43-year-old male patient had one and half year history of polyarthritis, fever, weight loss and worsening of pain in joints

Discussion of the case

The 43-year-old male patient had 1 and half year history of polyarthritis, involving both small and large joints. The initial presentation involved only hands and later progressed to elbows, knees, and feet. No antecedent fever, skin rashes, oral ulcers or backache was observed. Based on these symptoms, the patient was diagnosed as RA by the family physician and treated with MTX. The patient had significant improvement in pain and symptoms.  Soon after the completion of the treatment course, the patient developed fever, weight loss, and worsening of joint symptoms. His previous investigation revealed abnormal LFT and the current investigations suggested worsening of liver enzymes. The inflammatory parameters like CRP and ESR were elevated. Increase in ESR was noted when compared to the previous evaluation, but the CRP remained same. Patient's RF was negative and ANA was positive in both the evaluations.

One diagnostic possibility is the development of adverse effects secondary to MTX treatment and alcohol-related complications. Another possibility is that the initial diagnosis was wrong and it needs to be re-evaluated further. The third possibility is the development of an unrelated complication like viral infections.

The data across the globe, as presented from CORRONA study, elevations >2× upper limit of normal of SGPT and SGOT occurred in 1-2% of RA patients on MTX or LEF monotherapy compared to 5% with the combination.¹ As per the literature evidence and the recent recommendation, if the ALT/AST levels increase 3 times the upper limit, it is recommended to immediately withdrawal the drug.² Prompt follow-up and instructing the patient to stop alcohol was appropriate in the present case. The patient was previously not screened for hepatitis B/C by the family physician before initiating MTX. However, re-evaluation in our center had proven negative, thereby ruling out the possibility. The risk of elevated SGOT/PT is higher in patients receiving MTX doses> 10 mg.² The values had tripled when the patient visited our institution and a re-evaluation was done after the withdrawal of MTX. The Drug-Induced Liver Injury Network (DILIN) has developed a 5-point scale for grading the severity of liver injury based upon the presence of jaundice, hospitalization, signs of hepatic or other organ failure, and ultimate outcome (Table 1).³

Table 1: The 5-point scale for grading the severity of liver injury

The other viral markers like hepatitis A/E were negative in the current case, suggesting the need to evaluate other causes of hepatitis.  Although patient had discontinued alcohol consumption, it may take 2 to 3 months to reverse the effects of alcohol hepatitis and achieve normal enzyme levels. In contrast, the levels increased in the current case. Moreover, the ratio of AST to ALT is also not suggestive of alcohol hepatitis.

The presence of ANA positivity, non-deforming arthritis and low complement levels (both C3 & C4) suggest an autoimmune process.⁴ Alternative possibilities are SLE with lupus hepatitis and autoimmune hepatitis. In addition, the occurrence of intermittent mild fever suggests autoimmune involvement. As per the SLICC classification criteria for diagnosis of SLE, the patient fulfills only one clinical criterion the synovitis. Further evaluation of auto-antibodies may help to partially classify the patient, but 3 of the auto-antibodies included in criteria (Anti dsDNA, Anti Sm & APLA) are absent.  Moreover, the ANA profile for Ro, LA, ds-DNA, Sm, RNP, nucleosome and Rib-P protein was negative. APLA was not performed, since there was no clinical evidence.

The arthralgia involving small and large joints are one of the common presentations in autoimmune hepatitis (AIH).⁵ The AIH disease may often considered because of association with an additional auto-immune disease including RA. However, the current patient fulfills the ACR 2010 criteria for RA classification. The absence of RF is a consideration. Work-up for anti-CCP may help in further diagnosis and the patient was tested negative.

An opinion of gastroenterologist was sought and liver biopsy showed chronic hepatitis with distinguishable histopathology feature of plasma cell infiltrate. The patient was positive for anti-LKM-1 antibody, suggestive of autoimmune hepatitis.

Final diagnosis

Autoimmune hepatitis

Follow-up

The patient's liver enzymes had become normal following a treatment with azathioprine and small dose of steroid. He is in regular follow-up with gastroenterologist.

Learning points

• Regular LFT (particularly ALT/AST) should be performed in patients prescribed with methotrexate.
• Possible alternative diagnosis should be considered, even though alcohol and MTX toxicity is suspected.
• Autoimmune hepatitis can present with predominant musculoskeletal manifestations.

References

1. Curtis JR, Beukelman T, Onofrei A, Cassell S, Greenberg JD, Kavanaugh A, et al. Elevated liver enzyme tests among patients with rheumatoid arthritis or psoriatic arthritis treated with methotrexate and/or leflunomide. Ann Rheum Dis. 2010 Jan;69(1):43–7.
2. Visser K, Katchamart W, Loza E, Martinez-Lopez JA, Salliot C, Trudeau J, et al. Multinational evidence-based recommendations for the use of methotrexate in rheumatic disorders with a focus on rheumatoid arthritis: integrating systematic literature research and expert opinion of a broad international panel of rheumatologists in the 3E Initiative. Ann Rheum Dis. 2009 Jul;68(7):1086–93.
3. Severity Grading [Internet]. [cited 2015 Dec 3]. Available from: http://livertox.nih.gov/Severity.html
4. Vergani D, Wells L, Larcher VF, Nasaruddin BA, Davies ET, Mieli-Vergani G, et al. Genetically determined low C4: a predisposing factor to autoimmune chronic active hepatitis. Lancet. 1985 Aug 10;2(8450):294–8.
5. Krawitt, Edward L. Autoimmune hepatitis. New England Journal of Medicine354.1 (2006): 54-66.