A 52-year-old male with 10 years history of rheumatoid arthritis presented to the clinic with worsening pain and swelling in joints

Discussion of the case

The 52-year-old male, a diagnosed case of RA, was managed on DMARD therapy for the past 10 years. Despite adequate compliance to the treatment, the symptoms started relapsing. He developed a dry cough and papulosquamous rashes.

The possibilities to be considered in this case include gradual recurrence of disease activity and symptoms, development of extra-articular features like vasculitis and ILD, development of a secondary infection resulting in rashes and worsening of pain, and the DMARD-related adverse events.

The patient was experiencing a gradual worsening of pain and swelling for the past year, and it could be due to either treatment discontinuation or the development of secondary resistance to DMARDs. Since the patient history indicated treatment compliance, the possibility to be considered is resistance to DMARDs. On the day of presentation, the patient's inflammatory parameters were normal, and the physical examination revealed tender and swollen joints, suggesting the exacerbation of inflammation. In addition, the development of vasculitis and possible pulmonary involvement in the form of crepitation suggests the worsening of RA.

The other possibilities to be considered are the development of chest infection and skin rashes on the possibility of overlapping osteoarthritis on RA. The patient's age (>50) and normal inflammatory parameters support the possibility of osteoarthritis. However, the tenderness in the wrist and elbow due to osteoarthritis is unusual. Hence, further evaluation is needed to establish the diagnosis.

The recurrence of arthritis could be due to the worsening of RA, whereas the rashes and pulmonary involvement may be drug-induced. The development of itchy, hyperpigmented papulosquamous rashes, associated with hydroxychloroquine use, is observed in some patients during the later stages of treatment. On the other hand, the rashes due to leflunomide and methotrexate (MTX) rashes are generally noticed during the initial 3 months of treatment, and in some cases, they may occur in the later years.

Further evaluation including skin biopsy, chest X-ray, chest CT, and pulmonary function test is recommended to establish the diagnosis. X-ray and high-resolution computed tomography (HRCT) indicated changes due to early interstitial lung disease (ILD). Biopsy reported leukocytoclastic vasculitis. The presence of ILD and vasculitis favors the possibility of extra-articular manifestations (EAM) with worsening of RA. However, the drug-induced ILD should be differentiated from the rheumatoid lung.

In certain cases, it is very difficult to differentiate between MTX - and RA-associated lung conditions. MTX-associated lung disease is most often an idiosyncratic reaction to the drug, which may occur as a hypersensitivity pneumonitis at any time. On average, it occurs around 36 weeks of MTX therapy. Since the present patient was on MTX for around 10 years, the possibility is more for RA- associated lung condition. The biopsy may not be helpful to differentiate the conditions.

The most important clues for the diagnosis of MTX-associated pneumonitis are acute onset, rapidly deteriorating pulmonary functions including diffusing capacity for carbon monoxide (DLCO) and other pulmonary function tests (PFT) parameters, presence of systemic features, and HRCT chest demonstrating patchy pneumonitis with interstitial shadow and without pleural involvement. The current patient had an asymptomatic presentation and the HRCT showed only limited interstitial changes. However, MTX lung has also been described with bronchiolitis obliterans with organizing pneumonia (BOOP), acute lung injury with non-cardiogenic pulmonary edema, pulmonary fibrosis, and bronchitis with airways hyperreactivity.^{1, 2}

The following are the major and minor criteria to be considered for diagnosing MTX-lung injury.^{3, 4} MTX pneumonitis is characterized as “definite” if major criteria 1 or 2 and major criterion 3 are present in conjunction with three of the five minor criteria. Probable MTX pneumonitis is present if major criteria 2 and 3 plus two of the five minor criteria are present.

The three major criteria are:

1. Hypersensitivity pneumonitis by histopathologic examination
2. Radiologic evidence of pulmonary interstitial or alveolar infiltrates
3. Negative blood and sputum cultures for the pathogenic organisms

The minor criteria include:

1. Shortness of breath
2. A non-productive cough
3. O₂saturation ≤90% on room air at initial evaluation
4. DLCO ≤70% of that predicted for age
5. WBC ≤15,000 per mm³

Since the current patient does not fulfill any of the aforementioned criteria, the possibility of RA-associated-ILD should be considered.

Final diagnosis

RA with ILD and vasculitis

Learning points

• Always watch for extra-articular features of RA in patients with longer disease duration.
• Pulmonary disease and vasculitis may co-occur, although the possibilities are rare.
• The development of EAM may need a change in treatment.

References

1. Lynch JP, McCune WJ. Immunosuppressive and cytotoxic pharmacotherapy for pulmonary disorders. Am J Respir Crit Care Med. 1997; 155(2): 395–420.
2. Hilliquin P, Renoux M, Perrot S, Puéchal X, Menkès CJ. Occurrence of pulmonary complications during methotrexate therapy in rheumatoid arthritis. Br J Rheumatol. 1996; 35(5): 441–445.
3. Searles G, McKendry RJ. Methotrexate pneumonitis in rheumatoid arthritis: potential risk factors. Four case reports and a review of the literature. J Rheumatol. 1987; 14(6): 1164–1171.
4. Alarcón GS, Kremer JM, Macaluso M, Weinblatt ME, Cannon GW, Palmer WR, et al. Risk factors for methotrexate-induced lung injury in patients with rheumatoid arthritis. A multicenter, case-control study. Methotrexate-Lung Study Group. Ann Intern Med. 1997; 127(5): 356–364.