg daily while methylprednisolone was tapered to 16mg daily upon discharge (Figure 11 & 12).


Discussion:
Reported incidence of interstitial lung diseases (ILD) in polymyositis (PM) and dermatomyositis (DM) has been highly variable. Ten percent of the patients in 2 large series, each of which studied more than 100 PM/DM patients, were identified to have pulmonary infiltrates by roentgenographic criteria.1, 2 On the other hand, Songcharoen et al 3 , found that 7 of 15 (47%) cases had radiographic evidence of ILD in PM/DM, while Dickey and Myer 4 found that 12 of 42 (28.6%) cases with PM/DM were shown to possibly have ILD radiographically or by pulmonary function test results. ILD's occurrence has adverse impact on the prognosis of patients with PM/DM. Arsura et al 5, in a study of 67 patients with PM/DM and ILD, found a mortality rate of 40% after a period of 31 ± 32 months. Progressive ILD was the immediate cause of death in 58% of those who died. Marie et al 6, in a study of 55 PM/DM patients, identified a subgroup of 9 patients who developed ILD with a mortality rate as high as 22%, after a mean follow up of 70 ± 36 months. This mortality was significantly higher than those who did not have concomitant ILD (9%).

The pattern of lung diseases in PM/DM is summarized below



_____________________________________________________________________

Interstitial lung diseases
Bronchiolitis obliterans organising pneumonia (BOOP)
Usual interstitial pneumonia (UIP)
Non-specific interstitial pneumonia (NSIP)
Diffuse alveolar damage (DAD)
Pulmonary capillaritis

Pulmonary hypertension
Primary vasculopathy
Secondary to chronic heart or respiratory failure

Infective pneumonitis
Aspiration pneumonia
Secondary to immunosuppressive agent

Respiratory musculature dysfunction

________________________________________________________________________ Tazelaar et al 8 subclassified 14 open lung and 1 autopsy tissue biopsies and identified 6 BOOP, 5 usual interstitial pneumonia (UIP), 1 cellular interstitial pneumonia (CIP, which on subsequent review was found to be compatible with NSIP 9) and 3 diffuse alveolar damage (DAD). In this study, patients with BOOP were found to have a better outcome than UIP, while those patients with DAD had 100% mortality rate and the authors concluded that histological features were good predictors of survival.

The frequency of occurrence of various ILD varies in different studies. Douglas et al 10 identified 70 patients with both ILD and either PM or DM. In that cohort, 22 patients underwent surgical biopsies and 18 of them had NSIP while 2 patients had DAD, 1 each had BOOP and UIP respectively. Schwarz et al, in an analysis of 6 cases of ILD in PM and DM7, found that 3 of their patients had a histological combination of organizing pneumonia in addition to interstitial pneumonitis. In one of these cases, they were able to demonstrate evolution of the inflammatory process to fibrosis with honeycombing and interstitial ossification (an autopsy finding). In another patient, follow-up lung biopsy demonstrated clearing of the inflammatory process with residual interstitial fibrosis. It underlines that there is a histological stage in PM/DM pulmonary disease where features of both fibrosing alveolitis and organizing pneumonia coexist. This might represent a "progressing" single disease rather than 2 distinct patterns and thus a good outcome is not invariable in PM/DM patients with organizing pneumonia.

The clinical features of PM/DM has been described elsewhere. Females with PM or DM are more likely to develop ILD, and the mean age at presentation is 50 years. On physical examination basilar crackles are commonly recorded 7 while finger clubbing is uncommon, and is different from cryptogenic fibrosing alveolitis (70%). ILD can appear concomitantly with, follow, or precede the appearance of muscle disease.

Attempts had been made to correlate clinical presentations and behaviour of ILD with histopathological patterns.11 Patients presenting with acute respiratory symptoms with or without muscle or skin manifestations may have underlying DAD, BOOP or pulmonary capillaritis. While DAD can run a clinical course similar to the Hamman-Rich syndrome, where the prognosis is poor, BOOP and pulmonary capillaritis are often responsive to treatment with steroids. Those who present with asymptomatic radiographic infiltrates or chronic progressive symptoms in known cases of PM/DM may have underlying UIP or cellular IP (NSIP).

The aetiology and pathogenesis of ILD in PM and DM remains to be uncertain. An infective association has been considered and agents such as EBV, CMV, hepatitis C infection had all been investigated but none was found to have a definite causal relationship. An immunological contributing factor is a possibility. Autoantibodies which bind to intracellular antigens are commonly detected in patients with inflammatory myopathies. Such autoantibodies are detectable by indirect immunofluorescence or immunodiffusion. Among these intracellular/autoantigens, the aminoacyl transfer ribonucleic acid (tRNA) synthetases, a group of enzymes involved in the binding of amino acids to their tRNAs, and their corresponding antibodies are thought to be of importance.12

There are six anti-aminoacyl tRNA synthetase antibodies (AAs) known and antihistidyl tRNA synthetase (anti Jo-1) was the first of these AAs to be discovered, and is the most common. It is found in around 25% of patients with myositis overall, more commonly in PM than DM. About 50-80% of patients with anti-Jo-1 eventually develop myositis and ILD. Antithreonyl tRNA synthetase (anti-PL-7) and antialanyl tRNA synthetase (anti-PL-12) antibodies are less commonly found in PM/DM (3-4%). Autoantibodies to isoleucyl-tRNA synthetase (anti-OJ), glycyl-tRNA synthetase (anti-EJ), and asparaginyl-tRNA synthetase (anti-KS) are the least common, occurring in less than 2%.

The pathogenic relevance of the antisynthetase antibodies found in PM/DM patients is uncertain. No report of preferential disposition of such antisynthetase antibodies in the lung lesions had been found. The binding of antibodies in the sera of different PM/DM patients to different epitopes in the synthetase molecules suggest antisynthetase activity as a cross reacting antibody stimulated by environment.

Therapeutic options and their pros and cons must be discussed in detail with the patients and the physician must identify those with "potentially reversible disease" as opposed to those who are unlikely to respond. The rationale for long term treatment in the hope of achieving symptomatic/objective clinical improvement or stability needs to be explained carefully.

Corticosteroids alone have been the empirical treatment of choice for/subjective PM/DM with or without ILD. Steroid-resistant ILD is defined as disease progression despite administration of prednisolone. Under such circumstances, various immunosuppressive agents such as azathioprine, methotrexate, cyclophosphamide, each of them with specific adverse effect profiles 13, were reported to have favourable efficacy.14,15 Azathioprine or methotrexate, in combination with corticosteroid may be as efficacious as cyclophosphamide but no formal comparison has been made amongst them.

Nawata et al studied a cohort of 36 with ILD out of 111 PM/DM patients and further subdivided them into groups with either raised or normal serum CPK at the onset of ILD (for the latter group the patients fulfil all the other diagnostic criteria for PM/DM together with a raised serum aldolase level).16 They found that DM patients without CPK elevation at the onset of myositis developed ILD at a higher frequency (62.5%) than PM/DM patients with elevated CPK levels. All the patients were initially treated with corticosteroids, and while the therapy was fairly effective on rashes in DM and in treating muscle symptoms, 16 steroid-resistant ILD patients were identified. These were mostly from the group of patients who had normal CPK at the onset of ILD. Eleven of these 16 patients died from respiratory failure despite the addition of pulsed methylprednisolone therapy. The 5 remaining steroid-resistant ILD patients were treated with prednisolone and cyclosporin. Clinical deterioration was prevented in all these 5 patients. Cyclosporine, an immunosuppressive agent used widely in post organ transplantation, is known to preferentially suppress T cell activation, which might suggest a role of activated T cells in the pathogenesis of steroid resistant ILD in PM/DM.

Tacrolimus, a T-helper cell inhibitor, was reported to be effective in treatment of refractory PM. Oddis et al studied a group of 8 patients whose myositis had failed to respond to corticosteroids and at least one of the immunosuppressive agents given concomitantly.17 Six of these patients were anti-Jo-1 antibody positive, 5 of whom had radiologic evidence of parenchymal interstitial infiltrates. After receiving oral tacrolimus, 3 patients were noted to have responded favourably by pulmonary function measurements. The response in this group of PM patients is probably not too surprising since it is a predominantly cell mediated disease.

References

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