A 46 year old man presented with a 7 month history of episodic pain and swelling of left knee joint, nocturnal fever, productive cough, loss of appetite, and on and off painful erythematous skin nodules on arms and legs. He was a known patient with type 2 diabetes mellitus who was not receiving proper treatment. He was a smoker and admitted to excessive alcohol consumption. He was not taking any long-term medication. On examination, he was averagely built with a swollen, warm, and tender left knee joint with restricted movements. There were tender subcutaneous nodules over the left arm and right thigh, compatible with a clinical diagnosis of erythema nodosum. He also had finger clubbing and bilateral cervical and axillary lymphadenopathy but no hepatosplenomegaly or organomegaly, and the rest of the examination was essentially normal.
His initial investigations revealed a normochromic normocytic anaemia with haemoglobin of 84 g/L, moderate rouleaux formation, normal platelet, and white cell count with neutrophil predominance. The blood picture showed evidence of an infective or inflammatory process. His inflammatory markers were elevated, with a CRP of 42 mg/L and an erythrocyte sedimentation rate (ESR) of 138 mm/1st hour.
Renal and liver profiles were normal apart from hypoalbuminaemia with reversed albumin globulin ratio. Lactate dehydrogenase level (LDH) was elevated (398.4 U/L). His chest radiograph revealed prominent bilateral hilar lymphadenopathy. Contrast-enhanced computed tomography (CECT) of the abdomen and chest revealed multiple discrete lymphadenopathy in the bilateral axillae, cervical, hilar, paratracheal, subcarinal, and para-aortic regions. Additionally, the high-resolution computed tomography chest revealed paraseptal emphysema, fibrosis, a thick-walled cavity in the right upper lobe apical segment with a ground glass appearance, and a patchy consolidation in the left lingual region. Findings were more suggestive of an infective pathology than sarcoidosis. Mantoux test was 13 mm and sputum was thrice negative for acid fast bacilli initially. At this point, the patient defaulted on follow-up for 3 months until he presented to the medical casualty with severe pain and swelling of the left knee joint and painful subcutaneous nodules on the legs and arms. The joint aspirate was blood stained and subsequently diagnosed as haemarthrosis. A skin biopsy was done for the skin nodules as well, for which he developed delayed bleeding from the biopsy site.
A coagulation screen was performed, which revealed an isolated prolongation of activated partial thromboplastin time (APTT) of 139 seconds with normal prothrombin time, thrombin time, and fibrinogen levels. Further inquiry revealed no family history of bleeding tendency, but his episodic left knee joint swelling over the past few months was suggestive of recurrent haemarthrosis.
A detailed coagulation work-up was done at this time. APTT mixing test with pooled normal plasma (PNP) revealed uncorrected APTT and that the FVIII and factor IX levels were markedly low at 0.3% and 0.006%, respectively. Factor XI was undetectable. The inhibitor assay showed a very high titre of FVIII inhibitor of >1000 Bethesda units (BU).
A diagnosis of AHA was made, and a possible aetiology was sought. An autoimmune screen revealed weakly positive antinuclear antibodies, but double-stranded DNA and rheumatoid factor were negative.
With a strong suspicion of active tuberculosis, the CECT chest and abdomen were repeated which revealed a cavity with a tree in bud appearance in the right upper lobe with a progressive right hilar lymphadenopathy suggestive of active pulmonary tuberculosis with bronchogenic spread. His fourth and fifth sputum samples were positive for acid-fast bacilli which confirmed pulmonary tuberculosis. An APL antibody screen was done which revealed weakly positive DRVVT, moderately positive antibeta 2 glycoprotein IgM (53.8 U/L), and a weakly positive anticardiolipin IgM levels. Repeat testing after 3-months confirmed the persistence of APL antibodies with a moderately positive DRVVT.
A final diagnosis of AHA due to a possible underlying autoimmune disease in the background of active pulmonary tuberculosis was made. It was not clear whether pulmonary tuberculosis contributed to autoimmunity. However, the coexistence of secondary APS was still considered due to the persistence of APL antibodies.
Patient had several bleeding episodes involving the left knee joint and the right elbow joint. He also developed a gluteal muscle haematoma and all bleeding manifestations were successfully managed with recombinant factor VIIa (r FVIIa) infusions and tranexamic acid. Following a multidisciplinary meeting, antituberculous drugs (ATD) for pulmonary tuberculosis were started. Concurrent immunosuppression therapy commenced with high dose steroids including initial intravenous methyl prednisolone followed by oral prednisolone. After a period of 10 weeks, oral cyclophosphamide 100 mg daily was added while tapering off oral steroids as the APTT was persistently prolonged with poor response. With cyclophosphamide, APTT was reduced to 50 s and the inhibitor titre came down to 700 BU. He responded well to ATD, with clinical improvement, a declining ESR, and clearance of the initial findings on his repeat CECTs.
Unfortunately, the patient developed transaminitis during this time of high-dose cyclophosphamide therapy and ATD therapy requiring drug withdrawal. Interruption of cyclophosphamide therapy resulted in several episodes of bleeding (haemarthrosis and epistaxis) which required aggressive factor replacement therapy. As he had almost completed 11 months of therapy, ATD was also discontinued at the same time.
At this point, a combined-aggressive immunosuppression therapy was started with rituximab, high-dose oral prednisolone and low-dose cyclophosphamide, with close monitoring of liver functions aimed at disease remission.
He showed a dramatic response just after the third dose of rituximab with normalization of APTT with both lupus sensitive and insensitive reagents and normalization of ESR after completion of rituximab 4 doses.
He was given low-dose (50 mg daily) therapy with cyclophosphamide which was continued for another 6 months, and prednisolone was tailed off slowly with monthly monitoring of APTT, ESR, and liver functions.
Subsequent regular assessments showed persistently normal APTT with both lupus-sensitive and insensitive reagents and normalized ESR with a normal FVIII level (70%) and factor IX (90%). But we could not perform the Factor XI levels due to resource constraints at that time.
A repeat APL screen with DRVVT was still positive which confirmed the persistence of APL antibodies. We considered this could more likely to be due to secondary APS with an underlying, undetermined autoimmune disorder than tuberculosis which had been completely treated by that time.